Induced pluripotent stem cells attenuate chronic allogeneic vasculopathy in an integrin beta-1-dependent manner
Induced pluripotent stem cells attenuate chronic allogeneic vasculopathy in an integrin beta-1-dependent manner
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DOI：
10.1111/ajt.15900
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发表时间：
2020-04-28
影响因子：
8.8
通讯作者：
Chen, Sifeng
中科院分区：
文献类型：
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作者：
Lu, Meng;Xue, Rong;Chen, Sifeng
本研究旨在确定同基因诱导多能干细胞（iPSC）归巢至血管移植物的机制及其对慢性同种异体血管病的治疗作用。我们发现整合素β1（Intgβ1）是iPSC中主要的整合素β单元，介导循环细胞和内皮细胞（EC）的粘附。 Intg beta 1 敲除或 Intg beta 1-siRNA 抑制 iPSC 粘附和跨活化内皮单层的迁移。检查以下各项的治疗效果：iPSC、Intg β 1 敲除 iPSC、转染 Intg β 1-siRNA 或非靶向 siRNA 的 iPSC、iPSC 来源的 EC、同时过表达 Intg α 4 和 Intg β 1 的 iPSC 来源的 EC、在内皮培养基中预培养 3 天的 iPSC（内皮倾向干细胞）细胞）、原代主动脉 EC、小鼠胚胎成纤维细胞和磷酸盐缓冲盐水（对照）。每三天注射一次细胞，持续 8 周。 iPSC、转染非靶向 siRNA 的 iPSC 以及易内皮干细胞选择性地归巢于同种异体移植物的管腔表面，分化为 EC，并减少新内膜增殖。通过单次给药，我们发现iPSCs被运输到同种异体移植病变处，在1周内分化为ECs，并存活4-8周。单次给药治疗效果中等。因此，Intg beta 1 和多能性对于 iPSC 治疗同种异体血管病至关重要。
This study aimed to determine the mechanism of isogeneic-induced pluripotent stem cells (iPSCs) homing to vascular transplants and their therapeutic effect on chronic allogeneic vasculopathy. We found that integrin beta 1 (Intg beta 1) was the dominant integrin beta unit in iPSCs that mediates the adhesion of circulatory and endothelial cells (ECs). Intg beta 1 knockout or Intg beta 1-siRNAs inhibit iPSC adhesion and migration across activated endothelial monolayers. The therapeutic effects of the following were examined: iPSCs, Intg beta 1-knockout iPSCs, iPSCs transfected with Intg beta 1-siRNAs or nontargeting siRNAs, iPSC-derived ECs, iPSC-derived ECs simultaneously overexpressing Intg alpha 4 and Intg beta 1, iPSCs precultured in endothelial medium for 3 days (endothelial-prone stem cells), primary aortic ECs, mouse embryonic fibroblasts, and phosphate-buffered saline (control). The cells were administered every 3 days for a period of 8 weeks. iPSCs, iPSCs transfected with nontargeting siRNAs, and endothelial-prone stem cells selectively homed on the luminal surface of the allografts, differentiated into ECs, and decreased neointimal proliferation. Through a single administration, we found that iPSCs trafficked to allograft lesions, differentiated into ECs within 1 week, and survived for 4-8 weeks. The therapeutic effect of a single administration was moderate. Thus, Intg beta 1 and pluripotency are essential for iPSCs to treat allogeneic vasculopathy.