Induced Pluripotent Stem Cells Attenuate Chronic Allogeneic Vasculopathy In An Integrin Beta-1-Dependent Manner

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.