骨髓间充质干细胞不同移植方式治疗大鼠糖尿病足溃疡的疗效观察
|
摘要
【目的】：评价异体骨髓间充质干细胞(bone marrow-derived mesenchymal stem cells, BM-MSCs)经创缘皮下和小腿肌肉内移植对大鼠糖尿病足溃疡(diabetic foot ulcers, DFUs)的治疗效果以及可能的生物学机制。
【方法】：大鼠糖尿病经空腹腹腔注射链脲佐菌素(streptozotocin, STZ)诱导,而后在其双后足背做一大小为3mm×7mm矩形全层皮肤缺损制成大鼠DFUs模型。全骨髓贴壁法体外培养大鼠BM-MSCs至第三代,经4,6-联脒-2-苯基吲哚(4,6-diamino-2-phenylindole,DAPI)体外标记。48只雄性Wistar大鼠随机分成A组(正常大鼠对照组,n=12)、B组(DFUs对照组,n=12)、C组(BM-MSCs创缘皮下移植组,n=12)和D组(BM-MSCs小腿肌肉移植组,n=12)。于移植后第2、5、8、11天评估各组大鼠的创面愈合率,冰冻切片观察DAPI标记的BM-MSCs在创伤组织中的示踪,HE染色法检测早期肉芽组织的厚度,免疫组化法检测CD31和Ki-67在创伤组织中的表达,血管内皮细胞生长因子(vascular endothelial growth factor, VEGF)的表达采用ELISA和RT-PCR检测。
【结果】：A组的创面愈合最快,第11天D组的创面愈合率大于C组(P<0.05)。第2天和第5天的冰冻切片上D组的荧光强度及区域大小均大于C组。而HE染色显示第5天D组的肉芽厚于C组。CD31的免疫组化显示第5天和第8天D组的平均小血管数目均多于C组(分别为P＜0.05和P＜0.05),而Ki-67的免疫组化结果显示各时间点C、D两组之间无差异,但分别与B组比较均有显著差异(P＜0.01)。ELISA和RT-PCR的结果均显示第8天和第11天D组的VEGF表达水平高于C组(分别为P＜0.05和P＜0.001),而B组的表达水平始终最低。
[结论】：BM-MSCs经两种移植方式均促进了大鼠DFUs的愈合,但小腿肌肉内移植比创缘皮下移植更显著地促进了肉芽组织的形成、细胞增殖、血管化及VEGF持续稳定的表达,从而加速了上皮化进程,即加快了创面的愈合。因此,小腿肌肉内移植BM-MSCs治疗大鼠DFUs疗效更优。
Objective:To evaluate if transplantation of allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) could enhance the wound healing in rat diabetic foot ulcers (DFUs) and the therapeutic effect between intramuscular transplantation and subcutaneous transplantation and to investigate the possible underlying biological mechanisms involved in this process.
Methods:An animal model of rat DFUs was established by injecting intraperitoneally with streptozotocin (STZ) and making a rectangular wound (3mmx7mm) on both sides of the hind feet of diabetic rats. BM-MSCs from male Wistar rats were cultured by the whole bone marrow adherence method until the third generation and were labeled with4,6-diamino-2-phenylindole (DAPI) in vitro. Forty-eight male Wistar rats were randomly divided into four groups:group A, non-diabetic rats with PBS treatment; group B, DFUs rats with PBS treatment; group C, DFUs rats with subcutaneous transplantation of BM-MSCs; and group D, DFUs with intramuscular transplantation of BM-MSCs. On days2,5,8and11post-transplantation, trace of DAPI labeled-BM-MSCs in wound tissues were detected on frozen sections and the effect of wound healing was evaluated by the rate of wound contraction, granulation tissue formation and the expression of CD31, Ki-67as well as vascular endothelial growth factor (VEGF) in wound tissues.
Results:Compared to rats in group B (DFUs controls), which were treated with PBS, transplantation of BM-MSCs significantly promoted the wound healing in groups C and D. While the group D demonstrated better efficacy than group C, in which a higher rate of wound contraction (on day11, P<0.05), stronger and broader area of fluorescence on days2and5, thicker granulation tissue on day5, more CD31-positive small blood vessels (on day5and day8, P<0.05and P<0.05respectively), and a significantly higher expression of VEGF (on day8and day11, P<0.05and P<0.001respectively) were detected. While there were no differences on cellular proliferation at every time point between group C and group D. But there are significant differences when the two groups compared with group B respectively at every time point (P<0.01).
Conclusions:Both the subcutaneous transplantation and intramuscular transplantation of BM-MSCs promoted the wound healing of DFUs in rats. But the intramuscular transplantation of BM-MSCs significantly enhanced the wound healing of DFUs in rats. This effect is associated with better granulation tissue formation, increased angiogenesis, and higher lever of cellular proliferation and VEGF expressions in wound tissues.
【方法】：大鼠糖尿病经空腹腹腔注射链脲佐菌素(streptozotocin, STZ)诱导,而后在其双后足背做一大小为3mm×7mm矩形全层皮肤缺损制成大鼠DFUs模型。全骨髓贴壁法体外培养大鼠BM-MSCs至第三代,经4,6-联脒-2-苯基吲哚(4,6-diamino-2-phenylindole,DAPI)体外标记。48只雄性Wistar大鼠随机分成A组(正常大鼠对照组,n=12)、B组(DFUs对照组,n=12)、C组(BM-MSCs创缘皮下移植组,n=12)和D组(BM-MSCs小腿肌肉移植组,n=12)。于移植后第2、5、8、11天评估各组大鼠的创面愈合率,冰冻切片观察DAPI标记的BM-MSCs在创伤组织中的示踪,HE染色法检测早期肉芽组织的厚度,免疫组化法检测CD31和Ki-67在创伤组织中的表达,血管内皮细胞生长因子(vascular endothelial growth factor, VEGF)的表达采用ELISA和RT-PCR检测。
【结果】：A组的创面愈合最快,第11天D组的创面愈合率大于C组(P<0.05)。第2天和第5天的冰冻切片上D组的荧光强度及区域大小均大于C组。而HE染色显示第5天D组的肉芽厚于C组。CD31的免疫组化显示第5天和第8天D组的平均小血管数目均多于C组(分别为P＜0.05和P＜0.05),而Ki-67的免疫组化结果显示各时间点C、D两组之间无差异,但分别与B组比较均有显著差异(P＜0.01)。ELISA和RT-PCR的结果均显示第8天和第11天D组的VEGF表达水平高于C组(分别为P＜0.05和P＜0.001),而B组的表达水平始终最低。
[结论】：BM-MSCs经两种移植方式均促进了大鼠DFUs的愈合,但小腿肌肉内移植比创缘皮下移植更显著地促进了肉芽组织的形成、细胞增殖、血管化及VEGF持续稳定的表达,从而加速了上皮化进程,即加快了创面的愈合。因此,小腿肌肉内移植BM-MSCs治疗大鼠DFUs疗效更优。
Objective:To evaluate if transplantation of allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) could enhance the wound healing in rat diabetic foot ulcers (DFUs) and the therapeutic effect between intramuscular transplantation and subcutaneous transplantation and to investigate the possible underlying biological mechanisms involved in this process.
Methods:An animal model of rat DFUs was established by injecting intraperitoneally with streptozotocin (STZ) and making a rectangular wound (3mmx7mm) on both sides of the hind feet of diabetic rats. BM-MSCs from male Wistar rats were cultured by the whole bone marrow adherence method until the third generation and were labeled with4,6-diamino-2-phenylindole (DAPI) in vitro. Forty-eight male Wistar rats were randomly divided into four groups:group A, non-diabetic rats with PBS treatment; group B, DFUs rats with PBS treatment; group C, DFUs rats with subcutaneous transplantation of BM-MSCs; and group D, DFUs with intramuscular transplantation of BM-MSCs. On days2,5,8and11post-transplantation, trace of DAPI labeled-BM-MSCs in wound tissues were detected on frozen sections and the effect of wound healing was evaluated by the rate of wound contraction, granulation tissue formation and the expression of CD31, Ki-67as well as vascular endothelial growth factor (VEGF) in wound tissues.
Results:Compared to rats in group B (DFUs controls), which were treated with PBS, transplantation of BM-MSCs significantly promoted the wound healing in groups C and D. While the group D demonstrated better efficacy than group C, in which a higher rate of wound contraction (on day11, P<0.05), stronger and broader area of fluorescence on days2and5, thicker granulation tissue on day5, more CD31-positive small blood vessels (on day5and day8, P<0.05and P<0.05respectively), and a significantly higher expression of VEGF (on day8and day11, P<0.05and P<0.001respectively) were detected. While there were no differences on cellular proliferation at every time point between group C and group D. But there are significant differences when the two groups compared with group B respectively at every time point (P<0.01).
Conclusions:Both the subcutaneous transplantation and intramuscular transplantation of BM-MSCs promoted the wound healing of DFUs in rats. But the intramuscular transplantation of BM-MSCs significantly enhanced the wound healing of DFUs in rats. This effect is associated with better granulation tissue formation, increased angiogenesis, and higher lever of cellular proliferation and VEGF expressions in wound tissues.
引文
[1]Chun Q, Liang LS. Stem cell research, repairing, and regeneration medicine. Int J Low Extrem Wounds 2012,11(3):180-183.
[2]Ren G, Chen X, Dong F, Li W, Ren X, Zhang Y, Shi Y. Concise review:mesenchymal stem cells and translational medicine:emerging issues. Stem cells translational medicine 2012, 1(1):51-58.
[3]Maxson S, Lopez EA, Yoo D, Danilkovitch-Miagkova A, Leroux MA. Concise review:role of mesenchymal stem cells in wound repair. Stem cells translational medicine 2012, 1(2):142-149.
[4]Jiang XY, Lu DB, Chen B. Progress in stem cell therapy for the diabetic foot. Diabetes Res Clin Pract 2012,97(1):43-50.
[5]Li H, Fu X. Mechanisms of action of mesenchymal stem cells in cutaneous wound repair and regeneration. Cell and tissue research 2012,348(3):371-377.
[6]Kwon DS, Gao X, Liu YB, Dulchavsky DS, Danyluk AL, Bansal M, Chopp M, McIntosh K, Arbab AS, Dulchavsky SA et al. Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats. Int Wound J 2008,5(3):453-463.
[7]Blumberg SN, Berger A, Hwang L, Pastar I, Warren SM, Chen W. The role of stem cells in the treatment of diabetic foot ulcers. Diabetes Res Clin Pract 2012,96(1):1-9.
[8]Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem cells (Dayton, Ohio) 2007,25(10):2648-2659.
[9]Monteiro-Soares M, Boyko EJ, Ribeiro J, Ribeiro I, Dinis-Ribeiro M. Risk stratification systems for diabetic foot ulcers:a systematic review. Diabetologia 2011,54(5):1190-1199.
[10]Silva MB, Skare TL. Musculoskeletal disorders in diabetes mellitus. Revista brasileira de reumatologia 2012,52(4):601-609.
[11]Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA 2005,293(2):217-228.
[12]Consensus Development Conference on Diabetic Foot Wound Care.7-8 April 1999, Boston, Massachusetts. American Diabetes Association. J Am Podiatr Med Assoc 1999, 89(9):475-483.
[13]Larsson J, Agardh CD, Apelqvist J, Stenstrom A. Long-term prognosis after healed amputation in patients with diabetes. Clinical orthopaedics and related research 1998(350):149-158.
[14]Faglia E, Clerici G, Clerissi J, Gabrielli L, Losa S, Mantero M, Caminiti M, Curci V, Lupattelli T, Morabito A. Early and five-year amputation and survival rate of diabetic patients with critical limb ischemia:data of a cohort study of 564 patients. Eur J Vasc Endovasc Surg 2006,32(5):484-490.
[15]Miyajima S, Shirai A, Yamamoto S, Okada N, Matsushita T. Risk factors for major limb amputations in diabetic foot gangrene patients. Diabetes Res Clin Pract 2006,71(3):272-279.
[16]Falanga V. Wound healing and its impairment in the diabetic foot. Lancet 2005, 366(9498):1736-1743.
[17]Lev-Tov H, Li CS, Dahle S, Isseroff RR. Cellular versus acellular matrix devices in treatment of diabetic foot ulcers:study protocol for a comparative efficacy randomized controlled trial. Trials 2013,14:8.
[18]Chen JS, Wong VW, Gurtner GC. Therapeutic potential of bone marrow-derived mesenchymal stem cells for cutaneous wound healing. Frontiers in immunology 2012,3:192.
[19]Behm B, Babilas P, Landthaler M, Schreml S. Cytokines, chemokines and growth factors in wound healing. Journal of the European Academy of Dermatology and Venereology:JEADV 2012,26(7):812-820.
[20]Lobmann R, Schultz G, Lehnert H. [Molecular fundamentals of wound healing in diabetic foot syndrome]. Med Klin (Munich) 2003,98(5):292-301.
[21]Cha J, Falanga V. Stem cells in cutaneous wound healing. Clin Dermatol 2007,25(1):73-78.
[22]Gabr H, Hedayet A, Imam U, Nasser M. Limb salvage using intramuscular injection of unfractionated autologous bone marrow mononuclear cells in critical limb ischemia:a prospective pilot clinical trial. Experimental and clinical transplantation:official journal of the Middle East Society for Organ Transplantation 2011,9(3):197-202.
[23]Humpert PM, Bartsch U, Konrade I, Hammes HP, Morcos M, Kasper M, Bierhaus A, Nawroth PP. Locally applied mononuclear bone marrow cells restore angiogenesis and promote wound healing in a type 2 diabetic patient. Experimental and clinical endocrinology & diabetes:official journal, German Society of Endocrinology [and] German Diabetes Association 2005,113(9):538-540.
[24]Rogers LC, Bevilacqua NJ, Armstrong DG. The use of marrow-derived stem cells to accelerate healing in chronic wounds. Int Wound J 2008,5(1):20-25.
[25]Ruiz-Salmeron R, de la Cuesta-Diaz A, Constantino-Bermejo M, Perez-Camacho I, Marcos-Sanchez F, Hmadcha A, Soria B. ANGIOGRAPHIC DEMONSTRATION OF NEOANGIOGENESIS AFTER INTRA-ARTERIAL INFUSION OF AUTOLOGOUS BONE MARROW MONONUCLEAR CELLS IN DIABETIC PATIENTS WITH CRITICAL LIMB ISCHAEMIA. Cell Transplant 2011.
[26]Tark KC, Hong JW, Kim YS, Hahn SB, Lee WJ, Lew DH. Effects of human cord blood mesenchymal stem cells on cutaneous wound healing in leprdb mice. Ann Plast Surg 2010, 65(6):565-572.
[27]Leiker M, Suzuki G, Iyer VS, Canty JM, Jr., Lee T. Assessment of a nuclear affinity labeling method for tracking implanted mesenchymal stem cells. Cell Transplant 2008,17(8):911-922.
[28]Rich J, Lee JC. The pathogenesis of Staphylococcus aureus infection in the diabetic NOD mouse. Diabetes 2005,54(10):2904-2910.
[29]Lau TW, Sahota DS, Lau CH, Chan CM, Lam FC, Ho YY, Fung KP, Lau CB, Leung PC. An in vivo investigation on the wound-healing effect of two medicinal herbs using an animal model with foot ulcer. Eur Surg Res 2008,41(l):15-23.
[30]Elsharawy MA, Naim M, Greish S. Human CD34+ stem cells promote healing of diabetic foot ulcers in rats. Interact Cardiovasc Thorac Surg 2012,14(3):288-293.
[31]Chiquetti Junior A, Rodrigues MA, Delfino VD. An experimental model for the study of drug effects on cutaneous healing. Acta Cir Bras 2007,22(4):317-321.
[32]Carvalho Pde T, Silva IS, Reis FA, Perreira DM, Aydos RD. Influence of ingaalp laser (660nm) on the healing of skin wounds in diabetic rats. Acta Cir Bras 2010,25(1):71-79.
[33]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001,25(4):402-408.
[34]Friedenstein AJ, Piatetzky S,Ⅱ, Petrakova KV. Osteogenesis in transplants of bone marrow cells. Journal of embryology and experimental morphology 1966,16(3):381-390.
[35]Wu Y, Wang J, Scott PG, Tredget EE. Bone marrow-derived stem cells in wound healing:a review. Wound Repair Regen 2007,15 Suppl 1:S 18-26.
[36]Polisetti N, Chaitanya VG, Babu PP, Vemuganti GK. Isolation, characterization and differentiation potential of rat bone marrow stromal cells. Neurology India 2010, 58(2):201-208.
[37]Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006,8(4):315-317.
[38]Ocarino NM, Bozzi A, Pereira RD, Breyner NM, Silva VL, Castanheira P, Goes AM, Serakides R. Behavior of mesenchymal stem cells stained with 4', 6-diamidino-2-phenylindole dihydrochloride (DAPI) in osteogenic and non osteogenic cultures. Biocell:official journal of the Sociedades Latinoamericanas de Microscopia Electronica et al 2008,32(2):175-183.
[39]Williamson DH, Fennell DJ. Apparent dispersive replication of yeast mitochondrial DNA as revealed by density labelling experiments. Molecular & general genetics:MGG 1974, 131(3):193-207.
[40]Tang J, Xie Q, Pan G, Wang J, Wang M. Mesenchymal stem cells participate in angiogenesis and improve heart function in rat model of myocardial ischemia with reperfusion. European journal of cardio-thoracic surgery:official journal of the European Association for Cardio-thoracic Surgery 2006,30(2):353-361.
[41]Niu LL, Zheng M, Cao F, Xie C, Li HM, Yue W, Gao YH, Bai CX, Zhu SJ, Pei XT. [Migration and differentiation of exogenous rat mesenchymal stem cells engrafted into normal and injured hearts of rats]. Zhonghua yi xue za zhi 2004,84(1):38-42.
[42]Castanheira P, Torquetti LT, Magalhas DR, Nehemy MB, Goes AM. DAPI diffusion after intravitreal injection of mesenchymal stem cells in the injured retina of rats. Cell Transplant 2009,18(4):423-431.
[43]Chung JK, Park TK, Ohn YH, Park SK, Hong DS. Modulation of retinal wound healing by systemically administered bone marrow-derived mesenchymal stem cells. Korean journal of ophthalmology:KJO 2011,25(4):268-274.
[44]Kuo YR, Wang CT, Cheng JT, Wang FS, Chiang YC, Wang CJ. Bone marrow-derived mesenchymal stem cells enhanced diabetic wound healing through recruitment of tissue regeneration in a rat model of streptozotocin-induced diabetes. Plast Reconstr Surg 2011, 128(4):872-880.
[45]Hanson SE, Bentz ML, Hematti P. Mesenchymal stem cell therapy for nonhealing cutaneous wounds. Plast Reconstr Surg 2010,125(2):510-516.
[46]Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H. Mesenchymal stem ceils are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. Journal of immunology (Baltimore, Md:1950) 2008, 180(4):2581-2587.
[47]Hamou C, Callaghan MJ, Thangarajah H, Chang E, Chang El, Grogan RH, Paterno J, Vial IN, Jazayeri L, Gurtner GC. Mesenchymal stem cells can participate in ischemic neovascularization. Plast Reconstr Surg2009,123(2 Suppl):45S-55S.
[48]Wu Y, Zhao RC, Tredget EE. Concise review:bone marrow-derived stem/progenitor cells in cutaneous repair and regeneration. Stem cells (Dayton, Ohio) 2010,28(5):905-915.
[49]Zou Z, Zhang Y, Hao L, Wang F, Liu D, Su Y, Sun H. More insight into mesenchymal stem cells and their effects inside the body. Expert Opin Biol Ther 2010,10(2):215-230.
[50]Harris RG, Herzog EL, Bruscia EM, Grove JE, Van Arnam JS, Krause DS. Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 2004, 305(5680):90-93.
[51]Deng W, Han Q, Liao L, Li C, Ge W, Zhao Z, You S, Deng H, Murad F, Zhao RC. Engrafted bone marrow-derived flk-(1+) mesenchymal stem cells regenerate skin tissue. Tissue engineering 2005,11(1-2):110-119.
[52]Heng BC, Liu H, Cao T. Transplanted human embryonic stem cells as biological 'catalysts' for tissue repair and regeneration. Med Hypotheses 2005,64(6):1085-1088.
[53]Harding KG, Moore K, Phillips TJ. Wound chronicity and fibroblast senescence-implications for treatment. Int Wound J 2005,2(4):364-368.
[54]Campisi J. The role of cellular senescence in skin aging. The journal of investigative dermatology Symposium proceedings/the Society for Investigative Dermatology, Inc [and] European Society for Dermatological Research 1998,3(1):1-5.
[55]Hocking AM, Gibran NS:Mesenchymal stem cells.paracrine signaling and differentiation during cutaneous wound repair. Exp Cell Res 2010,316(14):2213-2219.
[56]Javazon EH, Keswani SG, Badillo AT, Crombleholme TM, Zoltick PW, Radu AP, Kozin ED, Beggs K, Malik AA, Flake AW. Enhanced epithelial gap closure and increased angiogenesis in wounds of diabetic mice treated with adult murine bone marrow stromal progenitor cells. Wound Repair Regen 2007,15(3):350-359.
[57]Lee EY, Xia Y, Kim WS, Kim MH, Kim TH, Kim KJ,Park BS, Sung JH. Hypoxia-enhanced wound-healing function of adipose-derived stem cells:increase in stem cell proliferation and up-regulation of VEGF and bFGF. Wound Repair Regen 2009,17(4):540-547.
[58]Borue X, Lee S, Grove J, Herzog EL, Harris R, Diflo T, Glusac E, Hyman K, Theise ND, Krause DS. Bone marrow-derived cells contribute to epithelial engraftment during wound healing. Am J Pathol 2004,165(5):1767-1772.
[59]Smith AN, Willis E, Chan VT, Muffley LA, Isik FF, Gibran NS, Hocking AM. Mesenchymal stem cells induce dermal fibroblast responses to injury. Exp Cell Res 2010,316(1):48-54.
[60]Kim WS, Park BS, Sung JH, Yang JM, Park SB, Kwak SJ, Park JS. Wound healing effect of adipose-derived stem cells:a critical role of secretory factors on human dermal fibroblasts. Journal of dermatological science 2007,48(1):15-24.
[61]Maderal AD, Vivas AC, Zwick TG, Kirsner RS. Diabetic foot ulcers:evaluation and management. Hospital practice (1995) 2012,40(3):102-115.
[62]Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med 2010,27(1):4-14.
[63]Guo S, Dipietro LA. Factors affecting wound healing. Journal of dental research 2010, 89(3):219-229.
[64]Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP, Brem H. The role of vascular endothelial growth factor in wound healing. J Surg Res 2009,153(2):347-358.
[65]Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res 2008,103(11):1204-1219.
[66]Stojadinovic O, Kodra A, Golinko M, Tomic-Canic M, Brem H:A novel, non-angiogenic mechanism of VEGF:Stimulation of keratinocyte and fibroblast migration. Wound Repair Regen 2007,15:A30.
[67]Drela E, Stankowska K, Kulwas A, Rosc D. Endothelial progenitor cells in diabetic foot syndrome. Advances in clinical and experimental medicine:official organ Wroclaw Medical University 2012,21(2):249-254.
[68]Marrotte EJ, Chen DD, Hakim JS, Chen AF. Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice. J Clin Invest 2010, 120(12):4207-4219.
[69]Lobmann R, Schultz G, Lehnert H. Proteases and the diabetic foot syndrome:mechanisms and therapeutic implications. Diabetes Care 2005,28(2):461-471.
[70]Discher DE, Mooney DJ, Zandstra PW. Growth factors, matrices, and forces combine and control stem cells. Science 2009,324(5935):1673-1677.
[71]Mishra PJ, Humeniuk R, Medina DJ, Alexe G, Mesirov JP, Ganesan S, Glod JW, Banerjee D. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer research 2008,68(11):4331-4339.
[72]Tolar J, Nauta AJ, Osborn MJ, Panoskaltsis Mortari A, McElmurry RT, Bell S, Xia L, Zhou N, Riddle M, Schroeder TM et al. Sarcoma derived from cultured mesenchymal stem cells. Stem cells (Dayton, Ohio) 2007,25(2):371-379.
[1]Wild S, Roglic G, Green A, et al. Global prevalence of diabetes:estimates for the year 2000 and projections for 2030[J]. Diabetes Care,2004,27(5):1047-1053.
[2]Singh N, Armstrong DG, Lipsky BA. Preventing Foot Ulcers in Patients With Diabetes[J]. JAMA:The Journal of the American Medical Association,2005,293(2):217-228.
[3]Lobmann R, Schultz G, Lehnert H. [Molecular fundamentals of wound healing in diabetic foot syndrome][J]. Med Klin (Munich),2003,98(5):292-301.
[4]Fernandez-Montequin JI, Valenzuela-Silva CM, Diaz OG et al. Intra-lesional injections of recombinant human epidermal growth factor promote granulation and healing in advanced diabetic foot ulcers:multicenter, randomised, placebo-controlled, double-blind study[J]. International Wound Journal,2009,6(6):432-443.
[5]Rathur HM, Boulton AJM. The neuropathic diabetic foot[J]. Nat Clin Pract End Met,2007, 3(1):14-25.
[6]Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes—a review[J]. Diabetic Medicine,2010,27(1):4-14.
[7]Falanga V. Wound healing and its impairment in the diabetic foot[J]. The Lancet,2005, 366(9498):1736-1743.
[8]Barrientos S, Stojadinovic O, Golinko MS et al. PERSPECTIVE ARTICLE:Growth factors and cytokines in wound healing[J]. Wound Repair and Regeneration,2008,16(5):585-601.
[9]Klass BR, Grobbelaar AO, Rolfe KJ. Transforming growth factor betal signalling, wound healing and repair:a multifunctional cytokine with clinical implications for wound repair, a delicate balance[J]. Postgrad Med J,2009,85(999):9-14.
[10]Meckmongkol TT, Harmon R, McKeown-Longo P et al. The fibronectin synergy site modulates TGF-beta-dependent fibroblast contraction[J]. Biochem Biophys Res Commun, 2007,360(4):709-714.
[11]Crowe MJ, Doetschman T, Greenhalgh DG. Delayed wound healing in immunodeficient TGF-beta 1 knockout mice [J]. J Invest Dermatol,2000,115(1):3-11.
[12]Jude EB, Blakytny R, Bulmer J et al. Transforming growth factor-beta 1,2,3 and receptor type Ⅰ and Ⅱ in diabetic foot ulcers[J]. Diabet Med,2002,19(6):440-447.
[13]Chesnoy S, Lee PY, Huang L. Intradermal injection of transforming growth factor-betal gene enhances wound healing in genetically diabetic mice[J]. Pharm Res,2003,20(3):345-350.
[14]Wang H, Chard T. IGFs and IGF-binding proteins in the regulation of human ovarian and endometrial function[J]. Journal of endocrinology,1999,161(1):1.
[15]Todorovic V, Pesko P, Micev M et al. Insulin-like growth factor-I in wound healing of rat skin[J]. Regulatory Peptides,2008,150(1-3):7-13.
[16]Velander P, Theopold C, Hirsch T et al. Impaired wound healing in an acute diabetic pig model and the effects of local hyperglycemia[J]. Wound Repair Regen,2008,16(2):288-293.
[17]Hirsch T, Spielmann M, Velander P et al. Insulin-like growth factor-1 gene therapy and cell transplantation in diabetic wounds[J]. The Journal of Gene Medicine,2008, 10(11):1247-1252.
[18]Lee JA, Conejero JA, Mason JM et al. Lentiviral Transfection with the PDGF-B Gene Improves Diabetic Wound Healing[J]. Plast Reconstr Surg,2005,116(2):532-538.
[19]Mulder G, Tallis AJ, Marshall VT et al. Treatment of nonhealing diabetic foot ulcers with a platelet-derived growth factor gene-activated matrix (GAM501):Results of a Phase 1/2 trial[J]. Wound Repair and Regeneration,2009,17(6):772-779.
[20]Nakamura T, Nawa K, Ichihara A. Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats* 1[J]. Biochemical and Biophysical Research Communications,1984,122(3):1450-1459.
[21]Conway K, Price P, Harding KG et al. The molecular and clinical impact of hepatocyte growth factor, its receptor, activators, and inhibitors in wound healing[J]. Wound Repair Regen,2006,14(1):2-10.
[22]Ha X, Yin Q, Dong F et al. [Study on bone marrow mesenchymal stem cells transfected with adenovirus hepatocyte growth factor gene promoting wounds repair in diabetic rats][J]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi,2010,24(12):1520-1524.
[23]Morishita R, Makino H, Aoki M et al. Phase Ⅰ/Ⅱa clinical trial of therapeutic angiogenesis using hepatocyte growth factor gene transfer to treat critical limb ischemia[J]. Arterioscler Thromb Vase Biol,2011,31(3):713-720.
[24]Ornitz DM, Itoh N. Fibroblast growth factors[J]. Genome Biol,2001,2(3):3005.3001-3005.
[25]Maulik N. NV1FGF, a pCOR plasmid-based angiogenic gene therapy for the treatment of intermittent claudication and critical limb ischemia[J]. Curr Opin Investig Drugs,2009, 10(3):259-268.
[26]Ferraro B, Cruz YL, Baldwin M et al. Increased perfusion and angiogenesis in a hindlimb ischemia model with plasmid FGF-2 delivered by noninvasive electroporation[J]. Gene Ther, 2010,17(6):763-769.
[27]Raab S, Plate KH. Different networks, common growth factors:shared growth factors and receptors of the vascular and the nervous system[J]. Acta Neuropathol,2007,113(6):607-626.
[28]Rivard A, Silver M, Chen D et al. Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF[J]. Am J Pathol,1999,154(2):355.
[29]Ropper AH, Gorson K.C, Gooch CL, et al. Vascular endothelial growth factor gene transfer for diabetic polyneuropathy:A randomized, double-blinded trial[J]. Annals of Neurology, 2009,65(4):386-393.
[30]Kastrup J, Jorgensen E, Fuchs S et al. A randomised, double-blind, placebo-controlled, multicentre study of the safety and efficacy of BIOBYPASS (AdGVVEGF121.10NH) gene therapy in patients with refractory advanced coronary artery disease:the NOVA trial[J]. EuroIntervention,2011,6(7):813-818.
[31]Kalil RA, Salles FB, Giusti, II et al. VEGF gene therapy for angiogenesis in refractory angina: phase Ⅰ/Ⅱ clinical trial[J]. Rev Bras Cir Cardiovasc,2010,25(3):311-321.
[32]Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor[J]. Endocr Rev, 1997,18(1):4-25.
[33]Koyama T, Hackl F, Aflaki P et al. A New Technique of Ex Vivo Gene Delivery of VEGF to Wounds Using Genetically Modified Skin Particles Promotes Wound Angiogenesis[J]. Journal of the American College of Surgeons,2011,212(3):340-348.
[34]Leong-Poi H, Kuliszewski MA, Lekas M et al. Therapeutic arteriogenesis by ultrasound-mediated VEGF 165 plasmid gene delivery to chronically ischemic skeletal muscle[J]. Circ Res,2007,101(3):295-303.
[35]Jazwa A, Kucharzewska P, Leja J et al. Combined vascular endothelial growth factor-A and fibroblast growth factor 4 gene transfer improves wound healing in diabetic mice[J]. Genetic Vaccines and Therapy,2010,8(1):6.
[2]Ren G, Chen X, Dong F, Li W, Ren X, Zhang Y, Shi Y. Concise review:mesenchymal stem cells and translational medicine:emerging issues. Stem cells translational medicine 2012, 1(1):51-58.
[3]Maxson S, Lopez EA, Yoo D, Danilkovitch-Miagkova A, Leroux MA. Concise review:role of mesenchymal stem cells in wound repair. Stem cells translational medicine 2012, 1(2):142-149.
[4]Jiang XY, Lu DB, Chen B. Progress in stem cell therapy for the diabetic foot. Diabetes Res Clin Pract 2012,97(1):43-50.
[5]Li H, Fu X. Mechanisms of action of mesenchymal stem cells in cutaneous wound repair and regeneration. Cell and tissue research 2012,348(3):371-377.
[6]Kwon DS, Gao X, Liu YB, Dulchavsky DS, Danyluk AL, Bansal M, Chopp M, McIntosh K, Arbab AS, Dulchavsky SA et al. Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats. Int Wound J 2008,5(3):453-463.
[7]Blumberg SN, Berger A, Hwang L, Pastar I, Warren SM, Chen W. The role of stem cells in the treatment of diabetic foot ulcers. Diabetes Res Clin Pract 2012,96(1):1-9.
[8]Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem cells (Dayton, Ohio) 2007,25(10):2648-2659.
[9]Monteiro-Soares M, Boyko EJ, Ribeiro J, Ribeiro I, Dinis-Ribeiro M. Risk stratification systems for diabetic foot ulcers:a systematic review. Diabetologia 2011,54(5):1190-1199.
[10]Silva MB, Skare TL. Musculoskeletal disorders in diabetes mellitus. Revista brasileira de reumatologia 2012,52(4):601-609.
[11]Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA 2005,293(2):217-228.
[12]Consensus Development Conference on Diabetic Foot Wound Care.7-8 April 1999, Boston, Massachusetts. American Diabetes Association. J Am Podiatr Med Assoc 1999, 89(9):475-483.
[13]Larsson J, Agardh CD, Apelqvist J, Stenstrom A. Long-term prognosis after healed amputation in patients with diabetes. Clinical orthopaedics and related research 1998(350):149-158.
[14]Faglia E, Clerici G, Clerissi J, Gabrielli L, Losa S, Mantero M, Caminiti M, Curci V, Lupattelli T, Morabito A. Early and five-year amputation and survival rate of diabetic patients with critical limb ischemia:data of a cohort study of 564 patients. Eur J Vasc Endovasc Surg 2006,32(5):484-490.
[15]Miyajima S, Shirai A, Yamamoto S, Okada N, Matsushita T. Risk factors for major limb amputations in diabetic foot gangrene patients. Diabetes Res Clin Pract 2006,71(3):272-279.
[16]Falanga V. Wound healing and its impairment in the diabetic foot. Lancet 2005, 366(9498):1736-1743.
[17]Lev-Tov H, Li CS, Dahle S, Isseroff RR. Cellular versus acellular matrix devices in treatment of diabetic foot ulcers:study protocol for a comparative efficacy randomized controlled trial. Trials 2013,14:8.
[18]Chen JS, Wong VW, Gurtner GC. Therapeutic potential of bone marrow-derived mesenchymal stem cells for cutaneous wound healing. Frontiers in immunology 2012,3:192.
[19]Behm B, Babilas P, Landthaler M, Schreml S. Cytokines, chemokines and growth factors in wound healing. Journal of the European Academy of Dermatology and Venereology:JEADV 2012,26(7):812-820.
[20]Lobmann R, Schultz G, Lehnert H. [Molecular fundamentals of wound healing in diabetic foot syndrome]. Med Klin (Munich) 2003,98(5):292-301.
[21]Cha J, Falanga V. Stem cells in cutaneous wound healing. Clin Dermatol 2007,25(1):73-78.
[22]Gabr H, Hedayet A, Imam U, Nasser M. Limb salvage using intramuscular injection of unfractionated autologous bone marrow mononuclear cells in critical limb ischemia:a prospective pilot clinical trial. Experimental and clinical transplantation:official journal of the Middle East Society for Organ Transplantation 2011,9(3):197-202.
[23]Humpert PM, Bartsch U, Konrade I, Hammes HP, Morcos M, Kasper M, Bierhaus A, Nawroth PP. Locally applied mononuclear bone marrow cells restore angiogenesis and promote wound healing in a type 2 diabetic patient. Experimental and clinical endocrinology & diabetes:official journal, German Society of Endocrinology [and] German Diabetes Association 2005,113(9):538-540.
[24]Rogers LC, Bevilacqua NJ, Armstrong DG. The use of marrow-derived stem cells to accelerate healing in chronic wounds. Int Wound J 2008,5(1):20-25.
[25]Ruiz-Salmeron R, de la Cuesta-Diaz A, Constantino-Bermejo M, Perez-Camacho I, Marcos-Sanchez F, Hmadcha A, Soria B. ANGIOGRAPHIC DEMONSTRATION OF NEOANGIOGENESIS AFTER INTRA-ARTERIAL INFUSION OF AUTOLOGOUS BONE MARROW MONONUCLEAR CELLS IN DIABETIC PATIENTS WITH CRITICAL LIMB ISCHAEMIA. Cell Transplant 2011.
[26]Tark KC, Hong JW, Kim YS, Hahn SB, Lee WJ, Lew DH. Effects of human cord blood mesenchymal stem cells on cutaneous wound healing in leprdb mice. Ann Plast Surg 2010, 65(6):565-572.
[27]Leiker M, Suzuki G, Iyer VS, Canty JM, Jr., Lee T. Assessment of a nuclear affinity labeling method for tracking implanted mesenchymal stem cells. Cell Transplant 2008,17(8):911-922.
[28]Rich J, Lee JC. The pathogenesis of Staphylococcus aureus infection in the diabetic NOD mouse. Diabetes 2005,54(10):2904-2910.
[29]Lau TW, Sahota DS, Lau CH, Chan CM, Lam FC, Ho YY, Fung KP, Lau CB, Leung PC. An in vivo investigation on the wound-healing effect of two medicinal herbs using an animal model with foot ulcer. Eur Surg Res 2008,41(l):15-23.
[30]Elsharawy MA, Naim M, Greish S. Human CD34+ stem cells promote healing of diabetic foot ulcers in rats. Interact Cardiovasc Thorac Surg 2012,14(3):288-293.
[31]Chiquetti Junior A, Rodrigues MA, Delfino VD. An experimental model for the study of drug effects on cutaneous healing. Acta Cir Bras 2007,22(4):317-321.
[32]Carvalho Pde T, Silva IS, Reis FA, Perreira DM, Aydos RD. Influence of ingaalp laser (660nm) on the healing of skin wounds in diabetic rats. Acta Cir Bras 2010,25(1):71-79.
[33]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001,25(4):402-408.
[34]Friedenstein AJ, Piatetzky S,Ⅱ, Petrakova KV. Osteogenesis in transplants of bone marrow cells. Journal of embryology and experimental morphology 1966,16(3):381-390.
[35]Wu Y, Wang J, Scott PG, Tredget EE. Bone marrow-derived stem cells in wound healing:a review. Wound Repair Regen 2007,15 Suppl 1:S 18-26.
[36]Polisetti N, Chaitanya VG, Babu PP, Vemuganti GK. Isolation, characterization and differentiation potential of rat bone marrow stromal cells. Neurology India 2010, 58(2):201-208.
[37]Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006,8(4):315-317.
[38]Ocarino NM, Bozzi A, Pereira RD, Breyner NM, Silva VL, Castanheira P, Goes AM, Serakides R. Behavior of mesenchymal stem cells stained with 4', 6-diamidino-2-phenylindole dihydrochloride (DAPI) in osteogenic and non osteogenic cultures. Biocell:official journal of the Sociedades Latinoamericanas de Microscopia Electronica et al 2008,32(2):175-183.
[39]Williamson DH, Fennell DJ. Apparent dispersive replication of yeast mitochondrial DNA as revealed by density labelling experiments. Molecular & general genetics:MGG 1974, 131(3):193-207.
[40]Tang J, Xie Q, Pan G, Wang J, Wang M. Mesenchymal stem cells participate in angiogenesis and improve heart function in rat model of myocardial ischemia with reperfusion. European journal of cardio-thoracic surgery:official journal of the European Association for Cardio-thoracic Surgery 2006,30(2):353-361.
[41]Niu LL, Zheng M, Cao F, Xie C, Li HM, Yue W, Gao YH, Bai CX, Zhu SJ, Pei XT. [Migration and differentiation of exogenous rat mesenchymal stem cells engrafted into normal and injured hearts of rats]. Zhonghua yi xue za zhi 2004,84(1):38-42.
[42]Castanheira P, Torquetti LT, Magalhas DR, Nehemy MB, Goes AM. DAPI diffusion after intravitreal injection of mesenchymal stem cells in the injured retina of rats. Cell Transplant 2009,18(4):423-431.
[43]Chung JK, Park TK, Ohn YH, Park SK, Hong DS. Modulation of retinal wound healing by systemically administered bone marrow-derived mesenchymal stem cells. Korean journal of ophthalmology:KJO 2011,25(4):268-274.
[44]Kuo YR, Wang CT, Cheng JT, Wang FS, Chiang YC, Wang CJ. Bone marrow-derived mesenchymal stem cells enhanced diabetic wound healing through recruitment of tissue regeneration in a rat model of streptozotocin-induced diabetes. Plast Reconstr Surg 2011, 128(4):872-880.
[45]Hanson SE, Bentz ML, Hematti P. Mesenchymal stem cell therapy for nonhealing cutaneous wounds. Plast Reconstr Surg 2010,125(2):510-516.
[46]Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H. Mesenchymal stem ceils are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. Journal of immunology (Baltimore, Md:1950) 2008, 180(4):2581-2587.
[47]Hamou C, Callaghan MJ, Thangarajah H, Chang E, Chang El, Grogan RH, Paterno J, Vial IN, Jazayeri L, Gurtner GC. Mesenchymal stem cells can participate in ischemic neovascularization. Plast Reconstr Surg2009,123(2 Suppl):45S-55S.
[48]Wu Y, Zhao RC, Tredget EE. Concise review:bone marrow-derived stem/progenitor cells in cutaneous repair and regeneration. Stem cells (Dayton, Ohio) 2010,28(5):905-915.
[49]Zou Z, Zhang Y, Hao L, Wang F, Liu D, Su Y, Sun H. More insight into mesenchymal stem cells and their effects inside the body. Expert Opin Biol Ther 2010,10(2):215-230.
[50]Harris RG, Herzog EL, Bruscia EM, Grove JE, Van Arnam JS, Krause DS. Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 2004, 305(5680):90-93.
[51]Deng W, Han Q, Liao L, Li C, Ge W, Zhao Z, You S, Deng H, Murad F, Zhao RC. Engrafted bone marrow-derived flk-(1+) mesenchymal stem cells regenerate skin tissue. Tissue engineering 2005,11(1-2):110-119.
[52]Heng BC, Liu H, Cao T. Transplanted human embryonic stem cells as biological 'catalysts' for tissue repair and regeneration. Med Hypotheses 2005,64(6):1085-1088.
[53]Harding KG, Moore K, Phillips TJ. Wound chronicity and fibroblast senescence-implications for treatment. Int Wound J 2005,2(4):364-368.
[54]Campisi J. The role of cellular senescence in skin aging. The journal of investigative dermatology Symposium proceedings/the Society for Investigative Dermatology, Inc [and] European Society for Dermatological Research 1998,3(1):1-5.
[55]Hocking AM, Gibran NS:Mesenchymal stem cells.paracrine signaling and differentiation during cutaneous wound repair. Exp Cell Res 2010,316(14):2213-2219.
[56]Javazon EH, Keswani SG, Badillo AT, Crombleholme TM, Zoltick PW, Radu AP, Kozin ED, Beggs K, Malik AA, Flake AW. Enhanced epithelial gap closure and increased angiogenesis in wounds of diabetic mice treated with adult murine bone marrow stromal progenitor cells. Wound Repair Regen 2007,15(3):350-359.
[57]Lee EY, Xia Y, Kim WS, Kim MH, Kim TH, Kim KJ,Park BS, Sung JH. Hypoxia-enhanced wound-healing function of adipose-derived stem cells:increase in stem cell proliferation and up-regulation of VEGF and bFGF. Wound Repair Regen 2009,17(4):540-547.
[58]Borue X, Lee S, Grove J, Herzog EL, Harris R, Diflo T, Glusac E, Hyman K, Theise ND, Krause DS. Bone marrow-derived cells contribute to epithelial engraftment during wound healing. Am J Pathol 2004,165(5):1767-1772.
[59]Smith AN, Willis E, Chan VT, Muffley LA, Isik FF, Gibran NS, Hocking AM. Mesenchymal stem cells induce dermal fibroblast responses to injury. Exp Cell Res 2010,316(1):48-54.
[60]Kim WS, Park BS, Sung JH, Yang JM, Park SB, Kwak SJ, Park JS. Wound healing effect of adipose-derived stem cells:a critical role of secretory factors on human dermal fibroblasts. Journal of dermatological science 2007,48(1):15-24.
[61]Maderal AD, Vivas AC, Zwick TG, Kirsner RS. Diabetic foot ulcers:evaluation and management. Hospital practice (1995) 2012,40(3):102-115.
[62]Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med 2010,27(1):4-14.
[63]Guo S, Dipietro LA. Factors affecting wound healing. Journal of dental research 2010, 89(3):219-229.
[64]Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP, Brem H. The role of vascular endothelial growth factor in wound healing. J Surg Res 2009,153(2):347-358.
[65]Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res 2008,103(11):1204-1219.
[66]Stojadinovic O, Kodra A, Golinko M, Tomic-Canic M, Brem H:A novel, non-angiogenic mechanism of VEGF:Stimulation of keratinocyte and fibroblast migration. Wound Repair Regen 2007,15:A30.
[67]Drela E, Stankowska K, Kulwas A, Rosc D. Endothelial progenitor cells in diabetic foot syndrome. Advances in clinical and experimental medicine:official organ Wroclaw Medical University 2012,21(2):249-254.
[68]Marrotte EJ, Chen DD, Hakim JS, Chen AF. Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice. J Clin Invest 2010, 120(12):4207-4219.
[69]Lobmann R, Schultz G, Lehnert H. Proteases and the diabetic foot syndrome:mechanisms and therapeutic implications. Diabetes Care 2005,28(2):461-471.
[70]Discher DE, Mooney DJ, Zandstra PW. Growth factors, matrices, and forces combine and control stem cells. Science 2009,324(5935):1673-1677.
[71]Mishra PJ, Humeniuk R, Medina DJ, Alexe G, Mesirov JP, Ganesan S, Glod JW, Banerjee D. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer research 2008,68(11):4331-4339.
[72]Tolar J, Nauta AJ, Osborn MJ, Panoskaltsis Mortari A, McElmurry RT, Bell S, Xia L, Zhou N, Riddle M, Schroeder TM et al. Sarcoma derived from cultured mesenchymal stem cells. Stem cells (Dayton, Ohio) 2007,25(2):371-379.
[1]Wild S, Roglic G, Green A, et al. Global prevalence of diabetes:estimates for the year 2000 and projections for 2030[J]. Diabetes Care,2004,27(5):1047-1053.
[2]Singh N, Armstrong DG, Lipsky BA. Preventing Foot Ulcers in Patients With Diabetes[J]. JAMA:The Journal of the American Medical Association,2005,293(2):217-228.
[3]Lobmann R, Schultz G, Lehnert H. [Molecular fundamentals of wound healing in diabetic foot syndrome][J]. Med Klin (Munich),2003,98(5):292-301.
[4]Fernandez-Montequin JI, Valenzuela-Silva CM, Diaz OG et al. Intra-lesional injections of recombinant human epidermal growth factor promote granulation and healing in advanced diabetic foot ulcers:multicenter, randomised, placebo-controlled, double-blind study[J]. International Wound Journal,2009,6(6):432-443.
[5]Rathur HM, Boulton AJM. The neuropathic diabetic foot[J]. Nat Clin Pract End Met,2007, 3(1):14-25.
[6]Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes—a review[J]. Diabetic Medicine,2010,27(1):4-14.
[7]Falanga V. Wound healing and its impairment in the diabetic foot[J]. The Lancet,2005, 366(9498):1736-1743.
[8]Barrientos S, Stojadinovic O, Golinko MS et al. PERSPECTIVE ARTICLE:Growth factors and cytokines in wound healing[J]. Wound Repair and Regeneration,2008,16(5):585-601.
[9]Klass BR, Grobbelaar AO, Rolfe KJ. Transforming growth factor betal signalling, wound healing and repair:a multifunctional cytokine with clinical implications for wound repair, a delicate balance[J]. Postgrad Med J,2009,85(999):9-14.
[10]Meckmongkol TT, Harmon R, McKeown-Longo P et al. The fibronectin synergy site modulates TGF-beta-dependent fibroblast contraction[J]. Biochem Biophys Res Commun, 2007,360(4):709-714.
[11]Crowe MJ, Doetschman T, Greenhalgh DG. Delayed wound healing in immunodeficient TGF-beta 1 knockout mice [J]. J Invest Dermatol,2000,115(1):3-11.
[12]Jude EB, Blakytny R, Bulmer J et al. Transforming growth factor-beta 1,2,3 and receptor type Ⅰ and Ⅱ in diabetic foot ulcers[J]. Diabet Med,2002,19(6):440-447.
[13]Chesnoy S, Lee PY, Huang L. Intradermal injection of transforming growth factor-betal gene enhances wound healing in genetically diabetic mice[J]. Pharm Res,2003,20(3):345-350.
[14]Wang H, Chard T. IGFs and IGF-binding proteins in the regulation of human ovarian and endometrial function[J]. Journal of endocrinology,1999,161(1):1.
[15]Todorovic V, Pesko P, Micev M et al. Insulin-like growth factor-I in wound healing of rat skin[J]. Regulatory Peptides,2008,150(1-3):7-13.
[16]Velander P, Theopold C, Hirsch T et al. Impaired wound healing in an acute diabetic pig model and the effects of local hyperglycemia[J]. Wound Repair Regen,2008,16(2):288-293.
[17]Hirsch T, Spielmann M, Velander P et al. Insulin-like growth factor-1 gene therapy and cell transplantation in diabetic wounds[J]. The Journal of Gene Medicine,2008, 10(11):1247-1252.
[18]Lee JA, Conejero JA, Mason JM et al. Lentiviral Transfection with the PDGF-B Gene Improves Diabetic Wound Healing[J]. Plast Reconstr Surg,2005,116(2):532-538.
[19]Mulder G, Tallis AJ, Marshall VT et al. Treatment of nonhealing diabetic foot ulcers with a platelet-derived growth factor gene-activated matrix (GAM501):Results of a Phase 1/2 trial[J]. Wound Repair and Regeneration,2009,17(6):772-779.
[20]Nakamura T, Nawa K, Ichihara A. Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats* 1[J]. Biochemical and Biophysical Research Communications,1984,122(3):1450-1459.
[21]Conway K, Price P, Harding KG et al. The molecular and clinical impact of hepatocyte growth factor, its receptor, activators, and inhibitors in wound healing[J]. Wound Repair Regen,2006,14(1):2-10.
[22]Ha X, Yin Q, Dong F et al. [Study on bone marrow mesenchymal stem cells transfected with adenovirus hepatocyte growth factor gene promoting wounds repair in diabetic rats][J]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi,2010,24(12):1520-1524.
[23]Morishita R, Makino H, Aoki M et al. Phase Ⅰ/Ⅱa clinical trial of therapeutic angiogenesis using hepatocyte growth factor gene transfer to treat critical limb ischemia[J]. Arterioscler Thromb Vase Biol,2011,31(3):713-720.
[24]Ornitz DM, Itoh N. Fibroblast growth factors[J]. Genome Biol,2001,2(3):3005.3001-3005.
[25]Maulik N. NV1FGF, a pCOR plasmid-based angiogenic gene therapy for the treatment of intermittent claudication and critical limb ischemia[J]. Curr Opin Investig Drugs,2009, 10(3):259-268.
[26]Ferraro B, Cruz YL, Baldwin M et al. Increased perfusion and angiogenesis in a hindlimb ischemia model with plasmid FGF-2 delivered by noninvasive electroporation[J]. Gene Ther, 2010,17(6):763-769.
[27]Raab S, Plate KH. Different networks, common growth factors:shared growth factors and receptors of the vascular and the nervous system[J]. Acta Neuropathol,2007,113(6):607-626.
[28]Rivard A, Silver M, Chen D et al. Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF[J]. Am J Pathol,1999,154(2):355.
[29]Ropper AH, Gorson K.C, Gooch CL, et al. Vascular endothelial growth factor gene transfer for diabetic polyneuropathy:A randomized, double-blinded trial[J]. Annals of Neurology, 2009,65(4):386-393.
[30]Kastrup J, Jorgensen E, Fuchs S et al. A randomised, double-blind, placebo-controlled, multicentre study of the safety and efficacy of BIOBYPASS (AdGVVEGF121.10NH) gene therapy in patients with refractory advanced coronary artery disease:the NOVA trial[J]. EuroIntervention,2011,6(7):813-818.
[31]Kalil RA, Salles FB, Giusti, II et al. VEGF gene therapy for angiogenesis in refractory angina: phase Ⅰ/Ⅱ clinical trial[J]. Rev Bras Cir Cardiovasc,2010,25(3):311-321.
[32]Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor[J]. Endocr Rev, 1997,18(1):4-25.
[33]Koyama T, Hackl F, Aflaki P et al. A New Technique of Ex Vivo Gene Delivery of VEGF to Wounds Using Genetically Modified Skin Particles Promotes Wound Angiogenesis[J]. Journal of the American College of Surgeons,2011,212(3):340-348.
[34]Leong-Poi H, Kuliszewski MA, Lekas M et al. Therapeutic arteriogenesis by ultrasound-mediated VEGF 165 plasmid gene delivery to chronically ischemic skeletal muscle[J]. Circ Res,2007,101(3):295-303.
[35]Jazwa A, Kucharzewska P, Leja J et al. Combined vascular endothelial growth factor-A and fibroblast growth factor 4 gene transfer improves wound healing in diabetic mice[J]. Genetic Vaccines and Therapy,2010,8(1):6.