The opposing roles of the mTOR signaling pathway in different phases of human umbilical cord blood‐derived CD34 + cell erythropoiesis

As an indispensable, even lifesaving practice, red blood cell (RBC) transfusion is challenging due to several issues, including supply shortage, immune incompatibility, and blood‐borne infections since donated blood is the only source of RBCs. Although large‐scale in vitro production of functional RBCs from human stem cells is a promising alternative, so far, no such system has been reported to produce clinically transfusable RBCs due to the poor understanding of mechanisms of human erythropoiesis, which is essential for the optimization of in vitro erythrocyte generation system. We previously reported that inhibition of mammalian target of rapamycin (mTOR) signaling significantly decreased the percentage of erythroid progenitor cells in the bone marrow of wild‐type mice. In contrast, rapamycin treatment remarkably improved terminal maturation of erythroblasts and anemia in a mouse model of β‐thalassemia. In the present study, we investigated the effect of mTOR inhibition with rapamycin from different time points on human umbilical cord blood‐derived CD34+ cell erythropoiesis in vitro and the underlying mechanisms. Our data showed that rapamycin treatment significantly suppressed erythroid colony formation in the commitment/proliferation phase of erythropoiesis through inhibition of cell‐cycle progression and proliferation. In contrast, during the maturation phase of erythropoiesis, mTOR inhibition dramatically promoted enucleation and mitochondrial clearance by enhancing autophagy. Collectively, our results suggest contrasting roles for mTOR in regulating different phases of human erythropoiesis.
Proposed model for regulation of human erythroid differentiation by the mammalian target of rapamycin (mTOR) inhibitor rapamycin. In the proliferation phase of erythropoiesis, rapamycin significantly suppressed burst‐forming unit‐erythroid (BFU‐E) and colony‐forming unit‐erythroid (CFU‐E) formation through the inhibition of cell‐cycle progression and cell proliferation. In the terminal phase, rapamycin promoted enucleation and mitochondrial removal through enhancing autophagy, thereby accelerating erythroid cell maturation.