内皮细胞靶向的D1R融合蛋白促进骨髓和肝脏造血干/祖细胞植入的研究
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摘要
目前造血干细胞移植已经成为临床治疗血液病和血液系统恶性肿瘤的重要手段之一，其中骨髓、外周血和脐血是其造血干细胞的重要来源。由于脐血来源丰富、采集方便、免疫原性弱，又较骨髓和外周血移植有更多优势，因此，近年来脐血移植越来越受到重视。然而，由于脐血造血干/祖细胞含量较低，难以满足成年及体重较大患者的需要；且脐血移植后造血重建延迟、感染性并发症增加，很难收到满意的疗效，已严重限制其在临床中的应用。如何有效地获取足量的造血干细胞以满足临床需要，已成为一个亟待解决的问题。
大量的研究表明，Notch信号途径是调控干细胞增殖分化的重要信号通路之一，Notch受体和配体在造血系统广泛表达，激活Notch信号通路能够促进HSCs的自我更新，这为有效获取足量的HSCs提供了新的思路。本课题以人脐静脉内皮细胞作为培养体系的支持细胞，模拟造血干细胞生长的微环境，联合应用外源性生长因子SCF、TPO、FL、IL-6、IL-3及一种内皮细胞靶向的Notch配体D1R(人D1R，hD1R），与造血干/祖细胞共培养，建立一种有效的体外扩增体系，并通过给照射小鼠体内直接注射D1R蛋白，重点观察了其对HSPCs在骨髓、肝脏的植入和对造血微环境的影响，进一步分析了内皮细胞靶向的Notch配体激活的Notch信号在维持造血干/祖细胞自我更新、促进植入的重要作用及相关机制。
研究结论如下：
1、建立了基于Notch信号调节的体外培养体系，明显地扩增了小鼠的造血干/祖细胞，并通过体内移植实验证明了扩增的造血细胞具有长期造血重建的能力。提示D1R激活的Notch信号维持了HSPCs自我更新的特性，促进了增殖。
2、在照射小鼠造血损伤实验中，同时给照射小鼠体内注射D1R融合蛋白，有效地保护了造血微环境，显著地扩增了体内残存的HSPCs，并通过骨髓移植实验证明扩增的体内HSPCs具有造血重建的能力。
3、在小鼠骨髓移植实验中，直接给移植后的受体小鼠注射D1R融合蛋白，有效地促进了供体细胞在骨髓、肝脏、脾脏的植入，并通过在肝脏、脾脏诱导形成血管龛样的结构支持扩增了供体细胞，提高小鼠存活率，并且降低了小鼠造血重建所需的最低造血细胞数量。
4、利用已建立的体外培养体系，有效地扩增了人脐血CD34+细胞，并通过NOD/SCID小鼠体内移植实验证明了扩增的造血细胞具有造血重建的能力。
综上所述，我们通过内皮细胞靶向的Notch配体（D1R、 hD1R）建立了有效的体外扩增体系，并首次将D1R融合蛋白直接在小鼠体内应用，重点观察了其对HSPCs的植入和对造血微环境的影响，进一步明确了血管内皮细胞靶向的Notch配体激活的Notch信号对维持造血干/祖细胞特性、促进植入的重要作用，为实现临床应用提供实验基础。
Recently, hematopoietic stem cell transplantation（HSCT）has become an importanttherapy for patients with hematonosis and hematologic malignancy.Umbilical cord blood(UCB), marrow and mobilized peripheral blood have been used successfully as principlesources of HSCT.UCB has become more attractive for its abundance, ready availabilityand immature immunogenicity compared to marrow or mobilized peripheral blood.Butumbilical cord blood transplantation (UCBT) in adults and high weigh patients is prevented by a limited number of hematopoietic stem cells (HSC) in each graft, whichleads to delayed engraftment and increased rates of infectious complications.Strategies toget sufficient HSCs for transplantation have been an important problem demandingprompt solution.
A growing body of work has identified that the Notch pathway plays a fundamentalrole in regulating stem cell fate decisions to self-renew or differentiate.Notch receptorsand ligands are widely expressed in hemopoietic system.Notch activation is able tomaintain self-renewal of HSCs,which will be a novel thought to gain sufficient HSCs.Wehave developed an ex vivo expansion system for hematopoietic stem and progenitor cells(HSPCs) that used human umbilical vein endothelial cells (HUVECs) as feeder cells tomimic hematopoietic microenvironment supplemented with cytokines(SCF,FL,TPO,IL-6,IL-3) and endothelial cells-targeted Notch ligand （D1R,humanD1R）.Importantly, through in vivo D1R administration we assessed its influence onHSPCs engraftment in the bone marrow, the liver and hematopoietic microenvironment,and further analyzled the related mechanisms of Notch activation by theendothelium-targeted D1R in keeping self-renewal of HSCs and promoting engraftment.
The main finds are as follows:
1. The Notch-mediated ex vivo expansion system has been established and resulted in amarked increase in mouse HSPCs capable of enhanced long-term repopulation in themarrow.These suggested that Notch activation by D1R maintain the “stemness” of HSCsand promote expansion.
2. Systemic administration of D1R to irradiated mice protected marrowmicroenvironment from the irradiation and caused a pronounced expansion of remnantbone marrow stem and progenitor cells in vivo, which were able to repopulate the marrow.
3. D1R administration effectively promoted HSCs engraftment in both bone marrowand liver of mice receiving BM transplantation.Futher study found the formation ofvascular niche-like structures in the liver of recipient mice, which resulted in donor HSPCsexpansion, improved mouse survival and decreased the lowest effective transplant cellsdose keeping hematopoietic reconstitution.
4. Treatment of human cord blood CD34+cells with hD1R also substantially increasedcell counts in the culture system,which were capable of enhanced repopulation in themarrow of immunodeficient nonobese diabetic–severe combined immunodeficient(NOD-SCID) mice.
In conclusion, the Notch-mediated ex vivo expansion system has successfully beenestablished and markedly increased HSPCs.We first used endothelial cells-targeted Notchligand D1R in vivo and observed its influence on HSPCs engraftment and hematopoieticmicroenvironment. Furthermore, we confirmed the role of Notch activation by using anendothelium-targeted Notch ligand in maintaining self-renewal of HSCs and promotingengraftment.
大量的研究表明，Notch信号途径是调控干细胞增殖分化的重要信号通路之一，Notch受体和配体在造血系统广泛表达，激活Notch信号通路能够促进HSCs的自我更新，这为有效获取足量的HSCs提供了新的思路。本课题以人脐静脉内皮细胞作为培养体系的支持细胞，模拟造血干细胞生长的微环境，联合应用外源性生长因子SCF、TPO、FL、IL-6、IL-3及一种内皮细胞靶向的Notch配体D1R(人D1R，hD1R），与造血干/祖细胞共培养，建立一种有效的体外扩增体系，并通过给照射小鼠体内直接注射D1R蛋白，重点观察了其对HSPCs在骨髓、肝脏的植入和对造血微环境的影响，进一步分析了内皮细胞靶向的Notch配体激活的Notch信号在维持造血干/祖细胞自我更新、促进植入的重要作用及相关机制。
研究结论如下：
1、建立了基于Notch信号调节的体外培养体系，明显地扩增了小鼠的造血干/祖细胞，并通过体内移植实验证明了扩增的造血细胞具有长期造血重建的能力。提示D1R激活的Notch信号维持了HSPCs自我更新的特性，促进了增殖。
2、在照射小鼠造血损伤实验中，同时给照射小鼠体内注射D1R融合蛋白，有效地保护了造血微环境，显著地扩增了体内残存的HSPCs，并通过骨髓移植实验证明扩增的体内HSPCs具有造血重建的能力。
3、在小鼠骨髓移植实验中，直接给移植后的受体小鼠注射D1R融合蛋白，有效地促进了供体细胞在骨髓、肝脏、脾脏的植入，并通过在肝脏、脾脏诱导形成血管龛样的结构支持扩增了供体细胞，提高小鼠存活率，并且降低了小鼠造血重建所需的最低造血细胞数量。
4、利用已建立的体外培养体系，有效地扩增了人脐血CD34+细胞，并通过NOD/SCID小鼠体内移植实验证明了扩增的造血细胞具有造血重建的能力。
综上所述，我们通过内皮细胞靶向的Notch配体（D1R、 hD1R）建立了有效的体外扩增体系，并首次将D1R融合蛋白直接在小鼠体内应用，重点观察了其对HSPCs的植入和对造血微环境的影响，进一步明确了血管内皮细胞靶向的Notch配体激活的Notch信号对维持造血干/祖细胞特性、促进植入的重要作用，为实现临床应用提供实验基础。
Recently, hematopoietic stem cell transplantation（HSCT）has become an importanttherapy for patients with hematonosis and hematologic malignancy.Umbilical cord blood(UCB), marrow and mobilized peripheral blood have been used successfully as principlesources of HSCT.UCB has become more attractive for its abundance, ready availabilityand immature immunogenicity compared to marrow or mobilized peripheral blood.Butumbilical cord blood transplantation (UCBT) in adults and high weigh patients is prevented by a limited number of hematopoietic stem cells (HSC) in each graft, whichleads to delayed engraftment and increased rates of infectious complications.Strategies toget sufficient HSCs for transplantation have been an important problem demandingprompt solution.
A growing body of work has identified that the Notch pathway plays a fundamentalrole in regulating stem cell fate decisions to self-renew or differentiate.Notch receptorsand ligands are widely expressed in hemopoietic system.Notch activation is able tomaintain self-renewal of HSCs,which will be a novel thought to gain sufficient HSCs.Wehave developed an ex vivo expansion system for hematopoietic stem and progenitor cells(HSPCs) that used human umbilical vein endothelial cells (HUVECs) as feeder cells tomimic hematopoietic microenvironment supplemented with cytokines(SCF,FL,TPO,IL-6,IL-3) and endothelial cells-targeted Notch ligand （D1R,humanD1R）.Importantly, through in vivo D1R administration we assessed its influence onHSPCs engraftment in the bone marrow, the liver and hematopoietic microenvironment,and further analyzled the related mechanisms of Notch activation by theendothelium-targeted D1R in keeping self-renewal of HSCs and promoting engraftment.
The main finds are as follows:
1. The Notch-mediated ex vivo expansion system has been established and resulted in amarked increase in mouse HSPCs capable of enhanced long-term repopulation in themarrow.These suggested that Notch activation by D1R maintain the “stemness” of HSCsand promote expansion.
2. Systemic administration of D1R to irradiated mice protected marrowmicroenvironment from the irradiation and caused a pronounced expansion of remnantbone marrow stem and progenitor cells in vivo, which were able to repopulate the marrow.
3. D1R administration effectively promoted HSCs engraftment in both bone marrowand liver of mice receiving BM transplantation.Futher study found the formation ofvascular niche-like structures in the liver of recipient mice, which resulted in donor HSPCsexpansion, improved mouse survival and decreased the lowest effective transplant cellsdose keeping hematopoietic reconstitution.
4. Treatment of human cord blood CD34+cells with hD1R also substantially increasedcell counts in the culture system,which were capable of enhanced repopulation in themarrow of immunodeficient nonobese diabetic–severe combined immunodeficient(NOD-SCID) mice.
In conclusion, the Notch-mediated ex vivo expansion system has successfully beenestablished and markedly increased HSPCs.We first used endothelial cells-targeted Notchligand D1R in vivo and observed its influence on HSPCs engraftment and hematopoieticmicroenvironment. Furthermore, we confirmed the role of Notch activation by using anendothelium-targeted Notch ligand in maintaining self-renewal of HSCs and promotingengraftment.
引文
[1] TILL JE, McCULLOCH EA. A direct measurement of the radiation sensitivity ofnormal mouse bone marrow cells. Radiat Res.1961,14:213-222.
[2] Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mousehematopoietic stem cells. Science.1988,241:58-62.
[3] Morrison SJ,Weissman IL.The long-term repopulating subset of hematopoietic stemcells is deterministic and isolatable by phenotype. Immunity.1994,1:661-673.
[4] Wang LD, Wagers AJ. Dynamic niches in the origination and differentiation ofhaematopoietic stem cells. Nat Rev Mol Cell Biol.2011,12(10):643-655.
[5]Osawa M, Hanada K, Hamada H, Nakauchi H.Long-term lymphohematopoieticreconstitution by a single CD34-low/negative hematopoietic stem cell.Science.1996,273:242-245.
[6] Mikkola HK, Orkin SH. The journey of developing hematopoietic stem cells.Development.2006,133:3733-3744.
[7] Kingsley PD, Malik J, Fantauzzo KA, Palis J. Yolk sac-derived primitive erythroblastsenucleate during mammalian embryogenesis.Blood.2004,104(1):19-25.
[8] Cumano A, Dieterlen-Lievre F, Godin I. Lymphoid potential, probed before circulationin mouse, is restricted to caudal intraembryonic splanchnopleura. Cell.1996,86(6):907-916.
[9] Kumaravelu P, Hook L, Morrison AM, Ure J, Zhao S, Zuyev S, Ansell J, Medvinsky A.Quantitative developmental anatomy of definitive haematopoietic stemcells/long-term repopulating units (HSC/RUs): role of the aorta-gonad-mesonephros(AGM) region and the yolk sac in colonisation of the mouse embryonic liver.Development.2002,129(21):4891-4899.
[10] Harrison DE, Zhong RK, Jordan CT, Lemischka IR, Astle CM. Relative to adultmarrow, fetal liver repopulates nearly five times more effectively long-term thanshort-term. Exp Hematol.1997,25(4):293-297.
[11] Emambokus NR, Frampton J. The glycoprotein IIb molecule is expressed on earlymurine hematopoietic progenitors and regulates their numbers in sites ofhematopoiesis. Immunity.2003,19(1):33-45.
[12] Gekas C, Dieterlen-Lièvre F, Orkin SH, Mikkola HK.The placenta is a niche forhematopoietic stem cells. Dev Cell.2005,8(3):365-375.
[13] Robin C, Bollerot K, Mendes S, Haak E, Crisan M, Cerisoli F, Lauw I, Kaimakis P,Jorna R, Vermeulen M, Kayser M, van der Linden R, Imanirad P, Verstegen M,Nawaz-Yousaf H, Papazian N, Steegers E, Cupedo T, Dzierzak E.Human placenta isa potent hematopoietic niche containing hematopoietic stem and progenitor cellsthroughout development. Cell Stem Cell.2009,5(4):385-395.
[14] Sabin, F.. Origin and development of the primitive vessels of the chick and of the pig.Contrib. Embryol.1917,226:61-124.
[15] Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G. A common precursorfor hematopoietic and endothelial cells. Development.1998,125(4):725-732.
[16] Fehling HJ, Lacaud G, Kubo A, Kennedy M, Robertson S, Keller G, Kouskoff V.Tracking mesoderm induction and its specification to the hemangioblast duringembryonic stem cell differentiation. Development.2003,130(17):4217-4227.
[17] Huber TL, Kouskoff V, Fehling HJ, Palis J, Keller G. Haemangioblast commitment isinitiated in the primitive streak of the mouse embryo. Nature.2004,432(7017):625-630.
[18] Jaffredo T, Gautier R, Eichmann A, Dieterlen-Lièvre F. Intraaortic hemopoietic cellsare derived from endothelial cells during ontogeny. Development.1998,125(22):4575-4583.
[19] de Bruijn MF, Ma X, Robin C, Ottersbach K, Sanchez MJ, Dzierzak E.Hematopoieticstem cells localize to the endothelial cell layer in the midgestation mouse aorta.Immunity.2002,16(5):673-683.
[20] North TE, de Bruijn MF, Stacy T, Talebian L, Lind E, Robin C, Binder M, Dzierzak E,Speck NA.Runx1expression marks long-term repopulating hematopoietic stem cellsin the midgestation mouse embryo. Immunity.2002,16(5):661-672.
[21] Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat RevImmunol.2006,6:93-106.
[22] Zon LI. Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal.Nature.2008,453:306-313.
[23] Staal FJ, Luis TC, Tiemessen MM. WNT signalling in the immune system: WNT isspreading its wings. Nat Rev Immunol.2008,8(8):581-593.
[24] Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R,Weissman IL.A role for Wnt signalling in self-renewal of haematopoietic stem cells.Nature.2003,423(6938):409-414.
[25] Austin TW, Solar GP, Ziegler FC, Liem L, Matthews W. A role for the Wnt genefamily in hematopoiesis: expansion of multilineage progenitor cells. Blood.1997,89(10):3624-3635.
[26] Van Den Berg DJ, Sharma AK, Bruno E, Hoffman R.Role of members of the Wntgene family in human hematopoiesis. Blood.1998,92(9):3189-3202.
[27] Murdoch B, Chadwick K, Martin M, Shojaei F, Shah KV, Gallacher L, Moon RT,Bhatia M. Wnt-5A augments repopulating capacity and primitive hematopoieticdevelopment of human blood stem cells in vivo. Proc Natl Acad Sci U S A.2003,100(6):3422-3427.
[28] Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates JR3rd,Nusse R.Wnt proteins are lipid-modified and can act as stem cell growth factors.Nature.2003,423(6938):448-452.
[29]Nemeth MJ, Topol L, Anderson SM, Yang Y, Bodine DM.Wnt5a inhibits canonicalWnt signaling in hematopoietic stem cells and enhances repopulation. Proc Natl AcadSci U S A.2007,104(39):15436-15441.
[30]Huang J, Nguyen-McCarty M, Hexner EO, Danet-Desnoyers G, Klein PS.Maintenance of hematopoietic stem cells through regulation of Wnt and mTORpathways. Nat Med.2012，18(12):1778-1785..
[31] Reya T, O'Riordan M, Okamura R, Devaney E, Willert K, Nusse R, GrosschedlR.Wnt signaling regulates B lymphocyte proliferation through a LEF-1dependentmechanism. Immunity.2000,13(1):15-24.
[32]Luis TC, Naber BA, Roozen PP, Brugman MH, de Haas EF, Ghazvini M, Fibbe WE,van Dongen JJ, Fodde R, Staal FJ. Canonical wnt signaling regulates hematopoiesis ina dosage-dependent fashion. Cell Stem Cell.2011,9(4):345-356.
[33] Kirstetter P, Anderson K, Porse BT, Jacobsen SE, Nerlov C. Activation of thecanonical Wnt pathway leads to loss of hematopoietic stem cell repopulation andmultilineage differentiation block. Nat Immunol.2006,7(10):1048-1056.
[34] Scheller M, Huelsken J, Rosenbauer F, Taketo MM, Birchmeier W, Tenen DG, LeutzA.Hematopoietic stem cell and multilineage defects generated by constitutivebeta-catenin activation. Nat Immunol.2006,7(10):1037-1047.
[35] Koch U, Wilson A, Cobas M, Kemler R, Macdonald HR, Radtke F. Simultaneous lossof beta-and gamma-catenin does not perturb hematopoiesis or lymphopoiesis. Blood.2008,111(1):160-164.
[36] Lawrence HJ, Largman C. Homeobox genes in normal hematopoiesis and leukemia.Blood.1992,80(10):2445-2453.
[37] Sauvageau G, Lansdorp PM, Eaves CJ, Hogge DE, Dragowska WH, Reid DS,Largman C, Lawrence HJ, Humphries RK. Differential expression of homeoboxgenes in functionally distinct CD34+subpopulations of human bone marrow cells.Proc Natl Acad Sci U S A.1994,91(25):12223-12227.
[38] Pineault N, Helgason CD, Lawrence HJ, Humphries RK. Differential expression ofHox, Meis1, and Pbx1genes in primitive cells throughout murine hematopoieticontogeny. Exp Hematol.2002,30(1):49-57.
[39] Antonchuk J, Sauvageau G, Humphries RK.HOXB4-induced expansion of adulthematopoietic stem cells ex vivo. Cell.2002,109(1):39-45.
[40]Amsellem S, Pflumio F, Bardinet D, Izac B, Charneau P, Romeo PH,Dubart-Kupperschmitt A, Fichelson S. Ex vivo expansion of human hematopoieticstem cells by direct delivery of the HOXB4homeoprotein. Nat Med.2003,9(11):1423-1427.
[41]Krosl J, Austin P, Beslu N, Kroon E, Humphries RK, Sauvageau G. In vitro expansionof hematopoietic stem cells by recombinant TAT-HOXB4protein. Nat Med.2003,9(11):1428-1432.
[42] Watts KL, Delaney C, Humphries RK, Bernstein ID, Kiem HP.Combination ofHOXB4and Delta-1ligand improves expansion of cord blood cells. Blood.2010,116(26):5859-5866.
[43] Robin C, Durand C. The roles of BMP and IL-3signaling pathways in the control ofhematopoietic stem cells in the mouse embryo. Int J Dev Biol.2010,54(6-7):1189-1200.
[44] Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K, Ling LE,Karanu FN, Bhatia M. Sonic hedgehog induces the proliferation of primitive humanhematopoietic cells via BMP regulation. Nat Immunol.2001,2(2):172-180.
[45] Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ,Harris S, Wiedemann LM, Mishina Y, Li L.Identification of the haematopoietic stemcell niche and control of the niche size. Nature.2003,425(6960):836-841.
[46]Goldman DC, Bailey AS, Pfaffle DL, Al Masri A, Christian JL, Fleming WH. BMP4regulates the hematopoietic stem cell niche. Blood.2009,114(20):4393-4401.
[47]Clària J.Cyclooxygenase-2biology.Curr Pharm Des.2003,9(27):2177-2190.
[48]Regan JW.EP2and EP4prostanoid receptor signaling.Life Sci.2003,74(2-3):143-153.
[49] Fujino H, West KA, Regan JW. Phosphorylation of glycogen synthase kinase-3andstimulation of T-cell factor signaling following activation of EP2and EP4prostanoidreceptors by prostaglandin E2. J Biol Chem.2002,277(4):2614-2619.
[50] Fujino H, Xu W, Regan JW.Prostaglandin E2induced functional expression of earlygrowth response factor-1by EP4, but not EP2, prostanoid receptors via thephosphatidylinositol3-kinase and extracellular signal-regulated kinases. J Biol Chem.2003,278(14):12151-12156.
[51] North TE, Goessling W, Walkley CR, Lengerke C, Kopani KR, Lord AM, Weber GJ,Bowman TV, Jang IH, Grosser T, Fitzgerald GA, Daley GQ, Orkin SH, Zon LI.Prostaglandin E2regulates vertebrate haematopoietic stem cell homeostasis. Nature.2007,447(7147):1007-1011.
[52]Hoggatt J, Singh P, Sampath J, Pelus LM. Prostaglandin E2enhances hematopoieticstem cell homing, survival, and proliferation. Blood.2009,113(22):5444-5455.
[53] Goessling W, North TE, Loewer S, Lord AM, Lee S, Stoick-Cooper CL, Weidinger G,Puder M, Daley GQ, Moon RT, Zon LI.Genetic interaction of PGE2and Wntsignaling regulates developmental specification of stem cells and regeneration. Cell.2009,136(6):1136-1147.
[54] Goessling W, Allen RS, Guan X, Jin P, Uchida N, Dovey M, Harris JM, Metzger ME,Bonifacino AC, Stroncek D, Stegner J, Armant M, Schlaeger T, Tisdale JF, Zon LI,Donahue RE, North TE. Prostaglandin E2enhances human cord blood stem cellxenotransplants and shows long-term safety in preclinical nonhuman primatetransplant models. Cell Stem Cell.2011,8(4):445-458.
[55] Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, Walker JR,Flaveny CA, Perdew GH, Denison MS, Schultz PG, Cooke MP.Aryl hydrocarbonreceptor antagonists promote the expansion of human hematopoietic stem cells.Science.2010,329(5997):1345-1348.
[56] Zhang CC, Kaba M, Iizuka S, Huynh H, Lodish HF.Angiopoietin-like5and IGFBP2stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayedby NOD/SCID transplantation. Blood.2008,111(7):3415-3423.
[57] Himburg HA, Muramoto GG, Daher P, Meadows SK, Russell JL, Doan P, Chi JT,Salter AB, Lento WE, Reya T, Chao NJ, Chute JP.Pleiotrophin regulates theexpansion and regeneration of hematopoietic stem cells. Nat Med.2010,16(4):475-482.
[58] Himburg HA, Harris JR, Ito T, Daher P, Russell JL, Quarmyne M, Doan PL, Helms K,Nakamura M, Fixsen E, Herradon G, Reya T, Chao NJ, Harroch S, Chute JP.Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells inthe bone marrow vascular niche. Cell.2012,25;2(4):964-975.
[59] Schofield R. The relationship between the spleen colony-forming cell and thehaemopoietic stem cell. Blood Cells.1978,4(1-2):7-25.
[60] Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP,Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, ScaddenDT.Osteoblastic cells regulate the haematopoietic stem cell niche. Nature.2003,425(6960):841-846.
[61] Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, Vincent P, Pumiglia K,Temple S.Endothelial cells stimulate self-renewal and expand neurogenesis of neuralstem cells. Science.2004,304(5675):1338-1340.
[62] Fliedner TM, Graessle D, Paulsen C, Reimers K. Structure and function of bonemarrow hemopoiesis: mechanisms of response to ionizing radiation exposure. CancerBiother Radiopharm.2002,17(4):405-426.
[63] Taichman RS, Reilly MJ, Emerson SG. Human osteoblasts support humanhematopoietic progenitor cells in vitro bone marrow cultures. Blood.1996,87(2):518-524.
[64]Lévesque JP, Helwani FM, Winkler IG. The endosteal 'osteoblastic' niche and its rolein hematopoietic stem cell homing and mobilization. Leukemia.2010,24(12):1979-1992.
[65]Chitteti BR, Cheng YH, Kacena MA, Srour EF. Hierarchical organization ofosteoblasts reveals the significant role of CD166in hematopoietic stem cellmaintenance and function. Bone.2013,54(1):58-67.
[66] Qian H, Buza-Vidas N, Hyland CD, Jensen CT, Antonchuk J, M nsson R, Thoren LA,Ekblom M, Alexander WS, Jacobsen SE.Critical role of thrombopoietin inmaintaining adult quiescent hematopoietic stem cells. Cell Stem Cell.2007,1(6):671-684.
[67]Nilsson SK, Johnston HM, Whitty GA, Williams B, Webb RJ, Denhardt DT,Bertoncello I, Bendall LJ, Simmons PJ, Haylock DN. Osteopontin, a key componentof the hematopoietic stem cell niche and regulator of primitive hematopoieticprogenitor cells. Blood.2005,106(4):1232-1239.
[68]Haug JS, He XC, Grindley JC, Wunderlich JP, Gaudenz K, Ross JT, Paulson A,Wagner KP, Xie Y, Zhu R, Yin T, Perry JM, Hembree MJ, Redenbaugh EP, Radice GL,Seidel C, Li L. N-cadherin expression level distinguishes reserved versus primedstates of hematopoietic stem cells. Cell Stem Cell.2008,2(4):367-379.
[69]Fleming HE, Janzen V, Lo Celso C, Guo J, Leahy KM, Kronenberg HM, Scadden DT.Wnt signaling in the niche enforces hematopoietic stem cell quiescence and isnecessary to preserve self-renewal in vivo. Cell Stem Cell.2008,2(3):274-283.
[70]Hosokawa K, Arai F, Yoshihara H, Iwasaki H, Hembree M, Yin T, Nakamura Y,Gomei Y, Takubo K, Shiama H, Matsuoka S, Li L, Suda T. Cadherin-based adhesionis a potential target for niche manipulation to protect hematopoietic stem cells in adultbone marrow. Cell Stem Cell.2010,6(3):194-198.
[71]Hosokawa K, Arai F, Yoshihara H, Iwasaki H, Nakamura Y, Gomei Y, Suda T.Knockdown of N-cadherin suppresses the long-term engraftment of hematopoieticstem cells. Blood.2010,116(4):554-563.
[72] Morrison SJ, Spradling AC. Stem cells and niches: mechanisms that promote stemcell maintenance throughout life. Cell.2008,132(4):598-611.
[73] Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA,Ebert BL, Al-Shahrour F, Hasserjian RP, Scadden EO, Aung Z, Matza M,Merkenschlager M, Lin C, Rommens JM, Scadden DT. Bone progenitor dysfunctioninduces myelodysplasia and secondary leukaemia. Nature.2010,464(7290):852-857.
[74]Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J, C té D, RoweDW, Lin CP, Scadden DT. Live-animal tracking of individual haematopoieticstem/progenitor cells in their niche. Nature.2009,457(7225):92-96.
[75]Takaku T, Malide D, Chen J, Calado RT, Kajigaya S, Young NS. Hematopoiesis in3dimensions: human and murine bone marrow architecture visualized by confocalmicroscopy. Blood.2010,116(15):e41-55.
[76]Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. SLAM familyreceptors distinguish hematopoietic stem and progenitor cells and reveal endothelialniches for stem cells. Cell.2005,121(7):1109-1121.
[77]Li W, Johnson SA, Shelley WC, Ferkowicz M, Morrison P, Li Y, Yoder MC. Primaryendothelial cells isolated from the yolk sac and para-aortic splanchnopleura supportthe expansion of adult marrow stem cells in vitro. Blood.2003,102(13):4345-4353.
[78]Li W, Johnson SA, Shelley WC, Yoder MC. Hematopoietic stem cell repopulatingability can be maintained in vitro by some primary endothelial cells. Exp Hematol.2004,32(12):1226-1237.
[79]Kopp HG, Avecilla ST, Hooper AT, Rafii S. The bone marrow vascular niche: home ofHSC differentiation and mobilization. Physiology (Bethesda).2005,20:349-356.
[80]Avecilla ST, Hattori K, Heissig B, Tejada R, Liao F, Shido K, Jin DK, Dias S, Zhang F,Hartman TE, Hackett NR, Crystal RG, Witte L, Hicklin DJ, Bohlen P, Eaton D, LydenD, de Sauvage F, Rafii S. Chemokine-mediated interaction of hematopoieticprogenitors with the bone marrow vascular niche is required for thrombopoiesis. NatMed.2004,10(1):64-71.
[81]Sipkins DA, Wei X, Wu JW, Runnels JM, C té D, Means TK, Luster AD, Scadden DT,Lin CP.In vivo imaging of specialized bone marrow endothelial microdomains fortumour engraftment. Nature.2005,435(7044):969-973.
[82]Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, Crystal RG, BesmerP, Lyden D, Moore MA, Werb Z, Rafii S.Recruitment of stem and progenitor cellsfrom the bone marrow niche requires MMP-9mediated release of kit-ligand. Cell.2002,109(5):625-637.
[83]Winkler IG, Barbier V, Nowlan B, Jacobsen RN, Forristal CE, Patton JT, Magnani JL,Lévesque JP. Vascular niche E-selectin regulates hematopoietic stem cell dormancy,self renewal and chemoresistance. Nat Med.2012,18(11):1651-1657.
[84]Rafii S, Shapiro F, Pettengell R, Ferris B, Nachman RL, Moore MA, Asch AS. Humanbone marrow microvascular endothelial cells support long-term proliferation anddifferentiation of myeloid and megakaryocytic progenitors. Blood.1995,86(9):3353-3363.
[85]Delehanty LL, Mogass M, Gonias SL, Racke FK, Johnstone B, Goldfarb AN. Stromalinhibition of megakaryocytic differentiation is associated with blockade of sustainedRap1activation. Blood.2003,101(5):1744-1751.
[86]Tokoyoda K, Egawa T, Sugiyama T, Choi BI, Nagasawa T.Cellular niches controllingB lymphocyte behavior within bone marrow during development. Immunity.2004,20(6):707-718.
[87]Visnjic D, Kalajzic Z, Rowe DW, Katavic V, Lorenzo J, Aguila HL. Hematopoiesis isseverely altered in mice with an induced osteoblast deficiency. Blood.2004,103(9):3258-3264.
[88]Guerrouahen BS, Al-Hijji I, Tabrizi AR. Osteoblastic and vascular endothelial niches,their control on normal hematopoietic stem cells, and their consequences on thedevelopment of leukemia. Stem Cells Int.2011,2011:375857.
[89] Cao JJ, Sun L, Gao H. Diet-induced obesity alters bone remodeling leading todecreased femoral trabecular bone mass in mice. Ann N Y Acad Sci.2010,1192:292-297.
[90]Rosen CJ, Ackert-Bicknell C, Rodriguez JP, Pino AM. Marrow fat and the bonemicroenvironment: developmental, functional, and pathological implications. Crit RevEukaryot Gene Expr.2009,19(2):109-124.
[91]Halade GV, Rahman MM, Williams PJ, Fernandes G. High fat diet-induced animalmodel of age-associated obesity and osteoporosis. J Nutr Biochem.2010,21(12):1162-1169.
[92]Casamassima F, Ruggiero C, Caramella D, Tinacci E, Villari N, Ruggiero M.Hematopoietic bone marrow recovery after radiation therapy: MRI evaluation. Blood.1989,73(6):1677-1681.
[93]Bredella MA, Torriani M, Ghomi RH, Thomas BJ, Brick DJ, Gerweck AV, Rosen CJ,Klibanski A, Miller KK. Vertebral bone marrow fat is positively associated withvisceral fat and inversely associated with IGF-1in obese women. Obesity (SilverSpring).2011,19(1):49-53.
[94]Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrowadipocytes as negative regulators of the haematopoietic microenvironment. Nature.2009,460(7252):259-263.
[95] Claycombe K, King LE, Fraker PJ.A role for leptin in sustaining lymphopoiesis andmyelopoiesis. Proc Natl Acad Sci U S A.2008,105(6):2017-2021.
[96]Pietramaggiori G, Scherer SS, Alperovich M, Chen B, Orgill DP, Wagers AJ.Improved cutaneous healing in diabetic mice exposed to healthy peripheral circulation.J Invest Dermatol.2009,129(9):2265-2274.
[97]Chitteti BR, Cheng YH, Poteat B, Rodriguez-Rodriguez S, Goebel WS, Carlesso N,Kacena MA, Srour EF. Impact of interactions of cellular components of the bonemarrow microenvironment on hematopoietic stem and progenitor cell function. Blood.2010,115(16):3239-3248.
[98]Belaid-Choucair Z, Lepelletier Y, Poncin G, Thiry A, Humblet C, Maachi M, BeaulieuA, Schneider E, Briquet A, Mineur P, Lambert C, Mendes-Da-Cruz D, Ahui ML,Asnafi V, Dy M, Boniver J, Nusgens BV, Hermine O, Defresne MP. Human bonemarrow adipocytes block granulopoiesis through neuropilin-1-induced granulocytecolony-stimulating factor inhibition. Stem Cells.2008,26(6):1556-1564.
[99] North TE, Goessling W. Previews. NOTCHing an arrow at cord blood: translatingstem cell knowledge into clinical practice. Cell Stem Cell.2010,6(3):186-187.
[100] Broxmeyer HE, Cooper S, Hass DM, Hathaway JK, Stehman FB, Hangoc G.Experimental basis of cord blood transplantation. Bone Marrow Transplant.2009,4:627-633.
[101] Norkin M, Lazarus HM, Wingard JR. Umbilical cord blood graft enhancementstrategies: has the time come to move these into the clinic? Bone Marrow Transplant.2012.
[102] Gluckman E, Rocha V, Arcese W, Michel G, Sanz G, Chan KW, Takahashi TA,Ortega J, Filipovich A, Locatelli F, Asano S, Fagioli F, Vowels M, Sirvent A, LaporteJP, Tiedemann K, Amadori S, Abecassis M, Bordigoni P, Diez B, Shaw PJ, Vora A,Caniglia M, Garnier F, Ionescu I, Garcia J, Koegler G, Rebulla P, Chevret S;Eurocord Group. Factors associated with outcomes of unrelated cord bloodtransplant: guidelines for donor choice. Exp Hematol.2004,32:397–407.
[103]Wagner JE, Barker JN, DeFor TE, Baker KS, Blazar BR, Eide C, Goldman A,Kersey J, Krivit W, MacMillan ML, Orchard PJ, Peters C, Weisdorf DJ, Ramsay NK,Davies SM. Transplantation of unrelated donor umbilical cord blood in102patientswith malignant and nonmalignant diseases: influence of CD34cell dose and HLAdisparity on treatment-related mortality and survival. Blood2002,100:1611–1618.
[104] Kelly SS, Sola CB, de Lima M, Shpall E. Ex vivo expansion of cord blood. BoneMarrow Transplant.2009,44:673-681.
[105]Shpall EJ, Quinones R, Giller R, Zeng C, Baron AE, Jones RB, Bearman SI, Nieto Y,Freed B, Madinger N, Hogan CJ, Slat-Vasquez V, Russell P, Blunk B, Schissel D,Hild E, Malcolm J, Ward W, McNiece IK.Transplantation of ex vivo expanded cordblood. Biol. Bone Marrow Transplant.2002,8:368–376.
[106] Delaney C, Ratajczak MZ, Laughlin MJ. Strategies to enhance umbilical cord bloodstem cell engraftment in adult patients. Expert Rev Hematol.2010,3:273-283.
[107] Christopherson KW II, Hangoc G, Mant CR, Broxmeyer HE. Modulation ofhematopoietic stem cell homing and engraftment by CD26.Science.2004,305:1000-1003.
[108]Wysoczynski M, Reca R, Ratajczak J, Kucia M, Shirvaikar N, Honczarenko M, MillsM, Wanzeck J, Janowska-Wieczorek A, Ratajczak MZ.Incorporation of CXCR4intomembrane lipid rafts primes homing-related responses of hematopoieticstem/progenitor cells to an SDF-1gradient. Blood.2005,105:40–48.
[109] Suárez-álvarez B, López-Vázquez A, López-Larrea C. Mobilization and homing ofhematopoietic stem cells. Adv Exp Med Biol.2012,741:152-170.
[110]Broxmeyer HE, Kohli L, Kim CH, Lee Y, Mantel C, Cooper S, Hangoc G, ShaheenM, Li X, Clapp DW.Stromal cell-derived factor-1/CXCL12directly enhancessurvival/antiapoptosis of myeloid progenitor cells through CXCR4and Gai proteinsand enhances engraftment of competitive, repopulating stem cells. J. Leukoc. Biol.2003,73:630–638.
[111] Khurana S, Margamuljana L, Joseph C, Schouteden S, Buckley SM, Verfaillie CM.Glypican-3mediated inhibition of CD26by TFPI: a novel mechanism inhematopoietic stem cell homing and maintenance. Blood.2013.
[112]Dahlberg A, Delaney C, Bernstein ID.Ex vivo expansion of human hematopoieticstem and progenitor cells. Blood.2011,117:6083-6090.
[113] Greenwald I. Structure/function studies of lin-12/Notch proteins. Curr Opin GenetDev.1994,4:556-562.
[114] Robbins J, Blondel BJ, Gallahan D, Callahan R. Mouse mammary tumor gene int-3:a member of the notch gene family transforms mammary epithelial cells. JVirol.1992,66:2594-2599.
[115] Kidd S, Baylies MK, Gasic GP, Young MW. Structure and distribution of the Notchprotein in developing Drosophila. Genes Dev.1989,3:1113-1129.
[116]Tanigaki K, Honjo T. Regulation of lymphocyte development by Notch signaling.Nat Immunol.2007,8:451-456.
[117]Panin VM, Shao L, Lei L, Moloney DJ, Irvine KD, Haltiwanger RS. Notch ligandsare substrates for protein O-fucosyltransferase-1and Fringe. J Biol Chem.2002,277:29945-29952.
[118] Singh N, Phillips RA, Iscove NN, Egan SE. Expression of notch receptors, notchligands, and fringe genes in hematopoiesis. Exp Hematol.2000,28:527-534.
[119] Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science.1995,268:225-232.
[120]Small D, Kovalenko D, Kacer D, Liaw L, Landriscina M, Di Serio C, Prudovsky I,Maciag T. Soluble Jagged1represses the function of its transmembrane form toinduce the formation of the Src-dependent chord-like phenotype. J Biol Chem.2001,276:32022-32030.
[121] Jacobsen TL, Brennan K, Arias AM, Muskavitch MA. Cis-interactions betweenDelta and Notch modulate neurogenic signalling in Drosophila. Development.1998,125:4531-4540.
[122]Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L, Wilson R, Wang Y, Stanley P,Irvine KD, Haltiwanger RS, Vogt TF.Fringe is a glycosyltransferase that modifiesNotch. Nature.2000,406:369-375.
[123] Correia T, Papayannopoulos V, Panin V, Woronoff P, Jiang J, Vogt TF, Irvine KD.Molecular genetic analysis of the glycosyltransferase Fringe in Drosophila. ProcNatl Acad Sci U S A.2003,100:6404-6409.
[124]Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P,Black RA, Isra l A.A novel proteolytic cleavage involved in Notch signaling: therole of the disintegrin-metalloprotease TACE. Mol Cell.2000,5:207-216.
[125] Struhl G, Greenwald I. Presenilin-mediated transmembrane cleavage is required forNotch signal transduction in Drosophila. Proc Natl Acad Sci U S A.2001,98:229-234.
[126]Mattson MP. Neurobiology: Ballads of a protein quartet. Nature.2003,422:385-387.
[127]Wu L, Sun T, Kobayashi K, Gao P, Griffin JD. Identification of a family ofmastermind-like transcriptional coactivators for mammalian notch receptors. MolCell Biol.2002,22:7688-7700.
[128] Bigas A, Robert-Moreno A, Espinosa L. The Notch pathway in the developinghematopoietic system. Int J Dev Biol.2010,54(6-7):1175-1188.
[129]Robert-Moreno A, Espinosa L, de la Pompa JL, Bigas A. RBPjkappa-dependentNotch function regulates Gata2and is essential for the formation of intra-embryonichematopoietic cells. Development.2005,132(5):1117-1126.
[130]Robert-Moreno A, Guiu J, Ruiz-Herguido C, López ME, Inglés-Esteve J, Riera L,Tipping A, Enver T, Dzierzak E, Gridley T, Espinosa L, Bigas A. Impairedembryonic haematopoiesis yet normal arterial development in the absence of theNotch ligand Jagged1. EMBO J.2008,27(13):1886-1895.
[131] Zhong TP, Childs S, Leu JP, Fishman MC. Gridlock signalling pathway fashions thefirst embryonic artery. Nature.2001,414:216-220.
[132]You LR, Lin FJ, Lee CT, DeMayo FJ, Tsai MJ, Tsai SY. Suppression of Notchsignalling by the COUP-TFII transcription factor regulates vein identity. Nature.2005,435:98-104.
[133]Aranguren XL, Beerens M, Coppiello G, Wiese C, Vandersmissen I, Nigro AL,Verfaillie CM, Gessler M, Luttun A. COUP-TFII orchestrates venous and lymphaticendothelial identity by homo-or heterodimerisation with PROX1. J Cell Sci.2013.
[134]Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP, Gallahan D,Closson V, Kitajewski J, Callahan R, Smith GH, Stark KL, Gridley T. Notchsignaling is essential for vascular morphogenesis in mice. Genes Dev.2000,14(11):1343-1352.
[135]Koo BK, Lim HS, Song R, Yoon MJ, Yoon KJ, Moon JS, Kim YW, Kwon MC, YooKW, Kong MP, Lee J, Chitnis AB, Kim CH, Kong YY. Mind bomb1is essential forgenerating functional Notch ligands to activate Notch. Development.2005,132(15):3459-3470.
[136]Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M. The Notch target genesHey1and Hey2are required for embryonic vascular development. Genes Dev.2004,18(8):901-911.
[137]Duarte A, Hirashima M, Benedito R, Trindade A, Diniz P, Bekman E, Costa L,Henrique D, Rossant J.Dosage-sensitive requirement for mouse Dll4in arterydevelopment. Genes Dev.2004,18(20):2474-2478.
[138]Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, Fairman RM, Velazquez OC,Herlyn M. Regulation of Notch1and Dll4by vascular endothelial growth factor inarterial endothelial cells: implications for modulating arteriogenesis andangiogenesis. Mol Cell Biol.2003,23(1):14-25.
[139]Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A,Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C. VEGF guides angiogenicsprouting utilizing endothelial tip cell filopodia. J Cell Biol.2003,161(6):1163-1177.
[140]Yang C, Guo Y, Jadlowiec CC, Li X, Lv W, Model LS, Collins MJ, Kondo Y, Muto A,Shu C, Dardik A. Vascular endothelial growth factor-A inhibits EphB4andstimulates delta-like ligand4expression in adult endothelial cells. J Surg Res.2013,S0022-4804(13)00010-3.
[141] S rensen I, Adams RH, Gossler A. DLL1-mediated Notch activation regulatesendothelial identity in mouse fetal arteries. Blood.2009,113:5680-5688.
[142] Pajcini KV, Speck NA, Pear WS. Notch signaling in mammalian hematopoietic stemcells. Leukemia.2011,25(10):1525-1532.
[143] Gering M, Patient R. Notch signalling and haematopoietic stem cell formationduring embryogenesis. J Cell Physiol.2010,222(1):11-16.
[144]Kumano K, Chiba S, Kunisato A, Sata M, Saito T, Nakagami-Yamaguchi E,Yamaguchi T, Masuda S, Shimizu K, Takahashi T, Ogawa S, Hamada Y, Hirai H.Notch1but not Notch2is essential for generating hematopoietic stem cells fromendothelial cells. Immunity.2003,18(5):699-711.
[145]Tang Y, Bai H, Urs S, Wang Z, Liaw L. Notch1activation in embryonic VE-cadherinpopulations selectively blocks hematopoietic stem cell generation and fetal liverhematopoiesis.Transgenic Res.2013,22(2):403-410.
[146]Yoon MJ, Koo BK, Song R, Jeong HW, Shin J, Kim YW, Kong YY, Suh PG. Mindbomb-1is essential for intraembryonic hematopoiesis in the aortic endothelium andthe subaortic patches. Mol Cell Biol.2008,28(15):4794-4804.
[147]Robert-Moreno A, Espinosa L, Sanchez MJ, de la Pompa JL, Bigas A. The notchpathway positively regulates programmed cell death during erythroid differentiation.Leukemia.2007,21(7):1496-1503.
[148]Hadland BK, Huppert SS, Kanungo J, Xue Y, Jiang R, Gridley T, Conlon RA, ChengAM, Kopan R, Longmore GD. A requirement for Notch1distinguishes2phases ofdefinitive hematopoiesis during development. Blood.2004,104(10):3097-3105.
[149]Liu H, Zhang W, Kennard S, Caldwell RB, Lilly B. Notch3is critical for properangiogenesis and mural cell investment.Circ Res.2010,107(7):860-870.
[150]McCright B, Gao X, Shen L, Lozier J, Lan Y, Maguire M, Herzlinger D, WeinmasterG, Jiang R, Gridley T.Defects in development of the kidney, heart and eyevasculature in mice homozygous for a hypomorphic Notch2mutation.Development.2001,128(4):491-502.
[151] Guiu J, Shimizu R, D'Altri T, Fraser ST, Hatakeyama J, Bresnick EH, Kageyama R,Dzierzak E, Yamamoto M, Espinosa L, Bigas A. Hes repressors are essentialregulators of hematopoietic stem cell development downstream of Notch signaling. JExp Med.2013,210(1):71-84.
[152]Challen GA, Goodell MA. Runx1isoforms show differential expression patternsduring hematopoietic development but have similar functional effects in adulthematopoietic stem cells. Exp Hematol.2010,38(5):403-416.
[153]Link KA, Chou FS, Mulloy JC.Core binding factor at the crossroads: determining thefate of the HSC. J Cell Physiol.2010,222(1):50-56.
[154] North T, Gu TL, Stacy T, Wang Q, Howard L, Binder M, Marín-Padilla M, SpeckNA. Cbfa2is required for the formation of intra-aortic hematopoietic clusters.Development.1999,126(11):2563-2575.
[155]Burns CE, Traver D, Mayhall E, Shepard JL, Zon LI. Hematopoietic stem cell fate isestablished by the Notch-Runx pathway. Genes Dev.2005,19:2331-2342.
[156]Bigas A, D'Altri T, Espinosa L. The Notch pathway in hematopoietic stem cells. CurrTop Microbiol Immunol.2012,360:1-18.
[157]Bigas A, Espinosa L. Hematopoietic stem cells: to be or Notch to be.Blood.2012,119(14):3226-335.
[158]Varnum-Finney B, Xu L, Brashem-Stein C, Nourigat C, Flowers D, Bakkour S, PearWS, Bernstein ID.Pluripotent, cytokine-dependent, hematopoietic stem cells areimmortalized by constitutive Notch1signaling. Nat Med.2000,6:1278-1281.
[159]Stier S, Cheng T, Dombkowski D, Carlesso N, Scadden DT. Notch1activationincreases hematopoietic stem cell self-renewal in vivo and favors lymphoid overmyeloid lineage outcome. Blood.2002,99:2369-2378.
[160]Vercauteren SM, Sutherland HJ. Constitutively active Notch4promotes early humanhematopoietic progenitor cell maintenance while inhibiting differentiation andcauses lymphoid abnormalities in vivo. Blood.2004,104:2315-2322.
[161]Maillard I, Koch U, Dumortier A, Shestova O, Xu L, Sai H, Pross SE, Aster JC,Bhandoola A, Radtke F, Pear WS.Canonical notch signaling is dispensable for themaintenance of adult hematopoietic stem cells. Cell Stem Cell.2008,2:356-366.
[162]Varnum-Finney B, Halasz LM, Sun M, Gridley T, Radtke F, Bernstein ID.Notch2governs the rate of generation of mouse long-and short-term repopulating stem cells.J Clin Invest.2011,121:1207-1216.
[163] Kunisato A, Chiba S, Nakagami-Yamaguchi E, Kumano K, Saito T, Masuda S,Yamaguchi T, Osawa M, Kageyama R, Nakauchi H, Nishikawa M, Hirai H. HES-1preserves purified hematopoietic stem cells ex vivo and accumulates side populationcells in vivo. Blood.2003,101:1777-1783.
[164] Duncan AW, Rattis FM, DiMascio LN, Congdon KL, Pazianos G, Zhao C, Yoon K,Cook JM, Willert K, Gaiano N, Reya T. Integration of Notch and Wnt signaling inhematopoietic stem cell maintenance.Nat Immunol.2005,6:314-322.
[165]Wu M, Kwon HY, Rattis F, Blum J, Zhao C, Ashkenazi R, Jackson TL, Gaiano N,Oliver T, Reya T. Imaging hematopoietic precursor division in real time. Cell StemCell.2007,1:541-554.
[166]Karanu FN, Murdoch B, Gallacher L, Wu DM, Koremoto M, Sakano S, Bhatia M.The notch ligand jagged-1represents a novel growth factor of human hematopoieticstem cells. J Exp Med.2000,192:1365-1372.
[167]Varnum-Finney B, Brashem-Stein C, Bernstein ID. Combined effects of Notchsignaling and cytokines induce a multiple log increase in precursors with lymphoidand myeloid reconstituting ability. Blood.2003,101:1784-1789.
[168]Ohishi K, Varnum-Finney B, Bernstein ID. Delta-1enhances marrow and thymusrepopulating ability of human CD34(+)CD38(-) cord blood cells. J Clin Invest.2002,110:1165-1174.
[169] Dallas MH, Varnum-Finney B, Delaney C, Kato K, Bernstein ID. Density of theNotch ligand Delta1determines generation of B and T cell precursors fromhematopoietic stem cells. J Exp Med.2005,201:1361-1366.
[170]Delaney C, Varnum-Finney B, Aoyama K, Brashem-Stein C, Bernstein ID.Dose-dependent effects of the Notch ligand Delta1on ex vivo differentiation and invivo marrow repopulating ability of cord blood cells. Blood.2005,106:2693-2699.
[171]Myers J, Huang Y, Wei L, Yan Q, Huang A, Zhou L. Fucose-deficient hematopoieticstem cells have decreased self-renewal and aberrant marrow niche occupancy.Transfusion.2010,50:2660-2669.
[172] Zhou L, Li LW, Yan Q, Petryniak B, Man Y, Su C, Shim J,Chervin S, Lowe JB.Notch-dependent control of myelopoiesis is regulated by fucosylation. Blood.2008,112:308-319.
[173]Hooper AT, Butler JM, Nolan DJ, Kranz A, Iida K, Kobayashi M, Kopp HG, Shido K,Petit I, Yanger K, James D, Witte L, Zhu Z, Wu Y, Pytowski B, Rosenwaks Z, MittalV, Sato TN, Rafii S. Engraftment and reconstitution of hematopoiesis is dependenton VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell StemCell.2009,4:263-274.
[174]Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT,Seandel M, Shido K, White IA, Kobayashi M, Witte L, May C, Shawber C, KimuraY, Kitajewski J, Rosenwaks Z, Bernstein ID, Rafii S.Endothelial cells are essentialfor the self-renewal and repopulation of Notch-dependent hematopoietic stem cells.Cell Stem Cell.2010,6:251-264.
[175]Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cellsmaintain haematopoietic stem cells. Nature.2012,481(7382):457-462.
[176]Butler JM, Gars EJ, James DJ, Nolan DJ, Scandura JM, Rafii S. Development of avascular niche platform for expansion of repopulating human cord blood stem andprogenitor cells. Blood.2012,120(6):1344-1347.
[177] Walasek MA, van Os R, de Haan G. Hematopoietic stem cell expansion: challengesand opportunities. Ann N Y Acad Sci.2012,1266:138-150.
[178] Suzuki T, Chiba S. Notch signaling in hematopoietic stem cells. Int J Hematol.2005,82(4):285-294.
[179]Ohishi K, Katayama N, Shiku H, Varnum-Finney B, Bernstein ID. Notch signallingin hematopoiesis. Semin Cell Dev Biol.2003,14(2):143-150.
[180] Ohishi K, Varnum-Finney B, Bernstein ID. The notch pathway: modulation of cellfate decisions in hematopoiesis. Int J Hematol.2002,75(5):449-459.
[181]Varnum-Finney B, Wu L, Yu M, Brashem-Stein C, Staats S, Flowers D, Griffin JD,Bernstein ID. Immobilization of Notch ligand, Delta-1, is required for induction ofnotch signaling. J Cell Sci.2000,113:4313-4318.
[182] Parks AL, Klueg KM, Stout JR, Muskavitch MA. Ligand endocytosis drivesreceptor dissociation and activation in the Notch pathway. Development.2000,127(7):1373-1385.
[183]Laje P, Zoltick PW, Flake AW. SLAM-enriched hematopoietic stem cells maintainlong-term repopulating capacity after lentiviral transduction using an abbreviatedprotocol. Gene Ther.2010,17(3):412-418.
[184]Iwasaki H, Arai F, Kubota Y, Dahl M, Suda T. Endothelial protein Creceptor-expressing hematopoietic stem cells reside in the perisinusoidal niche infetal liver. Blood.2010,116(4):544-553.
[185]Balazs AB, Fabian AJ, Esmon CT, Mulligan RC.Endothelial protein C receptor(CD201) explicitly identifies hematopoietic stem cells in murine bone marrow.Blood.2006,107(6):2317-2321.
[186]Mikkola HK, Klintman J, Yang H, Hock H, Schlaeger TM, Fujiwara Y, Orkin SH.Haematopoietic stem cells retain long-term repopulating activity and multipotencyin the absence of stem-cell leukaemia SCL/tal-1gene. Nature.2003,421(6922):547-551.
[187] Chen MJ, Yokomizo T, Zeigler BM, Dzierzak E, Speck NA.Runx1is required forthe endothelial to haematopoietic cell transition but not thereafter. Nature.2009,457(7231):887-891.
[188]Tsai FY, Orkin SH.Transcription factor GATA-2is required for proliferation/survivalof early hematopoietic cells and mast cell formation, but not for erythroid andmyeloid terminal differentiation. Blood.1997,89(10):3636-3643.
[189]Kitajima K, Masuhara M, Era T, Enver T, Nakano T.GATA-2and GATA-2/ERdisplay opposing activities in the development and differentiation of bloodprogenitors. EMBO J.2002,21(12):3060-3069.
[190]Lowell CA, Niwa M, Soriano P, Varmus HE. Deficiency of the Hck and Src tyrosinekinases results in extreme levels of extramedullary hematopoiesis.Blood.1996,87(5):1780-1792.
[191]Wang ZQ, Ovitt C, Grigoriadis AE, M hle-Steinlein U, Rüther U, Wagner EF.Boneand haematopoietic defects in mice lacking c-fos. Nature.1992,360(6406):741-745.
[2] Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mousehematopoietic stem cells. Science.1988,241:58-62.
[3] Morrison SJ,Weissman IL.The long-term repopulating subset of hematopoietic stemcells is deterministic and isolatable by phenotype. Immunity.1994,1:661-673.
[4] Wang LD, Wagers AJ. Dynamic niches in the origination and differentiation ofhaematopoietic stem cells. Nat Rev Mol Cell Biol.2011,12(10):643-655.
[5]Osawa M, Hanada K, Hamada H, Nakauchi H.Long-term lymphohematopoieticreconstitution by a single CD34-low/negative hematopoietic stem cell.Science.1996,273:242-245.
[6] Mikkola HK, Orkin SH. The journey of developing hematopoietic stem cells.Development.2006,133:3733-3744.
[7] Kingsley PD, Malik J, Fantauzzo KA, Palis J. Yolk sac-derived primitive erythroblastsenucleate during mammalian embryogenesis.Blood.2004,104(1):19-25.
[8] Cumano A, Dieterlen-Lievre F, Godin I. Lymphoid potential, probed before circulationin mouse, is restricted to caudal intraembryonic splanchnopleura. Cell.1996,86(6):907-916.
[9] Kumaravelu P, Hook L, Morrison AM, Ure J, Zhao S, Zuyev S, Ansell J, Medvinsky A.Quantitative developmental anatomy of definitive haematopoietic stemcells/long-term repopulating units (HSC/RUs): role of the aorta-gonad-mesonephros(AGM) region and the yolk sac in colonisation of the mouse embryonic liver.Development.2002,129(21):4891-4899.
[10] Harrison DE, Zhong RK, Jordan CT, Lemischka IR, Astle CM. Relative to adultmarrow, fetal liver repopulates nearly five times more effectively long-term thanshort-term. Exp Hematol.1997,25(4):293-297.
[11] Emambokus NR, Frampton J. The glycoprotein IIb molecule is expressed on earlymurine hematopoietic progenitors and regulates their numbers in sites ofhematopoiesis. Immunity.2003,19(1):33-45.
[12] Gekas C, Dieterlen-Lièvre F, Orkin SH, Mikkola HK.The placenta is a niche forhematopoietic stem cells. Dev Cell.2005,8(3):365-375.
[13] Robin C, Bollerot K, Mendes S, Haak E, Crisan M, Cerisoli F, Lauw I, Kaimakis P,Jorna R, Vermeulen M, Kayser M, van der Linden R, Imanirad P, Verstegen M,Nawaz-Yousaf H, Papazian N, Steegers E, Cupedo T, Dzierzak E.Human placenta isa potent hematopoietic niche containing hematopoietic stem and progenitor cellsthroughout development. Cell Stem Cell.2009,5(4):385-395.
[14] Sabin, F.. Origin and development of the primitive vessels of the chick and of the pig.Contrib. Embryol.1917,226:61-124.
[15] Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G. A common precursorfor hematopoietic and endothelial cells. Development.1998,125(4):725-732.
[16] Fehling HJ, Lacaud G, Kubo A, Kennedy M, Robertson S, Keller G, Kouskoff V.Tracking mesoderm induction and its specification to the hemangioblast duringembryonic stem cell differentiation. Development.2003,130(17):4217-4227.
[17] Huber TL, Kouskoff V, Fehling HJ, Palis J, Keller G. Haemangioblast commitment isinitiated in the primitive streak of the mouse embryo. Nature.2004,432(7017):625-630.
[18] Jaffredo T, Gautier R, Eichmann A, Dieterlen-Lièvre F. Intraaortic hemopoietic cellsare derived from endothelial cells during ontogeny. Development.1998,125(22):4575-4583.
[19] de Bruijn MF, Ma X, Robin C, Ottersbach K, Sanchez MJ, Dzierzak E.Hematopoieticstem cells localize to the endothelial cell layer in the midgestation mouse aorta.Immunity.2002,16(5):673-683.
[20] North TE, de Bruijn MF, Stacy T, Talebian L, Lind E, Robin C, Binder M, Dzierzak E,Speck NA.Runx1expression marks long-term repopulating hematopoietic stem cellsin the midgestation mouse embryo. Immunity.2002,16(5):661-672.
[21] Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat RevImmunol.2006,6:93-106.
[22] Zon LI. Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal.Nature.2008,453:306-313.
[23] Staal FJ, Luis TC, Tiemessen MM. WNT signalling in the immune system: WNT isspreading its wings. Nat Rev Immunol.2008,8(8):581-593.
[24] Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R,Weissman IL.A role for Wnt signalling in self-renewal of haematopoietic stem cells.Nature.2003,423(6938):409-414.
[25] Austin TW, Solar GP, Ziegler FC, Liem L, Matthews W. A role for the Wnt genefamily in hematopoiesis: expansion of multilineage progenitor cells. Blood.1997,89(10):3624-3635.
[26] Van Den Berg DJ, Sharma AK, Bruno E, Hoffman R.Role of members of the Wntgene family in human hematopoiesis. Blood.1998,92(9):3189-3202.
[27] Murdoch B, Chadwick K, Martin M, Shojaei F, Shah KV, Gallacher L, Moon RT,Bhatia M. Wnt-5A augments repopulating capacity and primitive hematopoieticdevelopment of human blood stem cells in vivo. Proc Natl Acad Sci U S A.2003,100(6):3422-3427.
[28] Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates JR3rd,Nusse R.Wnt proteins are lipid-modified and can act as stem cell growth factors.Nature.2003,423(6938):448-452.
[29]Nemeth MJ, Topol L, Anderson SM, Yang Y, Bodine DM.Wnt5a inhibits canonicalWnt signaling in hematopoietic stem cells and enhances repopulation. Proc Natl AcadSci U S A.2007,104(39):15436-15441.
[30]Huang J, Nguyen-McCarty M, Hexner EO, Danet-Desnoyers G, Klein PS.Maintenance of hematopoietic stem cells through regulation of Wnt and mTORpathways. Nat Med.2012，18(12):1778-1785..
[31] Reya T, O'Riordan M, Okamura R, Devaney E, Willert K, Nusse R, GrosschedlR.Wnt signaling regulates B lymphocyte proliferation through a LEF-1dependentmechanism. Immunity.2000,13(1):15-24.
[32]Luis TC, Naber BA, Roozen PP, Brugman MH, de Haas EF, Ghazvini M, Fibbe WE,van Dongen JJ, Fodde R, Staal FJ. Canonical wnt signaling regulates hematopoiesis ina dosage-dependent fashion. Cell Stem Cell.2011,9(4):345-356.
[33] Kirstetter P, Anderson K, Porse BT, Jacobsen SE, Nerlov C. Activation of thecanonical Wnt pathway leads to loss of hematopoietic stem cell repopulation andmultilineage differentiation block. Nat Immunol.2006,7(10):1048-1056.
[34] Scheller M, Huelsken J, Rosenbauer F, Taketo MM, Birchmeier W, Tenen DG, LeutzA.Hematopoietic stem cell and multilineage defects generated by constitutivebeta-catenin activation. Nat Immunol.2006,7(10):1037-1047.
[35] Koch U, Wilson A, Cobas M, Kemler R, Macdonald HR, Radtke F. Simultaneous lossof beta-and gamma-catenin does not perturb hematopoiesis or lymphopoiesis. Blood.2008,111(1):160-164.
[36] Lawrence HJ, Largman C. Homeobox genes in normal hematopoiesis and leukemia.Blood.1992,80(10):2445-2453.
[37] Sauvageau G, Lansdorp PM, Eaves CJ, Hogge DE, Dragowska WH, Reid DS,Largman C, Lawrence HJ, Humphries RK. Differential expression of homeoboxgenes in functionally distinct CD34+subpopulations of human bone marrow cells.Proc Natl Acad Sci U S A.1994,91(25):12223-12227.
[38] Pineault N, Helgason CD, Lawrence HJ, Humphries RK. Differential expression ofHox, Meis1, and Pbx1genes in primitive cells throughout murine hematopoieticontogeny. Exp Hematol.2002,30(1):49-57.
[39] Antonchuk J, Sauvageau G, Humphries RK.HOXB4-induced expansion of adulthematopoietic stem cells ex vivo. Cell.2002,109(1):39-45.
[40]Amsellem S, Pflumio F, Bardinet D, Izac B, Charneau P, Romeo PH,Dubart-Kupperschmitt A, Fichelson S. Ex vivo expansion of human hematopoieticstem cells by direct delivery of the HOXB4homeoprotein. Nat Med.2003,9(11):1423-1427.
[41]Krosl J, Austin P, Beslu N, Kroon E, Humphries RK, Sauvageau G. In vitro expansionof hematopoietic stem cells by recombinant TAT-HOXB4protein. Nat Med.2003,9(11):1428-1432.
[42] Watts KL, Delaney C, Humphries RK, Bernstein ID, Kiem HP.Combination ofHOXB4and Delta-1ligand improves expansion of cord blood cells. Blood.2010,116(26):5859-5866.
[43] Robin C, Durand C. The roles of BMP and IL-3signaling pathways in the control ofhematopoietic stem cells in the mouse embryo. Int J Dev Biol.2010,54(6-7):1189-1200.
[44] Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K, Ling LE,Karanu FN, Bhatia M. Sonic hedgehog induces the proliferation of primitive humanhematopoietic cells via BMP regulation. Nat Immunol.2001,2(2):172-180.
[45] Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ,Harris S, Wiedemann LM, Mishina Y, Li L.Identification of the haematopoietic stemcell niche and control of the niche size. Nature.2003,425(6960):836-841.
[46]Goldman DC, Bailey AS, Pfaffle DL, Al Masri A, Christian JL, Fleming WH. BMP4regulates the hematopoietic stem cell niche. Blood.2009,114(20):4393-4401.
[47]Clària J.Cyclooxygenase-2biology.Curr Pharm Des.2003,9(27):2177-2190.
[48]Regan JW.EP2and EP4prostanoid receptor signaling.Life Sci.2003,74(2-3):143-153.
[49] Fujino H, West KA, Regan JW. Phosphorylation of glycogen synthase kinase-3andstimulation of T-cell factor signaling following activation of EP2and EP4prostanoidreceptors by prostaglandin E2. J Biol Chem.2002,277(4):2614-2619.
[50] Fujino H, Xu W, Regan JW.Prostaglandin E2induced functional expression of earlygrowth response factor-1by EP4, but not EP2, prostanoid receptors via thephosphatidylinositol3-kinase and extracellular signal-regulated kinases. J Biol Chem.2003,278(14):12151-12156.
[51] North TE, Goessling W, Walkley CR, Lengerke C, Kopani KR, Lord AM, Weber GJ,Bowman TV, Jang IH, Grosser T, Fitzgerald GA, Daley GQ, Orkin SH, Zon LI.Prostaglandin E2regulates vertebrate haematopoietic stem cell homeostasis. Nature.2007,447(7147):1007-1011.
[52]Hoggatt J, Singh P, Sampath J, Pelus LM. Prostaglandin E2enhances hematopoieticstem cell homing, survival, and proliferation. Blood.2009,113(22):5444-5455.
[53] Goessling W, North TE, Loewer S, Lord AM, Lee S, Stoick-Cooper CL, Weidinger G,Puder M, Daley GQ, Moon RT, Zon LI.Genetic interaction of PGE2and Wntsignaling regulates developmental specification of stem cells and regeneration. Cell.2009,136(6):1136-1147.
[54] Goessling W, Allen RS, Guan X, Jin P, Uchida N, Dovey M, Harris JM, Metzger ME,Bonifacino AC, Stroncek D, Stegner J, Armant M, Schlaeger T, Tisdale JF, Zon LI,Donahue RE, North TE. Prostaglandin E2enhances human cord blood stem cellxenotransplants and shows long-term safety in preclinical nonhuman primatetransplant models. Cell Stem Cell.2011,8(4):445-458.
[55] Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, Walker JR,Flaveny CA, Perdew GH, Denison MS, Schultz PG, Cooke MP.Aryl hydrocarbonreceptor antagonists promote the expansion of human hematopoietic stem cells.Science.2010,329(5997):1345-1348.
[56] Zhang CC, Kaba M, Iizuka S, Huynh H, Lodish HF.Angiopoietin-like5and IGFBP2stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayedby NOD/SCID transplantation. Blood.2008,111(7):3415-3423.
[57] Himburg HA, Muramoto GG, Daher P, Meadows SK, Russell JL, Doan P, Chi JT,Salter AB, Lento WE, Reya T, Chao NJ, Chute JP.Pleiotrophin regulates theexpansion and regeneration of hematopoietic stem cells. Nat Med.2010,16(4):475-482.
[58] Himburg HA, Harris JR, Ito T, Daher P, Russell JL, Quarmyne M, Doan PL, Helms K,Nakamura M, Fixsen E, Herradon G, Reya T, Chao NJ, Harroch S, Chute JP.Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells inthe bone marrow vascular niche. Cell.2012,25;2(4):964-975.
[59] Schofield R. The relationship between the spleen colony-forming cell and thehaemopoietic stem cell. Blood Cells.1978,4(1-2):7-25.
[60] Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP,Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, ScaddenDT.Osteoblastic cells regulate the haematopoietic stem cell niche. Nature.2003,425(6960):841-846.
[61] Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, Vincent P, Pumiglia K,Temple S.Endothelial cells stimulate self-renewal and expand neurogenesis of neuralstem cells. Science.2004,304(5675):1338-1340.
[62] Fliedner TM, Graessle D, Paulsen C, Reimers K. Structure and function of bonemarrow hemopoiesis: mechanisms of response to ionizing radiation exposure. CancerBiother Radiopharm.2002,17(4):405-426.
[63] Taichman RS, Reilly MJ, Emerson SG. Human osteoblasts support humanhematopoietic progenitor cells in vitro bone marrow cultures. Blood.1996,87(2):518-524.
[64]Lévesque JP, Helwani FM, Winkler IG. The endosteal 'osteoblastic' niche and its rolein hematopoietic stem cell homing and mobilization. Leukemia.2010,24(12):1979-1992.
[65]Chitteti BR, Cheng YH, Kacena MA, Srour EF. Hierarchical organization ofosteoblasts reveals the significant role of CD166in hematopoietic stem cellmaintenance and function. Bone.2013,54(1):58-67.
[66] Qian H, Buza-Vidas N, Hyland CD, Jensen CT, Antonchuk J, M nsson R, Thoren LA,Ekblom M, Alexander WS, Jacobsen SE.Critical role of thrombopoietin inmaintaining adult quiescent hematopoietic stem cells. Cell Stem Cell.2007,1(6):671-684.
[67]Nilsson SK, Johnston HM, Whitty GA, Williams B, Webb RJ, Denhardt DT,Bertoncello I, Bendall LJ, Simmons PJ, Haylock DN. Osteopontin, a key componentof the hematopoietic stem cell niche and regulator of primitive hematopoieticprogenitor cells. Blood.2005,106(4):1232-1239.
[68]Haug JS, He XC, Grindley JC, Wunderlich JP, Gaudenz K, Ross JT, Paulson A,Wagner KP, Xie Y, Zhu R, Yin T, Perry JM, Hembree MJ, Redenbaugh EP, Radice GL,Seidel C, Li L. N-cadherin expression level distinguishes reserved versus primedstates of hematopoietic stem cells. Cell Stem Cell.2008,2(4):367-379.
[69]Fleming HE, Janzen V, Lo Celso C, Guo J, Leahy KM, Kronenberg HM, Scadden DT.Wnt signaling in the niche enforces hematopoietic stem cell quiescence and isnecessary to preserve self-renewal in vivo. Cell Stem Cell.2008,2(3):274-283.
[70]Hosokawa K, Arai F, Yoshihara H, Iwasaki H, Hembree M, Yin T, Nakamura Y,Gomei Y, Takubo K, Shiama H, Matsuoka S, Li L, Suda T. Cadherin-based adhesionis a potential target for niche manipulation to protect hematopoietic stem cells in adultbone marrow. Cell Stem Cell.2010,6(3):194-198.
[71]Hosokawa K, Arai F, Yoshihara H, Iwasaki H, Nakamura Y, Gomei Y, Suda T.Knockdown of N-cadherin suppresses the long-term engraftment of hematopoieticstem cells. Blood.2010,116(4):554-563.
[72] Morrison SJ, Spradling AC. Stem cells and niches: mechanisms that promote stemcell maintenance throughout life. Cell.2008,132(4):598-611.
[73] Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA,Ebert BL, Al-Shahrour F, Hasserjian RP, Scadden EO, Aung Z, Matza M,Merkenschlager M, Lin C, Rommens JM, Scadden DT. Bone progenitor dysfunctioninduces myelodysplasia and secondary leukaemia. Nature.2010,464(7290):852-857.
[74]Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J, C té D, RoweDW, Lin CP, Scadden DT. Live-animal tracking of individual haematopoieticstem/progenitor cells in their niche. Nature.2009,457(7225):92-96.
[75]Takaku T, Malide D, Chen J, Calado RT, Kajigaya S, Young NS. Hematopoiesis in3dimensions: human and murine bone marrow architecture visualized by confocalmicroscopy. Blood.2010,116(15):e41-55.
[76]Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. SLAM familyreceptors distinguish hematopoietic stem and progenitor cells and reveal endothelialniches for stem cells. Cell.2005,121(7):1109-1121.
[77]Li W, Johnson SA, Shelley WC, Ferkowicz M, Morrison P, Li Y, Yoder MC. Primaryendothelial cells isolated from the yolk sac and para-aortic splanchnopleura supportthe expansion of adult marrow stem cells in vitro. Blood.2003,102(13):4345-4353.
[78]Li W, Johnson SA, Shelley WC, Yoder MC. Hematopoietic stem cell repopulatingability can be maintained in vitro by some primary endothelial cells. Exp Hematol.2004,32(12):1226-1237.
[79]Kopp HG, Avecilla ST, Hooper AT, Rafii S. The bone marrow vascular niche: home ofHSC differentiation and mobilization. Physiology (Bethesda).2005,20:349-356.
[80]Avecilla ST, Hattori K, Heissig B, Tejada R, Liao F, Shido K, Jin DK, Dias S, Zhang F,Hartman TE, Hackett NR, Crystal RG, Witte L, Hicklin DJ, Bohlen P, Eaton D, LydenD, de Sauvage F, Rafii S. Chemokine-mediated interaction of hematopoieticprogenitors with the bone marrow vascular niche is required for thrombopoiesis. NatMed.2004,10(1):64-71.
[81]Sipkins DA, Wei X, Wu JW, Runnels JM, C té D, Means TK, Luster AD, Scadden DT,Lin CP.In vivo imaging of specialized bone marrow endothelial microdomains fortumour engraftment. Nature.2005,435(7044):969-973.
[82]Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, Crystal RG, BesmerP, Lyden D, Moore MA, Werb Z, Rafii S.Recruitment of stem and progenitor cellsfrom the bone marrow niche requires MMP-9mediated release of kit-ligand. Cell.2002,109(5):625-637.
[83]Winkler IG, Barbier V, Nowlan B, Jacobsen RN, Forristal CE, Patton JT, Magnani JL,Lévesque JP. Vascular niche E-selectin regulates hematopoietic stem cell dormancy,self renewal and chemoresistance. Nat Med.2012,18(11):1651-1657.
[84]Rafii S, Shapiro F, Pettengell R, Ferris B, Nachman RL, Moore MA, Asch AS. Humanbone marrow microvascular endothelial cells support long-term proliferation anddifferentiation of myeloid and megakaryocytic progenitors. Blood.1995,86(9):3353-3363.
[85]Delehanty LL, Mogass M, Gonias SL, Racke FK, Johnstone B, Goldfarb AN. Stromalinhibition of megakaryocytic differentiation is associated with blockade of sustainedRap1activation. Blood.2003,101(5):1744-1751.
[86]Tokoyoda K, Egawa T, Sugiyama T, Choi BI, Nagasawa T.Cellular niches controllingB lymphocyte behavior within bone marrow during development. Immunity.2004,20(6):707-718.
[87]Visnjic D, Kalajzic Z, Rowe DW, Katavic V, Lorenzo J, Aguila HL. Hematopoiesis isseverely altered in mice with an induced osteoblast deficiency. Blood.2004,103(9):3258-3264.
[88]Guerrouahen BS, Al-Hijji I, Tabrizi AR. Osteoblastic and vascular endothelial niches,their control on normal hematopoietic stem cells, and their consequences on thedevelopment of leukemia. Stem Cells Int.2011,2011:375857.
[89] Cao JJ, Sun L, Gao H. Diet-induced obesity alters bone remodeling leading todecreased femoral trabecular bone mass in mice. Ann N Y Acad Sci.2010,1192:292-297.
[90]Rosen CJ, Ackert-Bicknell C, Rodriguez JP, Pino AM. Marrow fat and the bonemicroenvironment: developmental, functional, and pathological implications. Crit RevEukaryot Gene Expr.2009,19(2):109-124.
[91]Halade GV, Rahman MM, Williams PJ, Fernandes G. High fat diet-induced animalmodel of age-associated obesity and osteoporosis. J Nutr Biochem.2010,21(12):1162-1169.
[92]Casamassima F, Ruggiero C, Caramella D, Tinacci E, Villari N, Ruggiero M.Hematopoietic bone marrow recovery after radiation therapy: MRI evaluation. Blood.1989,73(6):1677-1681.
[93]Bredella MA, Torriani M, Ghomi RH, Thomas BJ, Brick DJ, Gerweck AV, Rosen CJ,Klibanski A, Miller KK. Vertebral bone marrow fat is positively associated withvisceral fat and inversely associated with IGF-1in obese women. Obesity (SilverSpring).2011,19(1):49-53.
[94]Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrowadipocytes as negative regulators of the haematopoietic microenvironment. Nature.2009,460(7252):259-263.
[95] Claycombe K, King LE, Fraker PJ.A role for leptin in sustaining lymphopoiesis andmyelopoiesis. Proc Natl Acad Sci U S A.2008,105(6):2017-2021.
[96]Pietramaggiori G, Scherer SS, Alperovich M, Chen B, Orgill DP, Wagers AJ.Improved cutaneous healing in diabetic mice exposed to healthy peripheral circulation.J Invest Dermatol.2009,129(9):2265-2274.
[97]Chitteti BR, Cheng YH, Poteat B, Rodriguez-Rodriguez S, Goebel WS, Carlesso N,Kacena MA, Srour EF. Impact of interactions of cellular components of the bonemarrow microenvironment on hematopoietic stem and progenitor cell function. Blood.2010,115(16):3239-3248.
[98]Belaid-Choucair Z, Lepelletier Y, Poncin G, Thiry A, Humblet C, Maachi M, BeaulieuA, Schneider E, Briquet A, Mineur P, Lambert C, Mendes-Da-Cruz D, Ahui ML,Asnafi V, Dy M, Boniver J, Nusgens BV, Hermine O, Defresne MP. Human bonemarrow adipocytes block granulopoiesis through neuropilin-1-induced granulocytecolony-stimulating factor inhibition. Stem Cells.2008,26(6):1556-1564.
[99] North TE, Goessling W. Previews. NOTCHing an arrow at cord blood: translatingstem cell knowledge into clinical practice. Cell Stem Cell.2010,6(3):186-187.
[100] Broxmeyer HE, Cooper S, Hass DM, Hathaway JK, Stehman FB, Hangoc G.Experimental basis of cord blood transplantation. Bone Marrow Transplant.2009,4:627-633.
[101] Norkin M, Lazarus HM, Wingard JR. Umbilical cord blood graft enhancementstrategies: has the time come to move these into the clinic? Bone Marrow Transplant.2012.
[102] Gluckman E, Rocha V, Arcese W, Michel G, Sanz G, Chan KW, Takahashi TA,Ortega J, Filipovich A, Locatelli F, Asano S, Fagioli F, Vowels M, Sirvent A, LaporteJP, Tiedemann K, Amadori S, Abecassis M, Bordigoni P, Diez B, Shaw PJ, Vora A,Caniglia M, Garnier F, Ionescu I, Garcia J, Koegler G, Rebulla P, Chevret S;Eurocord Group. Factors associated with outcomes of unrelated cord bloodtransplant: guidelines for donor choice. Exp Hematol.2004,32:397–407.
[103]Wagner JE, Barker JN, DeFor TE, Baker KS, Blazar BR, Eide C, Goldman A,Kersey J, Krivit W, MacMillan ML, Orchard PJ, Peters C, Weisdorf DJ, Ramsay NK,Davies SM. Transplantation of unrelated donor umbilical cord blood in102patientswith malignant and nonmalignant diseases: influence of CD34cell dose and HLAdisparity on treatment-related mortality and survival. Blood2002,100:1611–1618.
[104] Kelly SS, Sola CB, de Lima M, Shpall E. Ex vivo expansion of cord blood. BoneMarrow Transplant.2009,44:673-681.
[105]Shpall EJ, Quinones R, Giller R, Zeng C, Baron AE, Jones RB, Bearman SI, Nieto Y,Freed B, Madinger N, Hogan CJ, Slat-Vasquez V, Russell P, Blunk B, Schissel D,Hild E, Malcolm J, Ward W, McNiece IK.Transplantation of ex vivo expanded cordblood. Biol. Bone Marrow Transplant.2002,8:368–376.
[106] Delaney C, Ratajczak MZ, Laughlin MJ. Strategies to enhance umbilical cord bloodstem cell engraftment in adult patients. Expert Rev Hematol.2010,3:273-283.
[107] Christopherson KW II, Hangoc G, Mant CR, Broxmeyer HE. Modulation ofhematopoietic stem cell homing and engraftment by CD26.Science.2004,305:1000-1003.
[108]Wysoczynski M, Reca R, Ratajczak J, Kucia M, Shirvaikar N, Honczarenko M, MillsM, Wanzeck J, Janowska-Wieczorek A, Ratajczak MZ.Incorporation of CXCR4intomembrane lipid rafts primes homing-related responses of hematopoieticstem/progenitor cells to an SDF-1gradient. Blood.2005,105:40–48.
[109] Suárez-álvarez B, López-Vázquez A, López-Larrea C. Mobilization and homing ofhematopoietic stem cells. Adv Exp Med Biol.2012,741:152-170.
[110]Broxmeyer HE, Kohli L, Kim CH, Lee Y, Mantel C, Cooper S, Hangoc G, ShaheenM, Li X, Clapp DW.Stromal cell-derived factor-1/CXCL12directly enhancessurvival/antiapoptosis of myeloid progenitor cells through CXCR4and Gai proteinsand enhances engraftment of competitive, repopulating stem cells. J. Leukoc. Biol.2003,73:630–638.
[111] Khurana S, Margamuljana L, Joseph C, Schouteden S, Buckley SM, Verfaillie CM.Glypican-3mediated inhibition of CD26by TFPI: a novel mechanism inhematopoietic stem cell homing and maintenance. Blood.2013.
[112]Dahlberg A, Delaney C, Bernstein ID.Ex vivo expansion of human hematopoieticstem and progenitor cells. Blood.2011,117:6083-6090.
[113] Greenwald I. Structure/function studies of lin-12/Notch proteins. Curr Opin GenetDev.1994,4:556-562.
[114] Robbins J, Blondel BJ, Gallahan D, Callahan R. Mouse mammary tumor gene int-3:a member of the notch gene family transforms mammary epithelial cells. JVirol.1992,66:2594-2599.
[115] Kidd S, Baylies MK, Gasic GP, Young MW. Structure and distribution of the Notchprotein in developing Drosophila. Genes Dev.1989,3:1113-1129.
[116]Tanigaki K, Honjo T. Regulation of lymphocyte development by Notch signaling.Nat Immunol.2007,8:451-456.
[117]Panin VM, Shao L, Lei L, Moloney DJ, Irvine KD, Haltiwanger RS. Notch ligandsare substrates for protein O-fucosyltransferase-1and Fringe. J Biol Chem.2002,277:29945-29952.
[118] Singh N, Phillips RA, Iscove NN, Egan SE. Expression of notch receptors, notchligands, and fringe genes in hematopoiesis. Exp Hematol.2000,28:527-534.
[119] Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science.1995,268:225-232.
[120]Small D, Kovalenko D, Kacer D, Liaw L, Landriscina M, Di Serio C, Prudovsky I,Maciag T. Soluble Jagged1represses the function of its transmembrane form toinduce the formation of the Src-dependent chord-like phenotype. J Biol Chem.2001,276:32022-32030.
[121] Jacobsen TL, Brennan K, Arias AM, Muskavitch MA. Cis-interactions betweenDelta and Notch modulate neurogenic signalling in Drosophila. Development.1998,125:4531-4540.
[122]Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L, Wilson R, Wang Y, Stanley P,Irvine KD, Haltiwanger RS, Vogt TF.Fringe is a glycosyltransferase that modifiesNotch. Nature.2000,406:369-375.
[123] Correia T, Papayannopoulos V, Panin V, Woronoff P, Jiang J, Vogt TF, Irvine KD.Molecular genetic analysis of the glycosyltransferase Fringe in Drosophila. ProcNatl Acad Sci U S A.2003,100:6404-6409.
[124]Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P,Black RA, Isra l A.A novel proteolytic cleavage involved in Notch signaling: therole of the disintegrin-metalloprotease TACE. Mol Cell.2000,5:207-216.
[125] Struhl G, Greenwald I. Presenilin-mediated transmembrane cleavage is required forNotch signal transduction in Drosophila. Proc Natl Acad Sci U S A.2001,98:229-234.
[126]Mattson MP. Neurobiology: Ballads of a protein quartet. Nature.2003,422:385-387.
[127]Wu L, Sun T, Kobayashi K, Gao P, Griffin JD. Identification of a family ofmastermind-like transcriptional coactivators for mammalian notch receptors. MolCell Biol.2002,22:7688-7700.
[128] Bigas A, Robert-Moreno A, Espinosa L. The Notch pathway in the developinghematopoietic system. Int J Dev Biol.2010,54(6-7):1175-1188.
[129]Robert-Moreno A, Espinosa L, de la Pompa JL, Bigas A. RBPjkappa-dependentNotch function regulates Gata2and is essential for the formation of intra-embryonichematopoietic cells. Development.2005,132(5):1117-1126.
[130]Robert-Moreno A, Guiu J, Ruiz-Herguido C, López ME, Inglés-Esteve J, Riera L,Tipping A, Enver T, Dzierzak E, Gridley T, Espinosa L, Bigas A. Impairedembryonic haematopoiesis yet normal arterial development in the absence of theNotch ligand Jagged1. EMBO J.2008,27(13):1886-1895.
[131] Zhong TP, Childs S, Leu JP, Fishman MC. Gridlock signalling pathway fashions thefirst embryonic artery. Nature.2001,414:216-220.
[132]You LR, Lin FJ, Lee CT, DeMayo FJ, Tsai MJ, Tsai SY. Suppression of Notchsignalling by the COUP-TFII transcription factor regulates vein identity. Nature.2005,435:98-104.
[133]Aranguren XL, Beerens M, Coppiello G, Wiese C, Vandersmissen I, Nigro AL,Verfaillie CM, Gessler M, Luttun A. COUP-TFII orchestrates venous and lymphaticendothelial identity by homo-or heterodimerisation with PROX1. J Cell Sci.2013.
[134]Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP, Gallahan D,Closson V, Kitajewski J, Callahan R, Smith GH, Stark KL, Gridley T. Notchsignaling is essential for vascular morphogenesis in mice. Genes Dev.2000,14(11):1343-1352.
[135]Koo BK, Lim HS, Song R, Yoon MJ, Yoon KJ, Moon JS, Kim YW, Kwon MC, YooKW, Kong MP, Lee J, Chitnis AB, Kim CH, Kong YY. Mind bomb1is essential forgenerating functional Notch ligands to activate Notch. Development.2005,132(15):3459-3470.
[136]Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M. The Notch target genesHey1and Hey2are required for embryonic vascular development. Genes Dev.2004,18(8):901-911.
[137]Duarte A, Hirashima M, Benedito R, Trindade A, Diniz P, Bekman E, Costa L,Henrique D, Rossant J.Dosage-sensitive requirement for mouse Dll4in arterydevelopment. Genes Dev.2004,18(20):2474-2478.
[138]Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, Fairman RM, Velazquez OC,Herlyn M. Regulation of Notch1and Dll4by vascular endothelial growth factor inarterial endothelial cells: implications for modulating arteriogenesis andangiogenesis. Mol Cell Biol.2003,23(1):14-25.
[139]Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A,Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C. VEGF guides angiogenicsprouting utilizing endothelial tip cell filopodia. J Cell Biol.2003,161(6):1163-1177.
[140]Yang C, Guo Y, Jadlowiec CC, Li X, Lv W, Model LS, Collins MJ, Kondo Y, Muto A,Shu C, Dardik A. Vascular endothelial growth factor-A inhibits EphB4andstimulates delta-like ligand4expression in adult endothelial cells. J Surg Res.2013,S0022-4804(13)00010-3.
[141] S rensen I, Adams RH, Gossler A. DLL1-mediated Notch activation regulatesendothelial identity in mouse fetal arteries. Blood.2009,113:5680-5688.
[142] Pajcini KV, Speck NA, Pear WS. Notch signaling in mammalian hematopoietic stemcells. Leukemia.2011,25(10):1525-1532.
[143] Gering M, Patient R. Notch signalling and haematopoietic stem cell formationduring embryogenesis. J Cell Physiol.2010,222(1):11-16.
[144]Kumano K, Chiba S, Kunisato A, Sata M, Saito T, Nakagami-Yamaguchi E,Yamaguchi T, Masuda S, Shimizu K, Takahashi T, Ogawa S, Hamada Y, Hirai H.Notch1but not Notch2is essential for generating hematopoietic stem cells fromendothelial cells. Immunity.2003,18(5):699-711.
[145]Tang Y, Bai H, Urs S, Wang Z, Liaw L. Notch1activation in embryonic VE-cadherinpopulations selectively blocks hematopoietic stem cell generation and fetal liverhematopoiesis.Transgenic Res.2013,22(2):403-410.
[146]Yoon MJ, Koo BK, Song R, Jeong HW, Shin J, Kim YW, Kong YY, Suh PG. Mindbomb-1is essential for intraembryonic hematopoiesis in the aortic endothelium andthe subaortic patches. Mol Cell Biol.2008,28(15):4794-4804.
[147]Robert-Moreno A, Espinosa L, Sanchez MJ, de la Pompa JL, Bigas A. The notchpathway positively regulates programmed cell death during erythroid differentiation.Leukemia.2007,21(7):1496-1503.
[148]Hadland BK, Huppert SS, Kanungo J, Xue Y, Jiang R, Gridley T, Conlon RA, ChengAM, Kopan R, Longmore GD. A requirement for Notch1distinguishes2phases ofdefinitive hematopoiesis during development. Blood.2004,104(10):3097-3105.
[149]Liu H, Zhang W, Kennard S, Caldwell RB, Lilly B. Notch3is critical for properangiogenesis and mural cell investment.Circ Res.2010,107(7):860-870.
[150]McCright B, Gao X, Shen L, Lozier J, Lan Y, Maguire M, Herzlinger D, WeinmasterG, Jiang R, Gridley T.Defects in development of the kidney, heart and eyevasculature in mice homozygous for a hypomorphic Notch2mutation.Development.2001,128(4):491-502.
[151] Guiu J, Shimizu R, D'Altri T, Fraser ST, Hatakeyama J, Bresnick EH, Kageyama R,Dzierzak E, Yamamoto M, Espinosa L, Bigas A. Hes repressors are essentialregulators of hematopoietic stem cell development downstream of Notch signaling. JExp Med.2013,210(1):71-84.
[152]Challen GA, Goodell MA. Runx1isoforms show differential expression patternsduring hematopoietic development but have similar functional effects in adulthematopoietic stem cells. Exp Hematol.2010,38(5):403-416.
[153]Link KA, Chou FS, Mulloy JC.Core binding factor at the crossroads: determining thefate of the HSC. J Cell Physiol.2010,222(1):50-56.
[154] North T, Gu TL, Stacy T, Wang Q, Howard L, Binder M, Marín-Padilla M, SpeckNA. Cbfa2is required for the formation of intra-aortic hematopoietic clusters.Development.1999,126(11):2563-2575.
[155]Burns CE, Traver D, Mayhall E, Shepard JL, Zon LI. Hematopoietic stem cell fate isestablished by the Notch-Runx pathway. Genes Dev.2005,19:2331-2342.
[156]Bigas A, D'Altri T, Espinosa L. The Notch pathway in hematopoietic stem cells. CurrTop Microbiol Immunol.2012,360:1-18.
[157]Bigas A, Espinosa L. Hematopoietic stem cells: to be or Notch to be.Blood.2012,119(14):3226-335.
[158]Varnum-Finney B, Xu L, Brashem-Stein C, Nourigat C, Flowers D, Bakkour S, PearWS, Bernstein ID.Pluripotent, cytokine-dependent, hematopoietic stem cells areimmortalized by constitutive Notch1signaling. Nat Med.2000,6:1278-1281.
[159]Stier S, Cheng T, Dombkowski D, Carlesso N, Scadden DT. Notch1activationincreases hematopoietic stem cell self-renewal in vivo and favors lymphoid overmyeloid lineage outcome. Blood.2002,99:2369-2378.
[160]Vercauteren SM, Sutherland HJ. Constitutively active Notch4promotes early humanhematopoietic progenitor cell maintenance while inhibiting differentiation andcauses lymphoid abnormalities in vivo. Blood.2004,104:2315-2322.
[161]Maillard I, Koch U, Dumortier A, Shestova O, Xu L, Sai H, Pross SE, Aster JC,Bhandoola A, Radtke F, Pear WS.Canonical notch signaling is dispensable for themaintenance of adult hematopoietic stem cells. Cell Stem Cell.2008,2:356-366.
[162]Varnum-Finney B, Halasz LM, Sun M, Gridley T, Radtke F, Bernstein ID.Notch2governs the rate of generation of mouse long-and short-term repopulating stem cells.J Clin Invest.2011,121:1207-1216.
[163] Kunisato A, Chiba S, Nakagami-Yamaguchi E, Kumano K, Saito T, Masuda S,Yamaguchi T, Osawa M, Kageyama R, Nakauchi H, Nishikawa M, Hirai H. HES-1preserves purified hematopoietic stem cells ex vivo and accumulates side populationcells in vivo. Blood.2003,101:1777-1783.
[164] Duncan AW, Rattis FM, DiMascio LN, Congdon KL, Pazianos G, Zhao C, Yoon K,Cook JM, Willert K, Gaiano N, Reya T. Integration of Notch and Wnt signaling inhematopoietic stem cell maintenance.Nat Immunol.2005,6:314-322.
[165]Wu M, Kwon HY, Rattis F, Blum J, Zhao C, Ashkenazi R, Jackson TL, Gaiano N,Oliver T, Reya T. Imaging hematopoietic precursor division in real time. Cell StemCell.2007,1:541-554.
[166]Karanu FN, Murdoch B, Gallacher L, Wu DM, Koremoto M, Sakano S, Bhatia M.The notch ligand jagged-1represents a novel growth factor of human hematopoieticstem cells. J Exp Med.2000,192:1365-1372.
[167]Varnum-Finney B, Brashem-Stein C, Bernstein ID. Combined effects of Notchsignaling and cytokines induce a multiple log increase in precursors with lymphoidand myeloid reconstituting ability. Blood.2003,101:1784-1789.
[168]Ohishi K, Varnum-Finney B, Bernstein ID. Delta-1enhances marrow and thymusrepopulating ability of human CD34(+)CD38(-) cord blood cells. J Clin Invest.2002,110:1165-1174.
[169] Dallas MH, Varnum-Finney B, Delaney C, Kato K, Bernstein ID. Density of theNotch ligand Delta1determines generation of B and T cell precursors fromhematopoietic stem cells. J Exp Med.2005,201:1361-1366.
[170]Delaney C, Varnum-Finney B, Aoyama K, Brashem-Stein C, Bernstein ID.Dose-dependent effects of the Notch ligand Delta1on ex vivo differentiation and invivo marrow repopulating ability of cord blood cells. Blood.2005,106:2693-2699.
[171]Myers J, Huang Y, Wei L, Yan Q, Huang A, Zhou L. Fucose-deficient hematopoieticstem cells have decreased self-renewal and aberrant marrow niche occupancy.Transfusion.2010,50:2660-2669.
[172] Zhou L, Li LW, Yan Q, Petryniak B, Man Y, Su C, Shim J,Chervin S, Lowe JB.Notch-dependent control of myelopoiesis is regulated by fucosylation. Blood.2008,112:308-319.
[173]Hooper AT, Butler JM, Nolan DJ, Kranz A, Iida K, Kobayashi M, Kopp HG, Shido K,Petit I, Yanger K, James D, Witte L, Zhu Z, Wu Y, Pytowski B, Rosenwaks Z, MittalV, Sato TN, Rafii S. Engraftment and reconstitution of hematopoiesis is dependenton VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell StemCell.2009,4:263-274.
[174]Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT,Seandel M, Shido K, White IA, Kobayashi M, Witte L, May C, Shawber C, KimuraY, Kitajewski J, Rosenwaks Z, Bernstein ID, Rafii S.Endothelial cells are essentialfor the self-renewal and repopulation of Notch-dependent hematopoietic stem cells.Cell Stem Cell.2010,6:251-264.
[175]Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cellsmaintain haematopoietic stem cells. Nature.2012,481(7382):457-462.
[176]Butler JM, Gars EJ, James DJ, Nolan DJ, Scandura JM, Rafii S. Development of avascular niche platform for expansion of repopulating human cord blood stem andprogenitor cells. Blood.2012,120(6):1344-1347.
[177] Walasek MA, van Os R, de Haan G. Hematopoietic stem cell expansion: challengesand opportunities. Ann N Y Acad Sci.2012,1266:138-150.
[178] Suzuki T, Chiba S. Notch signaling in hematopoietic stem cells. Int J Hematol.2005,82(4):285-294.
[179]Ohishi K, Katayama N, Shiku H, Varnum-Finney B, Bernstein ID. Notch signallingin hematopoiesis. Semin Cell Dev Biol.2003,14(2):143-150.
[180] Ohishi K, Varnum-Finney B, Bernstein ID. The notch pathway: modulation of cellfate decisions in hematopoiesis. Int J Hematol.2002,75(5):449-459.
[181]Varnum-Finney B, Wu L, Yu M, Brashem-Stein C, Staats S, Flowers D, Griffin JD,Bernstein ID. Immobilization of Notch ligand, Delta-1, is required for induction ofnotch signaling. J Cell Sci.2000,113:4313-4318.
[182] Parks AL, Klueg KM, Stout JR, Muskavitch MA. Ligand endocytosis drivesreceptor dissociation and activation in the Notch pathway. Development.2000,127(7):1373-1385.
[183]Laje P, Zoltick PW, Flake AW. SLAM-enriched hematopoietic stem cells maintainlong-term repopulating capacity after lentiviral transduction using an abbreviatedprotocol. Gene Ther.2010,17(3):412-418.
[184]Iwasaki H, Arai F, Kubota Y, Dahl M, Suda T. Endothelial protein Creceptor-expressing hematopoietic stem cells reside in the perisinusoidal niche infetal liver. Blood.2010,116(4):544-553.
[185]Balazs AB, Fabian AJ, Esmon CT, Mulligan RC.Endothelial protein C receptor(CD201) explicitly identifies hematopoietic stem cells in murine bone marrow.Blood.2006,107(6):2317-2321.
[186]Mikkola HK, Klintman J, Yang H, Hock H, Schlaeger TM, Fujiwara Y, Orkin SH.Haematopoietic stem cells retain long-term repopulating activity and multipotencyin the absence of stem-cell leukaemia SCL/tal-1gene. Nature.2003,421(6922):547-551.
[187] Chen MJ, Yokomizo T, Zeigler BM, Dzierzak E, Speck NA.Runx1is required forthe endothelial to haematopoietic cell transition but not thereafter. Nature.2009,457(7231):887-891.
[188]Tsai FY, Orkin SH.Transcription factor GATA-2is required for proliferation/survivalof early hematopoietic cells and mast cell formation, but not for erythroid andmyeloid terminal differentiation. Blood.1997,89(10):3636-3643.
[189]Kitajima K, Masuhara M, Era T, Enver T, Nakano T.GATA-2and GATA-2/ERdisplay opposing activities in the development and differentiation of bloodprogenitors. EMBO J.2002,21(12):3060-3069.
[190]Lowell CA, Niwa M, Soriano P, Varmus HE. Deficiency of the Hck and Src tyrosinekinases results in extreme levels of extramedullary hematopoiesis.Blood.1996,87(5):1780-1792.
[191]Wang ZQ, Ovitt C, Grigoriadis AE, M hle-Steinlein U, Rüther U, Wagner EF.Boneand haematopoietic defects in mice lacking c-fos. Nature.1992,360(6406):741-745.