The effects of adipose-derived stem cells protect skin flaps on ischemia/reperfusion injury and their related mechanisms

• Main Authors: Chi-Ming Pu, 蒲啟明
• Other Authors: 陳玉怜
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/qhm8n2

博士 === 國立臺灣大學 === 解剖學暨細胞生物學研究所 === 105 === Skin flap transplantation is the most widely used in plastic and reconstructive surgery. Unfortunately, flap necrosis is the most frequent postoperative complication encountered in reconstructive surgery. Thus, determining how to increase pro-angiogenic factor levels and augment angiogenesis plays an essential role in improving the survival of skin flaps and increasing the success rate of skin flap transplantation. Cell-based therapy with stem cells was a promising option for ischemia/reperfusion (I/R) injury. Mesenchymal stem cell (MSC) is one of the postnatal adult stem cells and possessed capacity for self-renewal and differentiation with a broad tissue distribution. Adipose-derived stem cells (ADSCs) is one of MSC with less ethical concern. We elucidated whether adipose-derived stem cells (ADSCs) and their derivatives might induce neovascularization and protect skin flaps during ischemia/reperfusion (I/R) injury. The skin flap was subjected to 3 h of ischemia by ligating long thoracic vessels and then to blood reperfusion. Q-tracker-labeled ADSCs, conditioned media (ADSC-CM), or exosomes (ADSC-Exo) from ADSCs were injected into the flap. These treatments led to a significant increase in flap survival and capillary density compared to I/R on postoperative day 5. Interleukin-6 (IL-6) is a pleiotropic cytokine that has a broad spectrum of biological activities such as regulation of inflammation, cell proliferation, immunomodulation, haematopoiesis and tumorigenesis. It was reported to be a potent pro-angiogenic mediator in microenvironment. IL-6 levels either in the cell lysates or in CM were significantly higher in ADSCs than in Hs68 fibroblasts. ADSC-CM and ADSC-Exo increased EC tube formation. This result was corroborated by a strong decrease in skin repair after adding IL-6 neutralizing antibodies or si-IL-6-ADSC. ADSCs transplantation also increased flap recovery in I/R injury of IL-6 knockout mice. The IL-6 production and angiogenesis were accomplished through classic signaling pathway and the signal transducer and activator of transcription (STAT) activation. The mechanism of skin recovery includes both the direct differentiation of ADSCs into ECs and the indirect paracrine effect of IL-6 released from ADSCs. In the current study, we demonstrated that IL-6 in ADSCs, ADSC-CM and ADSCExo increased angiogenesis and enhanced recovery from I/R injury in the long thoracic artery pattern of skin flap in mice. The ADSC-CM and ADSC-Exo could be used as “off-the-shelf” products for this therapy.