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博碩士論文 etd-0717115-185210 詳細資訊
Title page for etd-0717115-185210
論文名稱
Title
骨髓間質幹細胞促進糖尿病大鼠傷口癒合
Bone marrow mesenchymal stem cells enhance diabetic wound healing in diabetic rats
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
81
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2015-07-29
繳交日期
Date of Submission
2015-08-17
關鍵字
Keywords
糖尿病、間質幹細胞、傷口癒合
mesenchymal stem cells, wound healing, diabetes mellitus
統計
Statistics
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The thesis/dissertation has been browsed 5708 times, has been downloaded 59 times.
中文摘要
無法癒合的糖尿病慢性傷口常導致感染甚至截肢,目前各種針對糖尿病傷口癒合的研究與臨床治療仍不十分顯著。間質幹細胞 (mesenchymal stem cells, MSCs), 為非血源性初始幹細胞,在體內可以促進各種組織分化生成。近年已有體外研究及小鼠研究顯示間質幹細胞可促進組織修復及各種生長因子產生、膠原蛋白生成、體外間質合成等,並有促進皮膚細胞如角質細胞分化和移動。然而對於間質幹細胞在糖尿病傷口的癒合機轉仍不十分清楚,因此本研究採用活體大鼠動物實驗模式誘導糖尿病產生,即以Wistar品系之大鼠用鏈尿菌素(Streptozotocin;STZ)誘導成第一型糖尿病鼠並在背部製作一6×5平方公分大小之全層皮膚缺損的人造傷口再施以指定之治療後觀察其成效。,實驗組別共五組:第一組為正常對照組(Normal control group)、第二組為對照組(Diabetic control group)、第三組為一次低劑量(2x106個細胞)間質幹細胞治療組【MSC-1(L) group】、第四組為一次高劑量(1x107個細胞)間質幹細胞治療組(MSC-1 group)、第五組為二次高劑量(1x107個細胞)間質幹細胞治療組(MSC-2 group)。實驗結果發現,在傷口癒合所需要的時間上,不管是低劑量間質幹細胞相對於對照組(8.4 ± 0.79週vs 9.8 ± 0.75週,P < 0.05)或高劑量間質幹細胞相對於對照組(6.6 ± 1.13週vs 9.8 ± 0.75週,P < 0.001),都顯示出間質幹細胞治療能促進糖尿病傷口癒合,而其中又以二次性高劑量間質幹細胞治療糖尿病傷口更優於單次高劑量間質幹細胞治療(5.2 ± 0.75週與6.6 ± 1.13週,P = 0.026)。在H&E染色及CD45表現來看,不管在高劑量一次或高劑量二次相對於對照組都是來的有顯著減少(P< 0.001),顯示間質幹細胞確實能抑制傷口發炎反應。另外在ki-67、prolyl 4-hydroxylase、endothelial nitric oxide synthase(eNOS)、vascular endothelial growth factor(VEGF)及epidermal growth factor(EGF)其在高劑量MSC一次或高劑量MSC二次相對於對照組都有顯著的增加(P < 0.001),顯示間質幹細胞確實能透過增加血管新生及組織修復相關因子來促進糖尿病傷口癒合。本研究透過了大鼠糖尿病傷口模式,發現皮下注入同系的間質幹細胞能促進傷口癒合的情形。其作用機制來自於間質幹細胞處理後經由旁泌現象進而抑制傷口早期的發炎反應並誘導組織再生。此研究可了解間質幹細胞在傷口癒合上的療效,以利未來臨床上對困難複雜而難以癒合的傷口做更進一步治療。
Abstract
Non-healing foot ulcers in patients with diabetes is a leading cause of complications such as infection and amputation. Various studies report in diabetic wound healing with different treatment modalities, but remains controversial results. Mesenchymal stem cells (MSCs) are attractive cell sources to regenerative medicine. MSCs are multi-potential non-hematopoietic progenitor cells of differentiating into various lineages of the mesenchyme. MSCs have demonstrated a number of properties in vitro that can promote tissue repair, including the production of multiple growth factors, cytokines, collagens, and matrix metalloproteinases and the ability to promote migration of other skin cells such as keratinocytes. However, the bio-mechanisms underlying enhancement of MSCs to enhance diabetic wound are still unknown. Therefore, dorsal skin defect (6x5 cm) was designed as a wound healing model in an streptozotocin–induced diabetic rodents. Wistar rats were divided into five groups: group I, nondiabetic rats (normal controls); group II, diabetic controls receiving no MSCs; group III, rats receiving 2 × 106 stem cells per dose (subcutaneously administered in eight areas surrounding wound margin) on day 7; group IV, rats receiving 1 × 107 stem cells per dose on day 7, and group Ⅴ, rats receiving 1 × 107 stem cells per dose on days 7 and 10. Wound healing was assessed clinically. The results showed that wound size was significantly reduced in MSC–treated rats as compared with controls. Complete woundhealing time was statistically shorter in rats treated once as compared with controls (6.6 ± 1.13 weeks versus 9.8 ± 0.75 weeks; p <0.001). The wound healing time was significantly decreased in rats treated with MSCs twice as compared with rats treated once (5.2 ± 0.75 weeks versus 6.6 ± 1.13 weeks; p=0.026). Histologic analysis showed significant reduction in topical proinflammatory reaction and suppression of CD45 expression in the MSC-group as compared with the control group. The immunohistochemistry analyses revealed significant increases in EGF, eNOS , VEGF, rPH, and Ki-67 expression in the treated group as compared with the control group. These results indicated that MSCs significantly enhanced diabetic wound healing was associated with increasing biomarkers of neoangiogenesis and tissue regeneration and suppression of pre-wounding local inflammatory response. These results can apply in future clinical trials for MSCs in diabetic wound or other tough unhealed chronic ulcers.
目次 Table of Contents
審定書…………......………………..…………………………..………….. i
論文公開授權書……………..……..…………….……………………….... ii
誌謝……………...……...........…..….....................…………......…..... iii
中文摘要……………………..……..………………………………...…….. iv
Abstract……………………...………………..………………………........ vi
目錄........………………..…………..…………………..……………...….. viii
圖次........………………....……………………………………………….... xi
表次........……………………..……..…………..……………………...….. xiii
名詞對照表………………………..………………………………….......... xiv
一、 前言…………………………………………………………….......… 1
1.1 傷口癒合..................................………………...………...…… 1
1.1.1 止血期.........................................………………….....… 2
1.1.2 發炎期.............................................………….…...…… 2
1.1.3 增生期.............................................……………...….… 3
1.1.4 重塑期.........................................……………….....…… 3
1.2 糖尿病之介紹.......…………………………………….........…… 4
1.2.1 糖尿病的定義診斷及分類...……………………...….......... 4
1.2.2 糖尿病的分類...…………...………………………..........… 5
1.2.2.1 第一型糖尿病.....................…………..........…….. 5
1.2.2.2 第二型糖尿病.....................……………............… 6
1.2.2.3 特殊類型...............................…………........…… 7
1.2.3 傷口延遲癒合為糖尿病患者之併發症...……............…… 7
1.2.3.1 神經病變型.............................................……… 8
1.2.3.2 神經病變缺血型.............................................… 8
1.3 幹細胞…………………………………………………........…… 8
1.3.1 間質幹細胞…………………………………...........…...… 9
1.3.2 間質幹細胞的分化能力.......…...…….....….......…….… 10
1.3.3 間質幹細胞之應用...…...….…………....……….........… 11
1.4 研究目的...…………………………………………...…........… 14
二、 材料與方法...………………………………………….….....….… 15
2.1 動物實驗設計.................................................................. 15
2.1.1 動物來源...…...…………………….………….......…..…. 15
2.1.2 誘導第一型糖尿病鼠……………………….................... 16
2.1.3 糖尿病鼠背部傷口模型…………………….........…..…... 18
2.2 培養骨髓間質幹細胞 ……………………….….......….…....... 19
2.3 間質幹細胞的特徵及分化能力分析....................…….…...... 19
2.3.1 間質幹細胞對單株抗體的專一性分析 …….…............… 19
2.3.2 間質幹細胞的多能性之確認..……………………............ 20
2.3.2.1 脂肪分化................................……...…........…. 20
2.3.2.2 硬骨分化...............................…….....…......….. 21
2.3.2.3 軟骨分化........................................…….....….. 21
2.4 實驗組別..........................................……………….…...… 22
2.5 傷口面積的測量及傷口癒合速度計算..........…….….........… 24
2.6 老鼠背部傷口檢體採樣...…….………...…………..........…… 25
2.7 背部傷口檢體處理及染色...…………………………...........… 26
2.7.1 組織固定...………………………………..........…….…… 27
2.7.2 組織脫水包埋...…………………………………...........… 27
2.7.3 組織石蠟塊切片...……………………………...........…… 27
2.7.4 組織切片脫蠟...………………………………..........….… 27
2.7.5 蘇木紫與伊紅染色 ...……....…………...….........…….... 28
2.7.6 免疫組織染色...........…….…………..………….......….. 28
2.8 統計分析...…………………………………………….........…. 30
三、 結果...…………………………………………...………...…...… 31
3.1 間質幹細胞的表面抗原分子的專一性分析...………..........… 31
3.2 間質幹細胞的多能性測定..............................................… 31
3.3 間質幹細胞能促進糖尿病的傷口癒合...…………..…........... 32
3.4 間質幹細胞能抑制傷口發炎反應...………………..…........… 33
3.5 間質幹細胞能促進傷口細胞增生...……………........……..… 34
3.6 間質幹細胞能促進組織再生...……………………. ........…… 34
3.7 間質幹細胞能促進血管新生...…………………….. ..........… 34
3.8 間質幹細胞能促進表皮細胞增生...…………………......... … 35
四、 討論...…………………………………………………….….....… 37
五、 結論...…………………………………………………….….....… 40
六、 參考文獻..................................................................……. 41
七、 歷年發表作品...…………………………....……….……...….... 63

圖次
圖1 傷口癒合的四個時期…………………....……........……..…..… 4
圖2 動物實驗管理委員會審查同意書…….….…..……..……......… 15
圖3 誘導成糖尿病鼠所需藥物及後續照顧所需設備…..........…..… 16
圖3E實驗期間實驗動物體重之變化………...….....……..…........… 17
圖3F 實驗期間實驗動物血糖之變化…….….….....……….…......… 17
圖4 老鼠背部設計6×5公分大小的全層皮膚缺損的傷口.............… 18
圖5 糖尿病鼠皮膚缺損手術流程……...……………...…….........… 18
圖6 流式細胞儀………………...…………………………….........… 20
圖7 糖尿病鼠背部傷口施打間質幹細胞流程……………............… 24
圖8 間質幹細胞均勻施打於傷口邊緣……………….……...........… 24
圖9 翻拍架固定之相機進行老鼠背部傷口拍照...……...............… 25
圖10 老鼠背部傷口以Image J軟體分析計算...……...................… 25
圖11 老鼠背部傷口檢體採樣時間點...…………...…..................… 26
圖12 使用bio punch在傷口邊緣採取檢體位置.…......................… 26
圖13 間質幹細胞的表面抗原分子的專一性分析........................… 51
A幹細胞型態.................................................................… 51
B流式細胞儀分析間質幹細胞表面抗原反應.......................… 51
圖14 間質幹細胞的多能性測定...............................................… 52
A脂肪分化....................................................................… 52
B軟骨分化....................................................................… 52
C硬骨分化....................................................................… 52
圖15 A各組大鼠傷口癒合圖...................................................… 53
B各組大鼠傷口癒合面積.................................................… 54
C各組大鼠傷口癒合時間.................................................… 55
圖16 間質幹細胞能抑制傷口發炎反應.....................................… 56
圖17 間質幹細胞能促進傷口細胞增生-由核增生蛋白表現..........… 57
圖18 間質幹細胞能促進組織再生-由纖維母細胞表現.................... 58
圖19 間質幹細胞能促進血管新生-由血管內皮生長因子表現.......... 59
圖20 間質幹細胞能促進血管新生-由內皮型一氧化氮合成酶表現.... 60
圖21 間質幹細胞能促進表皮細胞增生-由表皮生長因子表現........... 61
圖22 間質幹細胞促進糖尿病傷口癒合相關因子總結..................… 62

表次
表1 動物實驗組別設計........................................................... 23
參考文獻 References
何橈通。1986。糖尿病與公共衛生。臨床醫學。17: 300-17。
Akino, K., T. Mineda, and S. Akita. "Early cellular changes of human mesenchymal stem cells and their interaction with other cells." Wound Repair Regen. 2005;13:434-40.
Amendt, C., A. Mann, P. Schirmacher, and M. Blessing. "Resistance of keratinocytes to TGFbeta-mediated growth restriction and apoptosis induction accelerates re-epithelialization in skin wounds." J Cell Sci. 2002;115:2189-98.
Amendt, C., P. Schirmacher, H. Weber, and M. Blessing. "Expression of a dominant negative type II TGF-beta receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development." Oncogene. 1998;17:25-34.
Ansel, J. C., J. P. Tiesman, J. E. Olerud, J. G. Krueger, J. F. Krane, D. C. Tara, G. D. Shipley, D. Gilbertson, M. L. Usui, and C. E. Hart. "Human keratinocytes are a major source of cutaneous platelet-derived growth factor." J Clin Invest. 1993;92:671-8.
Antoniades, H. N., T. Galanopoulos, J. Neville-Golden, C. P. Kiritsy, and S. E. Lynch. "Injury induces in vivo expression of platelet-derived growth factor (PDGF) and PDGF receptor mRNAs in skin epithelial cells and PDGF mRNA in connective tissue fibroblasts." Proc Natl Acad Sci U S A. 1991;88:565-9.
Badiavas, E. V., and V. Falanga. "Treatment of chronic wounds with bone marrow-derived cells." Arch Dermatol. 2003; 139:510-6.
Bell, A. L., and J. Cavorsi. "Noncontact ultrasound therapy for adjunctive treatment of nonhealing wounds: retrospective analysis." Phys Ther. 2008;88:1517-24.
Bellayr, I., K. Holden, X. Mu, H. Pan, and Y. Li. "Matrix metalloproteinase inhibition negatively affects muscle stem cell behavior." Int J Clin Exp Pathol . 2013;6:124-41.
Benvenuto, F., S. Ferrari, E. Gerdoni, F. Gualandi, F. Frassoni, V. Pistoia, G. Mancardi, and A. Uccelli. "Human mesenchymal stem cells promote survival of T cells in a quiescent state." Stem Cells. 2007;25:1753-60.
Boulton, A. J., L. Vileikyte, G. Ragnarson-Tennvall, and J. Apelqvist. "The global burden of diabetic foot disease." Lancet. 2005;366:1719-24.
Brem, H., P. Sheehan, H. J. Rosenberg, J. S. Schneider, and A. J. Boulton. "Evidence-based protocol for diabetic foot ulcers." Plast Reconstr Surg. 2006;117:193S-209S; discussion 210S-211S.
Brown, L. F., K. T. Yeo, B. Berse, T. K. Yeo, D. R. Senger, H. F. Dvorak, and L. van de Water. "Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing." J Exp Med. 1992;176:1375-9.
Cavanagh, P. R., B. A. Lipsky, A. W. Bradbury, and G. Botek. "Treatment for diabetic foot ulcers." Lancet. 2005;366:1725-35.
Chen, C. C., F. E. Mo, and L. F. Lau. "The angiogenic factor Cyr61 activates a genetic program for wound healing in human skin fibroblasts." J Biol Chem. 2001;276:47329-37.
Chen, X., H. Xu, C. Wan, M. McCaigue, and G. Li. "Bioreactor expansion of human adult bone marrow-derived mesenchymal stem cells." Stem Cells. 2006;24:2052-9.
Clark, R. A. "Fibrin and wound healing." Ann N Y Acad Sci. 2001;936:355-67.
Corral, C. J., A. Siddiqui, L. Wu, C. L. Farrell, D. Lyons, and T. A. Mustoe. "Vascular endothelial growth factor is more important than basic fibroblastic growth factor during ischemic wound healing." Arch Surg. 1999;134:200-5.
da Silva Meirelles, L., P. C. Chagastelles, and N. B. Nardi. "Mesenchymal stem cells reside in virtually all post-natal organs and tissues." J Cell Sci. 2006;119:2204-13.
Falanga, V. "Wound healing and its impairment in the diabetic foot." Lancet. 2005;366:1736-43.
Fathke, C., L. Wilson, J. Hutter, V. Kapoor, A. Smith, A. Hocking, and F. Isik. "Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair." Stem Cells. 2004;22:812-22.
Feng, C., J. Zhu, L. Zhao, T. Lu, W. Zhang, Z. Liu, and J. Tian. "Suberoylanilide hydroxamic acid promotes cardiomyocyte differentiation of rat mesenchymal stem cells." Exp Cell Res. 2009;315:3044-51.
Fife, C. E., C. Buyukcakir, G. Otto, P. Sheffield, T. Love, and R. Warriner, 3rd. "Factors influencing the outcome of lower-extremity diabetic ulcers treated with hyperbaric oxygen therapy." Wound Repair Regen. 2007;15:322-31.
Freitas, T. P., M. Gomes, D. B. Fraga, L. S. Freitas, G. T. Rezin, P. M. Santos, P. C. Silveira, M. M. Paula, R. A. Pinho, and E. L. Streck. "Effect of therapeutic pulsed ultrasound on lipoperoxidation and fibrogenesis in an animal model of wound healing." J Surg Res. 2010;161:168-71.
Galiano, R. D., O. M. Tepper, C. R. Pelo, K. A. Bhatt, M. Callaghan, N. Bastidas, S. Bunting, H. G. Steinmetz, and G. C. Gurtner. "Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells." Am J Pathol. 2004;164:1935-47.
Ghajar, C. M., S. C. George, and A. J. Putnam. "Matrix metalloproteinase control of capillary morphogenesis." Crit Rev Eukaryot Gene Expr. 2008;18:251-78.
Goldstein, D. A., and S. G. Massry. "Diabetic nephropathy: clinical course and effect of hemodialysis." Nephron. 1978;20:286-96.
Gong, Z., G. Calkins, E. C. Cheng, D. Krause, and L. E. Niklason. "Influence of culture medium on smooth muscle cell differentiation from human bone marrow-derived mesenchymal stem cells." Tissue Eng Part A. 2009;15:319-30.
Han, Z., Y. Jing, S. Zhang, Y. Liu, Y. Shi, and L. Wei. "The role of immunosuppression of mesenchymal stem cells in tissue repair and tumor growth." Cell Biosci. 2012;2:8.
Hanson, S. E., M. L. Bentz, and P. Hematti. "Mesenchymal stem cell therapy for nonhealing cutaneous wounds." Plast Reconstr Surg. 2010;125:510-6.
Kim, D. H., K. H. Yoo, K. S. Choi, J. Choi, S. Y. Choi, S. E. Yang, Y. S. Yang, H. J. Im, K. H. Kim, H. L. Jung, K. W. Sung, and H. H. Koo. "Gene expression profile of cytokine and growth factor during differentiation of bone marrow-derived mesenchymal stem cell." Cytokine. 2005;31:119-26.
Kim, W. J., G. K. Gittes, and M. T. Longaker. "Signal transduction in wound pharmacology." Arch Pharm Res. 1998;21:487-95.
Kinnaird, T., E. Stabile, M. S. Burnett, M. Shou, C. W. Lee, S. Barr, S. Fuchs, and S. E. Epstein. "Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms." Circulation. 2004;109:1543-9.
Kotwal, G. J., H. Sarojini, and S. Chien. "Pivotal role of ATP in Macrophages fast tracking wound repair and regeneration." Wound Repair Regen. 2015
Kuo, Y. R., S. Goto, H. S. Shih, F. S. Wang, C. C. Lin, C. T. Wang, E. Y. Huang, C. L. Chen, F. C. Wei, X. X. Zheng, and W. P. Lee. "Mesenchymal stem cells prolong composite tissue allotransplant survival in a swine model." Transplantation. 2009;87:1769-77.
Kuo, Y. R., C. T. Wang, F. S. Wang, Y. C. Chiang, and C. J. Wang. "Extracorporeal shock-wave therapy enhanced wound healing via increasing topical blood perfusion and tissue regeneration in a rat model of STZ-induced diabetes." Wound Repair Regen. 2009;17:522-30.
Mahdavian Delavary, B., W. M. van der Veer, M. van Egmond, F. B. Niessen, and R. H. Beelen. "Macrophages in skin injury and repair." Immunobiology. 2011;216:753-62.
Makino, S., K. Fukuda, S. Miyoshi, F. Konishi, H. Kodama, J. Pan, M. Sano, T. Takahashi, S. Hori, H. Abe, J. Hata, A. Umezawa, and S. Ogawa. "Cardiomyocytes can be generated from marrow stromal cells in vitro." J Clin Invest. 1999;103:697-705.
Martin, P. "Wound healing--aiming for perfect skin regeneration." Science. 1997;276:75-81.
Novak, M. L., and T. J. Koh. "Phenotypic transitions of macrophages orchestrate tissue repair." Am J Pathol. 2013;183:1352-63.
Parikka, V., A. Vaananen, J. Risteli, T. Salo, T. Sorsa, H. K. Vaananen, and P. Lehenkari. "Human mesenchymal stem cell derived osteoblasts degrade organic bone matrix in vitro by matrix metalloproteinases." Matrix Biol. 2005;24:438-47.
Pittenger, M. F., A. M. Mackay, S. C. Beck, R. K. Jaiswal, R. Douglas, J. D. Mosca, M. A. Moorman, D. W. Simonetti, S. Craig, and D. R. Marshak. "Multilineage potential of adult human mesenchymal stem cells." Science. 1999;284:143-7.
Qian, Q., H. Qian, X. Zhang, W. Zhu, Y. Yan, S. Ye, X. Peng, W. Li, Z. Xu, L. Sun, and W. Xu. "5-Azacytidine induces cardiac differentiation of human umbilical cord-derived mesenchymal stem cells by activating extracellular regulated kinase." Stem Cells Dev. 2012;21:67-75.
Rabelo, S. B., A. B. Villaverde, R. Nicolau, M. C. Salgado, S. Melo Mda, and M. T. Pacheco. "Comparison between wound healing in induced diabetic and nondiabetic rats after low-level laser therapy." Photomed Laser Surg. 2006;24:474-9.
Ramalho-Santos, M., and H. Willenbring. "On the origin of the term "stem cell"." Cell Stem Cell. 2007;1:35-8.
Rogers, T. B., S. Pati, S. Gaa, D. Riley, A. Y. Khakoo, S. Patel, R. D. Wardlow, 2nd, C. A. Frederick, G. Hall, L. P. He, and W. J. Lederer. "Mesenchymal stem cells stimulate protective genetic reprogramming of injured cardiac ventricular myocytes." J Mol Cell Cardiol. 2011;50:346-56.
Ross, R., and E. P. Benditt. "Wound healing and collagen formation. I. Sequential changes in components of guinea pig skin wounds observed in the electron microscope." J Biophys Biochem Cytol. 1961;11:677-700.
Saad, M. F., W. C. Knowler, D. J. Pettitt, R. G. Nelson, D. M. Mott, and P. H. Bennett. "The natural history of impaired glucose tolerance in the Pima Indians." N Engl J Med. 1988;319:1500-6.
Salem, H. K., and C. Thiemermann. "Mesenchymal stromal cells: current understanding and clinical status." Stem Cells. 2010;28:585-96.
Sanchez-Ramos, J. R. "Neural cells derived from adult bone marrow and umbilical cord blood." J Neurosci Res. 2002;69:880-93.
Sasaki, M., R. Abe, Y. Fujita, S. Ando, D. Inokuma, and H. Shimizu. "Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type." J Immunol. 2008;180:2581-7.
Sayegh, H. A., and R. J. Jarrett. "Oral glucose-tolerance tests and the diagnosis of diabetes: results of a prospective study based on the Whitehall survey." Lancet. 1979;2:431-3.
Serafini, M., and C. M. Verfaillie. "Pluripotency in adult stem cells: state of the art." Semin Reprod Med. 2006;24:379-88.
Singer, A. J., and R. A. Clark. "Cutaneous wound healing." N Engl J Med. 1999;341:738-46.
Stadelmann, W. K., A. G. Digenis, and G. R. Tobin. "Physiology and healing dynamics of chronic cutaneous wounds." Am J Surg. 1998;176:26s-38s.
Suzuki, S., Y. Narita, A. Yamawaki, Y. Murase, M. Satake, M. Mutsuga, H. Okamoto, H. Kagami, M. Ueda, and Y. Ueda. "Effects of extracellular matrix on differentiation of human bone marrow-derived mesenchymal stem cells into smooth muscle cell lineage: utility for cardiovascular tissue engineering." Cells Tissues Organs. 2010;191:269-80.
Taylor, S. I., and E. Arioglu. "Syndromes associated with insulin resistance and acanthosis nigricans." J Basic Clin Physiol Pharmacol. 1998;9:419-39.
Wang, Y., W. He, H. Bian, C. Liu, and S. Li. "Small molecule induction of neural-like cells from bone marrow-mesenchymal stem cells." J Cell Biochem. 2012;113:1527-36.
Werner, S., T. Krieg, and H. Smola. "Keratinocyte-fibroblast interactions in wound healing." J Invest Dermatol. 2007;127:998-1008.
Wislet-Gendebien, S., G. Hans, P. Leprince, J. M. Rigo, G. Moonen, and B. Rogister. "Plasticity of cultured mesenchymal stem cells: switch from nestin-positive to excitable neuron-like phenotype." Stem Cells. 2005;23:392-402.
Wu, Y., L. Chen, P. G. Scott, and E. E. Tredget. "Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis." Stem Cells. 2007;25:2648-59.
Xi-Qiao, W., L. Ying-Kai, Q. Chun, and L. Shu-Liang. "Hyperactivity of fibroblasts and functional regression of endothelial cells contribute to microvessel occlusion in hypertrophic scarring." Microvasc Res. 2009;77:204-11.
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