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

Abstract

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.

Effect of Glucocorticosteroids in Diamond-Blackfan Anaemia: Maybe Not as Elusive as It Seems

“…Notably, increased mTOR leads to macrocytic anaemia [80], consistent with the DBA phenotype [81]. mTOR has a dual role in RBC development [82]. Its activity is necessary for proper BFU-E and CFU-E cell proliferation in the primary steps of RBC development.…”

“…The other important pathway is inactivation of Akt signalling by GCs in DBA cells [13,93]. Even though GC-induced mTOR inactivation may lead to decreased proliferation of BFU-E and CFU-E cells [82], stress-induced erythropoiesis may compensate for this [39] (Figure 3).…”

Fine‐Tuning of Cholesterol Homeostasis Controls Erythroid Differentiation

“…mTORC1 has been shown to play distinct roles at different stages of erythropoiesis, and its perturbations result in anemia. [ 61,62 ] The requirements of mTORC1 activation for erythroid progenitor proliferation and mTORC1 inhibition for terminal enucleation are highly relevant with our findings. It is possible that high levels of cholesterol activate mTORC1 and subsequent ribosome biogenesis to enhance protein and lipid synthesis that are required for the rapid cell divisions in the early stage of terminal differentiation, while lower cholesterol inhibits mTORC1 activity and ribosome biogenesis and activates p53, thereby coordinating termination of cell proliferation and cell cycling in the later stage of erythroid differentiation.…”

Dihydroartemisinin Inhibits TGF-β-Induced Fibrosis in Human Tenon Fibroblasts via Inducing Autophagy

“…Autophagy is an important cellular process, which enables cytoplasmic components to move to the lysosome for degradation. 10 The aberrant occurrence of autophagy can lead to the dysfunction of cellular organelles. 11 , 12 On the other hand, autophagy protects organisms from inflammatory injuries via the modulation of the apoptotic cascade.…”