Adipose-Derived Stem Cells Protect Skin Flaps against Ischemia/Reperfusion Injury via IL-6 Expression.
Flap necrosis is the most frequent postoperative complication encountered in reconstructive surgery. We elucidated whether adipose-derived stem cells (ADSCs) and their derivatives might induce neovascularization and protect skin flaps during ischemia/reperfusion (I/R) injury. Flaps were subjected to 3 hours of ischemia by ligating long thoracic vessels and then to blood reperfusion. Qtracker-labeled ADSCs, ADSCs in conditioned medium (ADSC-CM), or ADSC exosomes (ADSC-Exo) were injected into the flaps. These treatments led to significantly increased flap survival and capillary density compared with I/R on postoperative day 5. IL-6 levels in the cell lysates or in conditioned medium were significantly higher in ADSCs than in Hs68 fibroblasts. ADSC-CM and ADSC-Exo increased tube formation. This result was corroborated by a strong decrease in skin repair after adding IL-6-neutralizing antibodies or small interfering RNA for IL-6 ADSCs. ADSC transplantation also increased flap recovery in I/R injury of IL-6-knockout mice. IL-6 was secreted from ADSCs through signal transducer and activator of transcription phosphorylation, and then IL-6 stimulated angiogenesis and enhanced recovery after I/R injury by the classic signaling pathway. The mechanism of skin recovery includes the direct differentiation of ADSCs into endothelial cells and the indirect effect of IL-6 released from ADSCs. ADSC-CM and ADSC-Exo could be used as off-the-shelf products for this therapy.
Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan; Division of Plastic Surgery, Department of Surgery, Cathay General Hospital, Taipei, Taiwan.
Chi-Ming
CM
Pu
Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chen-Wei
CW
Liu
Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
Chan-Jung
CJ
Liang
Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan; Division of Plastic Surgery, Department of Surgery, Cathay General Hospital, Taipei, Taiwan.
Yu-Hsiu
YH
Yen
Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Shun-Hua
SH
Chen
Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Ya-Fen
YF
Jiang-Shieh
Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chung-Liang
CL
Chien
Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Ya-Chun
YC
Chen
Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: ylchenv@ntu.edu.tw.
Yuh-Lien
YL
Chen
D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006085:Graft Survival; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D011897:Random Allocation; D015427:Reperfusion Injury / Q000517:prevention & control*; D050796:STAT3 Transcription Factor / Q000235:genetics*; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology; D013524:Surgical Flaps / Q000276:immunology* / Q000473:pathology
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human