Am J Transplant. 2020 Apr 10. doi: 10.1111/ajt.15900. [Epub ahead of print]

Induced pluripotent stem cells attenuate chronic allogeneic vasculopathy in an integrin beta-1-dependent manner.

Lu M¹, Xue R¹, Wang P¹, Wang X¹, Tian X¹, Liu Y¹, Wang S¹, Cui A¹, Xie J¹, Le L¹, Zhao M¹, Quan J¹, Li N¹, Meng D¹, Wang X¹, Sun N¹, Chen AF¹, Xiang M¹, Chen S¹.

Abstract

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 β1 (Intgβ1) was the dominant integrin β unit in iPSCs that mediates the adhesion of circulatory and endothelial cells (ECs). Intgβ1 knockout or Intgβ1-siRNAs inhibit iPSC adhesion and migration across activated endothelial monolayers. The therapeutic effects of the following were examined: iPSCs, Intgβ1-knockout iPSCs, iPSCs transfected with Intgβ1-siRNAs or non-targeting siRNAs, iPSC-derived ECs, iPSC-derived ECs simultaneously overexpressing Intgα4 and Intgβ1, iPSCs pre-cultured in endothelial medium for 3 days (endothelial prone stem cells), primary aortic ECs, mouse embryonic fibroblasts (MEFs), and phosphate-buffered saline (control). The cells were administered every 3 days for a period of 8 weeks. iPSCs, iPSCs transfected with non-targeting 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, Intgβ1 and pluripotency are essential for iPSCs to treat allogeneic vasculopathy.