Endothelial progenitor cells improve intestinal homeostasis after hematopoietic stem cell transplantation in mice

Abstract

Transplant conditioning regimens disrupt the intestinal barriers, leading to delayed vascularity and impeded the regenerative process. However, our understanding of the specific mechanisms underlying the use of cellular therapy to accelerate revascularization for intestinal repair is currently limited. To address this knowledge gap, we conducted a longitudinal study to investigate the effects and potential benefits of endothelial progenitor cells (EPCs) infusion on the restoration of intestinal homeostasis in a murine model of bone marrow transplantation (BMT). Our results revealed that the EPCs infusion improved the structure status of the intestine, as demonstrated by a well-preserved crypt structure, longer villi, reduced infiltration of inflammatory cells, and increased expression of ZO-1 and MECA-32. Additionally, EPCs infusion resulted in significantly lower proportions of Tc1 and Th1 cells on day 10, as well as a delayed peak in Tc17 cells on day 20, with no differences compared with BMT group thereafter. Moreover, EPCs infusion enhanced the expression of immune regulatory molecules IL-10, IL-17, IL-18, and NLRP6 on day 15. Mechanistically, EPCs infusion up-regulated phos-ERK1/2 and down-regulated phos-p38 MAPK on day 5 (early transplantation). The richness of intestinal microbiota changed significantly, and Erysipelotrichaceae was identified as the main index to differentiate the BMT and EPC treatments, exhibiting a significant negative correlation with IL-10 and IL-18 in the EPC group. Taken together, this study highlights the protective role of EPCs in post-transplantation intestinal damage, and identifies critical immune cells, signaling pathways, and selectively enriched intestinal microbes contributing to the beneficial effects of EPCs during intestinal repair.