Red blood cell-mediated enhancement of hematopoietic stem cell functions via Hes1-dependent pathway

In bone marrow the number of cells is balanced between production and loss. After chemotherapy, blood cell counts initially drop but later recover as hematopoietic progenitor cells expand, although the mechanisms behind this recovery were still elusive. The study investigates how red blood cells (RBCs) influence hematopoietic stem cell (HSC) function during bone marrow recovery. Following chemotherapy, RBC concentration in bone marrow peaked on the 5th day post-treatment, coinciding with the recovery of hematopoiesis. Co-culturing HSCs with RBCs resulted in a significant increase in hematopoiesis, preferentially differentiating into myeloid lineage cells. Direct contact between RBCs and HSCs is essential for the hematopoietic enhancement, and HSCs pre-cultured with RBCs showed higher levels of donor-derived mature hematopoietic cells after transplantation. RNA sequencing identified Hes1 being the most significantly upregulated transcription factor in RBC co-culture and Hes1-deficient HSCs showed a reduced response to RBC-induced hematopoiesis. These findings highlight the importance of RBCs and Hes1 in enhancing hematopoietic recovery following bone marrow stress. To identify the molecular basis responsible for the RBC-induced enhancement of hematopoietic function of hematopoetic stem cells, we compared gene profiling of hematopoetic stem cells (LT-HSC and LSK) cultured in the presence or absence of RBCs.