Cytomegalovirus Results in Poor Graft Function via Bone Marrow-Derived Endothelial Progenitor Cells

Abstract Poor graft function (PGF), characterized by myelosuppression, represents a significant challenge following allogeneic hematopoietic stem cell transplantation (allo-HSCT) with human cytomegalovirus (HCMV) being established as a risk factor for PGF. However, the underlying mechanism remains unclear. Bone marrow endothelial progenitor cells (BM-EPCs) can support hematopoiesis. We aim to explore the effects of CMV on BM-EPCs and its underlying mechanism. We investigated the compromised functionality of EPCs derived from individuals diagnosed with HCMV viremia (HCMV-emia) accompanied by PGF as well as after infected by HCMV AD 169 strain in vitro. We found dysfunction of HCMV-infected EPCs was characterized by decreased cell proliferation, tube formation, migration and hematopoietic support, and increased apoptosis and secretion of TGF-β1. We demonstrated that HCMV-induced TGF-β1 secretion by BM-EPCs played a dominant role in hematopoiesis suppression in vitro experiment. Moreover, HCMV up-regulates the p38 MAPK and its downstream transcription factor AP-1 to induce myelosuppression through promoting TGF-β1 secretion. In conclusion, HCMV could infect BM-EPCs and lead to their dysfunction. Enhanced secretion of TGF-β1 by BM-PECs is induced by HCMV through the up-regulation of p38 MAPK and its downstream transcription factor AP-1, resulting in myelosuppression, which might make a substantial contribution to the pathogenesis of PGF after allo-HSCT.