Red Blood Cell-Mediated Enhancement of Hematopoietic Stem Cell Functions via a Hes1-Dependent Pathway

In bone marrow, cell numbers are balanced between production and loss. After chemotherapy, blood cell counts decrease initially but later recover as hematopoietic progenitor cells expand, although the mechanisms underlying this recovery are still unclear. We investigated the influence of red blood cells (RBCs) on hematopoietic stem cell (HSC) function during bone marrow recovery. Following chemotherapy, RBC concentrations in bone marrow peaked on day 5 posttreatment, coinciding with the recovery of hematopoiesis. Coculture of HSCs with RBCs resulted in a significant increase in hematopoiesis. Direct contact between RBCs and HSCs was essential for enhancement of hematopoiesis, and HSCs precultured with RBCs resulted in greater numbers of donor-derived mature hematopoietic cells after transplantation. RNA-sequencing analysis showed that Hes1 was the most significantly upregulated transcription factor in RBC coculture, and the response to RBC-induced hematopoiesis of Hes1-deficient HSCs was reduced. These findings imply a role of RBCs and Hes1 in the enhancement of hematopoietic recovery following bone marrow stress.