Crucial Role for Endoplasmic Reticulum Stress During Megakaryocyte Maturation

Abstract

Objective-Apoptotic-like phase is an essential step for the platelet formation from megakaryocytes. How controlled is this signaling pathway remained poorly understood. The aim of this study was to determine whether endoplasmic reticulum (ER) stress-induced apoptosis occurs during thrombopoiesis. Approach and Results-Investigation of ER stress and maturation markers in different models of human thrombopoiesis (CHRF, DAMI, MEG-01 cell lines, and hematopoietic stem cells: CD34 + ) as well as in immature pathological platelets clearly indicated that ER stress occurs transiently during thrombopoiesis. Direct ER stress induction by tunicamycin, an inhibitor of N-glycosylation, or by sarco/endoplasmic reticulum Ca 2+ ATPase type 3b overexpression, which interferes with reticular calcium, leads to some degree of maturation in megakaryocytic cell lines. On the contrary, exposure to salubrinal, a phosphatase inhibitor that prevents eukaryotic translation initiation factor 2α-P dephosphorylation and inhibits ER stress-induced apoptosis, decreased both expression of maturation markers in MEG-01 and CD34 + cells as well as numbers of mature megakaryocytes and proplatelet formation in cultured CD34 + cells. Conclusions-Taken

The unfolded protein response in retinal vascular diseases: Implications and therapeutic potential beyond protein folding

“…For instance, ER stress was induced in hematopoietic CD34 + cells isolated from cord blood when treated with thrombopoietin to promote magakaryocyte differentiation and maturation (Lopez, Palazzo et al 2013). Moreover, induction of ER stress was observed in embryonic stem cells and in bone marrow stromal cells when these cells were differentiated into neurons (Cho, Jang et al 2009).…”

Calreticulin gene exon 9 frameshift mutations in patients with thrombocytosis

“…For example, as a Ca 2+ -sensor calreticulin regulates Ca 2+ homeostasis and the ER stress response, which is important for megakaryocyte maturation and platelet formation. 7 Interactions of the calreticulin N domain with thrombospondin-1 and LRP1 mediate focal adhesion disassembly, 8 keratinocyte and fibroblast migration 9 as well as the expression of TGF β 3 and collagen. 4 Collectively, these processes are related to wound healing and fibrosis, a hallmark of MPN pathology.…”

Platelet dense granules begin to selectively accumulate mepacrine during proplatelet formation

“…However, while TPO is well-established as the main driver of MK differentiation 55–57 , the signals that trigger proplatelet formation are much less characterized. One hypothesis in the field suggests that controlled apoptosis through transient ER stress may initiate thrombopoiesis 58 . It is thus conceivable that the process of DG maturation might be initiated by activation of ER stress-regulated unfolded response effectors such as IRE1, ATF1 or PERK 59 , or by altered activity of kinases, such as mTORC1, that stimulate autophagy 60 .…”