干细胞治疗皮肤缺损:是未来研究的重点
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摘要
背景:干细胞作为一种具备自我更新和多向分化能力的特殊细胞,有潜力应用于治疗皮肤缺损,并因其来源丰富、低免疫原性、能够分化为多个谱系细胞等特性,有望克服现有治疗手段的局限性并发展为新的治疗手段。目的:阐明不同干细胞治疗皮肤缺损的机制及研究热点,寻求一种能够符合临床需求的细胞来源。?方法:由第一作者检索1998至2018年PubMed数据库收录的与干细胞治疗皮肤缺损相关的文献。检索词为"stem cell,skin defect,wound healing",按纳入、排除标准最后共纳入文献63篇进行综述。结果与结论:干细胞在皮肤缺损治疗上具有巨大潜力,其不仅可以重建损伤的组织,而且可以通过免疫调节及血管新生促进伤口愈合。间充质干细胞与其他种类干细胞相比拥有更大优势,近年来间充质干细胞应用于皮肤缺损修复的研究取得了令人满意的结果,成为目前最理想的细胞来源,也是未来研究的重点。
BACKGROUND: As a kind of special cells capable of self-renewal and multidirectional differentiation, stem cells have the potential in the treatment of skin defects. Owing to their rich sources, low immunogenicity, and multipotent differentiation ability, stem cells are expected to overcome the limitations of existing therapies and develop into new therapies.OBJECTIVE: To overview the mechanisms and research focus of different stem cells in the treatment of skin defects, and to seek a kind of stem cells that meet clinical needs.METHODS: The first author retrieved the databases of PubMed for relevant articles about stem cell-based therapies for skin defects published from 1998 to 2018. The key words were "stem cell, skin defect, wound healing" in English. In accordance with the inclusion and exclusion criteria, 63 articles were finally reviewed.?RESULTS AND CONCLUSION: Stem cells have tremendous potential in the treatment of skin defects. These cells cannot only regenerate damaged tissue, but also promote the wound healing by immunomodulation and angiogenesis. Compared with other types of stem cells, mesenchymal stem cells have more advantages. Studies concerning mesenchymal stem cells have achieved satisfactory results in recent years. Mesenchymal stem cells have become the most ideal cells for the treatment of skin defects, and they are also the focus of future research.
BACKGROUND: As a kind of special cells capable of self-renewal and multidirectional differentiation, stem cells have the potential in the treatment of skin defects. Owing to their rich sources, low immunogenicity, and multipotent differentiation ability, stem cells are expected to overcome the limitations of existing therapies and develop into new therapies.OBJECTIVE: To overview the mechanisms and research focus of different stem cells in the treatment of skin defects, and to seek a kind of stem cells that meet clinical needs.METHODS: The first author retrieved the databases of PubMed for relevant articles about stem cell-based therapies for skin defects published from 1998 to 2018. The key words were "stem cell, skin defect, wound healing" in English. In accordance with the inclusion and exclusion criteria, 63 articles were finally reviewed.?RESULTS AND CONCLUSION: Stem cells have tremendous potential in the treatment of skin defects. These cells cannot only regenerate damaged tissue, but also promote the wound healing by immunomodulation and angiogenesis. Compared with other types of stem cells, mesenchymal stem cells have more advantages. Studies concerning mesenchymal stem cells have achieved satisfactory results in recent years. Mesenchymal stem cells have become the most ideal cells for the treatment of skin defects, and they are also the focus of future research.
引文
[1]Hanson SE,Bentz ML,Hematti P.Mesenchymal stem cell therapy for nonhealing cutaneous wounds.Plast Reconstr Surg.2010;125(2):510-516.
[2]Levy V,Lindon C,Zheng Y,et al.Epidermal stem cells arise from the hair follicle after wounding.FASEB J.2007;21(7):1358-1366.
[3]Langton AK,Herrick SE,Headon DJ.An extended epidermal response heals cutaneous wounds in the absence of a hair follicle stem cell contribution.J Invest Dermatol.2008;128(5):1311-1318.
[4]Jiménez F,Garde C,Poblet E,et al.A pilot clinical study of hair grafting in chronic leg ulcers.Wound Repair Regen.2012;20(6):806-814.
[5]Navsaria HA,Ojeh NO,Moiemen N,et al.Reepithelialization of a full-thickness burn from stem cells of hair follicles micrografted into a tissue-engineered dermal template(Integra).Plast Reconstr Surg.2004;113(3):978-981.
[6]Ackermann M,Pabst AM,Houdek JP,et al.Priming with proangiogenic growth factors and endothelial progenitor cells improves revascularization in linear diabetic wounds.Int J Mol Med.2014;33(4):833-839.
[7]Chopra H,Hung MK,Kwong DL,et al.Insights into Endothelial Progenitor Cells:Origin,Classification,Potentials,and Prospects.Stem Cells Int.2018;2018:9847015.
[8]De Rosa L,Carulli S,Cocchiarella F,et al.Long-term stability and safety of transgenic cultured epidermal stem cells in gene therapy of junctional epidermolysis bullosa.Stem Cell Reports.2013;2(1):1-8.
[9]Wang X,Wang X,Liu J,et al.Hair Follicle and Sebaceous Gland De Novo Regeneration With Cultured Epidermal Stem Cells and Skin-Derived Precursors.Stem Cells Transl Med.2016;5(12):1695-1706.
[10]Jackson CJ,T?nseth KA,Utheim TP.Cultured epidermal stem cells in regenerative medicine.Stem Cell Res Ther.2017;8(1):155.
[11]Aberdam D.Derivation of keratinocyte progenitor cells and skin formation from embryonic stem cells.Int J Dev Biol.2004;48(2-3):203-206.
[12]Suh HN,Han HJ.Sonic hedgehog increases the skin wound-healing ability of mouse embryonic stem cells through the microRNA 200 family.Br J Pharmacol.2015;172(3):815-828.
[13]Uluer ET,Vatansever HS,Aydede H,et al.Keratinocytes derived from embryonic stem cells induce wound healing in mice.Biotech Histochem.2018:1-10.
[14]Jeong D,Jo W,Yoon J,et al.Nanovesicles engineered from ES cells for enhanced cell proliferation.Biomaterials.2014;35(34):9302-9310.
[15]Guha P,Morgan JW,Mostoslavsky G,et al.Lack of Immune Response to Differentiated Cells Derived from Syngeneic Induced Pluripotent Stem Cells.Cell Stem Cell.2017;21(1):144-148.
[16]Lu Q,Yu M,Shen C,et al.Negligible immunogenicity of induced pluripotent stem cells derived from human skin fibroblasts.PLoS One.2014;9(12):e114949.
[17]Sugiyama-Nakagiri Y,Fujimura T,Moriwaki S.Induction of Skin-Derived Precursor Cells from Human Induced Pluripotent Stem Cells.PLoS One.2016;11(12):e0168451.
[18]Veraitch O,Mabuchi Y,Matsuzaki Y,et al.Induction of hair follicle dermal papilla cell properties in human induced pluripotent stem cell-derived multipotent LNGFR(+)THY-1(+)mesenchymal cells.Sci Rep.2017;7:42777.
[19]Hewitt KJ,Shamis Y,Hayman RB,et al.Epigenetic and phenotypic profile of fibroblasts derived from induced pluripotent stem cells.PLoS One.2011;6(2):e17128.
[20]Ohta S,Imaizumi Y,Akamatsu W,et al.Generation of human melanocytes from induced pluripotent stem cells.Methods Mol Biol.2013;989:193-215.
[21]Bilousova G,Chen J,Roop DR.Differentiation of mouse induced pluripotent stem cells into a multipotent keratinocyte lineage.J Invest Dermatol.2011;131(4):857-864.
[22]Zhang J,Guan J,Niu X,et al.Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis.J Transl Med.2015;13:49.
[23]Itoh M,Kiuru M,Cairo MS,et al.Generation of keratinocytes from normal and recessive dystrophic epidermolysis bullosa-induced pluripotent stem cells.Proc Natl Acad Sci US A.2011;108(21):8797-8802.
[24]Sebastiano V,Zhen HH,Haddad B,et al.Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa.Sci Transl Med.2014;6(264):264ra163.
[25]Okita K,Ichisaka T,Yamanaka S.Generation of germline-competent induced pluripotent stem cells.Nature.2007;448(7151):313-317.
[26]Nakagawa H,Akita S,Fukui M,et al.Human mesenchymal stem cells successfully improve skin-substitute wound healing.Br J Dermatol.2005;153(1):29-36.
[27]Hoogduijn MJ,Crop MJ,Peeters AM,et al.Human heart,spleen,and perirenal fat-derived mesenchymal stem cells have immunomodulatory capacities.Stem Cells Dev.2007;16(4):597-604.
[28]Yen BL,Huang HI,Chien CC,et al.Isolation of multipotent cells from human term placenta.Stem Cells.2005;23(1):3-9.
[29]Wang HS,Hung SC,Peng ST,et al.Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord.Stem Cells.2004;22(7):1330-1337.
[30]Falanga V,Iwamoto S,Chartier M,et al.Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds.Tissue Eng.2007;13(6):1299-1312.
[31]Dai Y,Li J,Li J,et al.Skin epithelial cells in mice from umbilical cord blood mesenchymal stem cells.Burns.2007;33(4):418-428.
[32]Lataillade JJ,Doucet C,Bey E,et al.New approach to radiation burn treatment by dosimetry-guided surgery combined with autologous mesenchymal stem cell therapy.Regen Med.2007;2(5):785-794.
[33]Grayson WL,Zhao F,Bunnell B,et al.Hypoxia enhances proliferation and tissue formation of human mesenchymal stem cells.Biochem Biophys Res Commun.2007;358(3):948-953.
[34]Kanji S,Das M,Aggarwal R,et al.Nanofiber-expanded human umbilical cord blood-derived CD34(+)cell therapy accelerates cutaneous wound closure in NOD/SCID mice.JCell Mol Med.2014;18(4):685-697.
[35]Kanji S,Das M,Aggarwal R,et al.Nanofiber-expanded human umbilical cord blood-derived CD34+cell therapy accelerates murine cutaneous wound closure by attenuating pro-inflammatory factors and secreting IL-10.Stem Cell Res.2014;12(1):275-288.
[36]Badiavas EV,Falanga V.Treatment of chronic wounds with bone marrow-derived cells.Arch Dermatol.2003;139(4):510-516.
[37]Dash NR,Dash SN,Routray P,et al.Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells.Rejuvenation Res.2009;12(5):359-366.
[38]Sarasúa JG,López SP,Viejo MA,et al.Treatment of pressure ulcers with autologous bone marrow nuclear cells in patients with spinal cord injury.J Spinal Cord Med.2011;34(3):301-307.
[39]Nuschke A.Activity of mesenchymal stem cells in therapies for chronic skin wound healing.Organogenesis.2014;10(1):29-37.
[40]Satija NK,Singh VK,Verma YK,et al.Mesenchymal stem cell-based therapy:a new paradigm in regenerative medicine.J Cell Mol Med.2009;13(11-12):4385-4402.
[41]Liu L,Yu Y,Hou Y,et al.Human umbilical cord mesenchymal stem cells transplantation promotes cutaneous wound healing of severe burned rats.PLoS One.2014;9(2):e88348.
[42]Smith AN,Willis E,Chan VT,et al.Mesenchymal stem cells induce dermal fibroblast responses to injury.Exp Cell Res.2010;316(1):48-54.
[43]Krasnodembskaya A,Song Y,Fang X,et al.Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37.Stem Cells.2010;28(12):2229-2238.
[44]Mei SH,Haitsma JJ,Dos Santos CC,et al.Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis.Am J Respir Crit Care Med.2010;182(8):1047-1057.
[45]Cho DI,Kim MR,Jeong HY,et al.Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages.Exp Mol Med.2014;46:e70.
[46]Zhang QZ,Su WR,Shi SH,et al.Human gingiva-derived mesenchymal stem cells elicit polarization of m2macrophages and enhance cutaneous wound healing.Stem Cells.2010;28(10):1856-1868.
[47]Wu Y,Huang S,Enhe J,et al.Bone marrow-derived mesenchymal stem cell attenuates skin fibrosis development in mice.Int Wound J.2014;11(6):701-710.
[48]Sasaki M,Abe R,Fujita Y,et al.Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type.J Immunol.2008;180(4):2581-2587.
[49]Kumamoto T,Shalhevet D,Matsue H,et al.Hair follicles serve as local reservoirs of skin mast cell precursors.Blood.2003;102(5):1654-1660.
[50]Lako M,Armstrong L,Cairns PM,et al.Hair follicle dermal cells repopulate the mouse haematopoietic system.J Cell Sci.2002;115(Pt 20):3967-3974.
[51]Altman AM,Matthias N,Yan Y,et al.Dermal matrix as a carrier for in vivo delivery of human adipose-derived stem cells.Biomaterials.2008;29(10):1431-1442.
[52]Gnecchi M,Zhang Z,Ni A,et al.Paracrine mechanisms in adult stem cell signaling and therapy.Circ Res.2008;103(11):1204-1219.
[53]Dougherty JA,Kumar N,Noor M,et al.Extracellular Vesicles Released by Human Induced-Pluripotent Stem Cell-Derived Cardiomyocytes Promote Angiogenesis.Front Physiol.2018;9:1794.
[54]Crisan M,Yap S,Casteilla L,et al.A perivascular origin for mesenchymal stem cells in multiple human organs.Cell Stem Cell.2008;3(3):301-313.
[55]Kwon DS,Gao X,Liu YB,et al.Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats.Int Wound J.2008;5(3):453-463.
[56]Wang Q,Yang Q,Wang Z,et al.Comparative analysis of human mesenchymal stem cells from fetal-bone marrow,adipose tissue,and Warton's jelly as sources of cell immunomodulatory therapy.Hum Vaccin Immunother.2016;12(1):85-96.
[57]Wu Y,Chen L,Scott PG,et al.Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis.Stem Cells.2007;25(10):2648-2659.
[58]Edwards N,Feliers D,Zhao Q,et al.An electrochemically deposited collagen wound matrix combined with adipose-derived stem cells improves cutaneous wound healing in a mouse model of type 2 diabetes.J Biomater Appl.2018;33(4):553-565.
[59]Samsonraj RM,Raghunath M,Nurcombe V,et al.Concise Review:Multifaceted Characterization of Human Mesenchymal Stem Cells for Use in Regenerative Medicine.Stem Cells Transl Med.2017;6(12):2173-2185.
[60]Shohara R,Yamamoto A,Takikawa S,et al.Mesenchymal stromal cells of human umbilical cord Wharton's jelly accelerate wound healing by paracrine mechanisms.Cytotherapy.2012;14(10):1171-1181.
[61]Arno AI,Amini-Nik S,Blit PH,et al.Human Wharton's jelly mesenchymal stem cells promote skin wound healing through paracrine signaling.Stem Cell Res Ther.2014;5(1):28.
[62]Chen L,Xu Y,Zhao J,et al.Conditioned medium from hypoxic bone marrow-derived mesenchymal stem cells enhances wound healing in mice.PLoS One.2014;9(4):e96161.
[63]Kordelas L,Rebmann V,Ludwig AK,et al.MSC-derived exosomes:a novel tool to treat therapy-refractory graft-versus-host disease.Leukemia.2014;28(4):970-973.
[2]Levy V,Lindon C,Zheng Y,et al.Epidermal stem cells arise from the hair follicle after wounding.FASEB J.2007;21(7):1358-1366.
[3]Langton AK,Herrick SE,Headon DJ.An extended epidermal response heals cutaneous wounds in the absence of a hair follicle stem cell contribution.J Invest Dermatol.2008;128(5):1311-1318.
[4]Jiménez F,Garde C,Poblet E,et al.A pilot clinical study of hair grafting in chronic leg ulcers.Wound Repair Regen.2012;20(6):806-814.
[5]Navsaria HA,Ojeh NO,Moiemen N,et al.Reepithelialization of a full-thickness burn from stem cells of hair follicles micrografted into a tissue-engineered dermal template(Integra).Plast Reconstr Surg.2004;113(3):978-981.
[6]Ackermann M,Pabst AM,Houdek JP,et al.Priming with proangiogenic growth factors and endothelial progenitor cells improves revascularization in linear diabetic wounds.Int J Mol Med.2014;33(4):833-839.
[7]Chopra H,Hung MK,Kwong DL,et al.Insights into Endothelial Progenitor Cells:Origin,Classification,Potentials,and Prospects.Stem Cells Int.2018;2018:9847015.
[8]De Rosa L,Carulli S,Cocchiarella F,et al.Long-term stability and safety of transgenic cultured epidermal stem cells in gene therapy of junctional epidermolysis bullosa.Stem Cell Reports.2013;2(1):1-8.
[9]Wang X,Wang X,Liu J,et al.Hair Follicle and Sebaceous Gland De Novo Regeneration With Cultured Epidermal Stem Cells and Skin-Derived Precursors.Stem Cells Transl Med.2016;5(12):1695-1706.
[10]Jackson CJ,T?nseth KA,Utheim TP.Cultured epidermal stem cells in regenerative medicine.Stem Cell Res Ther.2017;8(1):155.
[11]Aberdam D.Derivation of keratinocyte progenitor cells and skin formation from embryonic stem cells.Int J Dev Biol.2004;48(2-3):203-206.
[12]Suh HN,Han HJ.Sonic hedgehog increases the skin wound-healing ability of mouse embryonic stem cells through the microRNA 200 family.Br J Pharmacol.2015;172(3):815-828.
[13]Uluer ET,Vatansever HS,Aydede H,et al.Keratinocytes derived from embryonic stem cells induce wound healing in mice.Biotech Histochem.2018:1-10.
[14]Jeong D,Jo W,Yoon J,et al.Nanovesicles engineered from ES cells for enhanced cell proliferation.Biomaterials.2014;35(34):9302-9310.
[15]Guha P,Morgan JW,Mostoslavsky G,et al.Lack of Immune Response to Differentiated Cells Derived from Syngeneic Induced Pluripotent Stem Cells.Cell Stem Cell.2017;21(1):144-148.
[16]Lu Q,Yu M,Shen C,et al.Negligible immunogenicity of induced pluripotent stem cells derived from human skin fibroblasts.PLoS One.2014;9(12):e114949.
[17]Sugiyama-Nakagiri Y,Fujimura T,Moriwaki S.Induction of Skin-Derived Precursor Cells from Human Induced Pluripotent Stem Cells.PLoS One.2016;11(12):e0168451.
[18]Veraitch O,Mabuchi Y,Matsuzaki Y,et al.Induction of hair follicle dermal papilla cell properties in human induced pluripotent stem cell-derived multipotent LNGFR(+)THY-1(+)mesenchymal cells.Sci Rep.2017;7:42777.
[19]Hewitt KJ,Shamis Y,Hayman RB,et al.Epigenetic and phenotypic profile of fibroblasts derived from induced pluripotent stem cells.PLoS One.2011;6(2):e17128.
[20]Ohta S,Imaizumi Y,Akamatsu W,et al.Generation of human melanocytes from induced pluripotent stem cells.Methods Mol Biol.2013;989:193-215.
[21]Bilousova G,Chen J,Roop DR.Differentiation of mouse induced pluripotent stem cells into a multipotent keratinocyte lineage.J Invest Dermatol.2011;131(4):857-864.
[22]Zhang J,Guan J,Niu X,et al.Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis.J Transl Med.2015;13:49.
[23]Itoh M,Kiuru M,Cairo MS,et al.Generation of keratinocytes from normal and recessive dystrophic epidermolysis bullosa-induced pluripotent stem cells.Proc Natl Acad Sci US A.2011;108(21):8797-8802.
[24]Sebastiano V,Zhen HH,Haddad B,et al.Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa.Sci Transl Med.2014;6(264):264ra163.
[25]Okita K,Ichisaka T,Yamanaka S.Generation of germline-competent induced pluripotent stem cells.Nature.2007;448(7151):313-317.
[26]Nakagawa H,Akita S,Fukui M,et al.Human mesenchymal stem cells successfully improve skin-substitute wound healing.Br J Dermatol.2005;153(1):29-36.
[27]Hoogduijn MJ,Crop MJ,Peeters AM,et al.Human heart,spleen,and perirenal fat-derived mesenchymal stem cells have immunomodulatory capacities.Stem Cells Dev.2007;16(4):597-604.
[28]Yen BL,Huang HI,Chien CC,et al.Isolation of multipotent cells from human term placenta.Stem Cells.2005;23(1):3-9.
[29]Wang HS,Hung SC,Peng ST,et al.Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord.Stem Cells.2004;22(7):1330-1337.
[30]Falanga V,Iwamoto S,Chartier M,et al.Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds.Tissue Eng.2007;13(6):1299-1312.
[31]Dai Y,Li J,Li J,et al.Skin epithelial cells in mice from umbilical cord blood mesenchymal stem cells.Burns.2007;33(4):418-428.
[32]Lataillade JJ,Doucet C,Bey E,et al.New approach to radiation burn treatment by dosimetry-guided surgery combined with autologous mesenchymal stem cell therapy.Regen Med.2007;2(5):785-794.
[33]Grayson WL,Zhao F,Bunnell B,et al.Hypoxia enhances proliferation and tissue formation of human mesenchymal stem cells.Biochem Biophys Res Commun.2007;358(3):948-953.
[34]Kanji S,Das M,Aggarwal R,et al.Nanofiber-expanded human umbilical cord blood-derived CD34(+)cell therapy accelerates cutaneous wound closure in NOD/SCID mice.JCell Mol Med.2014;18(4):685-697.
[35]Kanji S,Das M,Aggarwal R,et al.Nanofiber-expanded human umbilical cord blood-derived CD34+cell therapy accelerates murine cutaneous wound closure by attenuating pro-inflammatory factors and secreting IL-10.Stem Cell Res.2014;12(1):275-288.
[36]Badiavas EV,Falanga V.Treatment of chronic wounds with bone marrow-derived cells.Arch Dermatol.2003;139(4):510-516.
[37]Dash NR,Dash SN,Routray P,et al.Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells.Rejuvenation Res.2009;12(5):359-366.
[38]Sarasúa JG,López SP,Viejo MA,et al.Treatment of pressure ulcers with autologous bone marrow nuclear cells in patients with spinal cord injury.J Spinal Cord Med.2011;34(3):301-307.
[39]Nuschke A.Activity of mesenchymal stem cells in therapies for chronic skin wound healing.Organogenesis.2014;10(1):29-37.
[40]Satija NK,Singh VK,Verma YK,et al.Mesenchymal stem cell-based therapy:a new paradigm in regenerative medicine.J Cell Mol Med.2009;13(11-12):4385-4402.
[41]Liu L,Yu Y,Hou Y,et al.Human umbilical cord mesenchymal stem cells transplantation promotes cutaneous wound healing of severe burned rats.PLoS One.2014;9(2):e88348.
[42]Smith AN,Willis E,Chan VT,et al.Mesenchymal stem cells induce dermal fibroblast responses to injury.Exp Cell Res.2010;316(1):48-54.
[43]Krasnodembskaya A,Song Y,Fang X,et al.Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37.Stem Cells.2010;28(12):2229-2238.
[44]Mei SH,Haitsma JJ,Dos Santos CC,et al.Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis.Am J Respir Crit Care Med.2010;182(8):1047-1057.
[45]Cho DI,Kim MR,Jeong HY,et al.Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages.Exp Mol Med.2014;46:e70.
[46]Zhang QZ,Su WR,Shi SH,et al.Human gingiva-derived mesenchymal stem cells elicit polarization of m2macrophages and enhance cutaneous wound healing.Stem Cells.2010;28(10):1856-1868.
[47]Wu Y,Huang S,Enhe J,et al.Bone marrow-derived mesenchymal stem cell attenuates skin fibrosis development in mice.Int Wound J.2014;11(6):701-710.
[48]Sasaki M,Abe R,Fujita Y,et al.Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type.J Immunol.2008;180(4):2581-2587.
[49]Kumamoto T,Shalhevet D,Matsue H,et al.Hair follicles serve as local reservoirs of skin mast cell precursors.Blood.2003;102(5):1654-1660.
[50]Lako M,Armstrong L,Cairns PM,et al.Hair follicle dermal cells repopulate the mouse haematopoietic system.J Cell Sci.2002;115(Pt 20):3967-3974.
[51]Altman AM,Matthias N,Yan Y,et al.Dermal matrix as a carrier for in vivo delivery of human adipose-derived stem cells.Biomaterials.2008;29(10):1431-1442.
[52]Gnecchi M,Zhang Z,Ni A,et al.Paracrine mechanisms in adult stem cell signaling and therapy.Circ Res.2008;103(11):1204-1219.
[53]Dougherty JA,Kumar N,Noor M,et al.Extracellular Vesicles Released by Human Induced-Pluripotent Stem Cell-Derived Cardiomyocytes Promote Angiogenesis.Front Physiol.2018;9:1794.
[54]Crisan M,Yap S,Casteilla L,et al.A perivascular origin for mesenchymal stem cells in multiple human organs.Cell Stem Cell.2008;3(3):301-313.
[55]Kwon DS,Gao X,Liu YB,et al.Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats.Int Wound J.2008;5(3):453-463.
[56]Wang Q,Yang Q,Wang Z,et al.Comparative analysis of human mesenchymal stem cells from fetal-bone marrow,adipose tissue,and Warton's jelly as sources of cell immunomodulatory therapy.Hum Vaccin Immunother.2016;12(1):85-96.
[57]Wu Y,Chen L,Scott PG,et al.Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis.Stem Cells.2007;25(10):2648-2659.
[58]Edwards N,Feliers D,Zhao Q,et al.An electrochemically deposited collagen wound matrix combined with adipose-derived stem cells improves cutaneous wound healing in a mouse model of type 2 diabetes.J Biomater Appl.2018;33(4):553-565.
[59]Samsonraj RM,Raghunath M,Nurcombe V,et al.Concise Review:Multifaceted Characterization of Human Mesenchymal Stem Cells for Use in Regenerative Medicine.Stem Cells Transl Med.2017;6(12):2173-2185.
[60]Shohara R,Yamamoto A,Takikawa S,et al.Mesenchymal stromal cells of human umbilical cord Wharton's jelly accelerate wound healing by paracrine mechanisms.Cytotherapy.2012;14(10):1171-1181.
[61]Arno AI,Amini-Nik S,Blit PH,et al.Human Wharton's jelly mesenchymal stem cells promote skin wound healing through paracrine signaling.Stem Cell Res Ther.2014;5(1):28.
[62]Chen L,Xu Y,Zhao J,et al.Conditioned medium from hypoxic bone marrow-derived mesenchymal stem cells enhances wound healing in mice.PLoS One.2014;9(4):e96161.
[63]Kordelas L,Rebmann V,Ludwig AK,et al.MSC-derived exosomes:a novel tool to treat therapy-refractory graft-versus-host disease.Leukemia.2014;28(4):970-973.