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    • The sorted BMSC and HSPC populations were observed

    2018-11-06

    The sorted BMSC and HSPC populations were observed to exist in distinct states of the cell cycle, equally important for their functions as stem cells. The MG-132 gene expression studies further ascertained the cellular physiology of both the sorted cell populations. Our results also coincide with studies reported by Zou et al., that both p57 and p27 cooperate with Hsp-70 to maintain HSPC quiescence (Zou et al., 2011). Similarly, Passague et al., demonstrated a sequential expression pattern of cyclins and CKIs during different stages of self-renewal and differentiation in HSPCs (Passegue et al., 2005). The literature suggested that overexpression of cyclin D2 also led to an increased proliferation in human BMSCs (Kono et al., 2013). It is pertinent to mention that although we demonstrated a high percentage of BMSCs expressing cyclins D2 and B1 in the proliferative phase, the data do not exclude the existence of a fraction of BMSCs in G0 phase. In the bone marrow stem cell niche, various molecular cues maintain the physiological states such as proliferation or differentiation of BMSCs and HSPCs. Emerging evidences suggest that stem cells undergo major epigenetic alterations during development and differentiation (Huang et al., 2015). Epigenetic regulation via histone acetylation/deacetylation is a dynamic process that is orchestrated by the interplay between histone acetyl transferases and HDACs. Studies in the past revealed an important role of HDACs in stem cell differentiation of both adult and embryonic stem cells. Small molecule HDAC inhibitors have been shown to enhance BMSC\'s differentiation into the adipocyte lineages by upregulating the expression of PPAR gamma (Yoo et al., 2006). Further, in human embryonic stem cells (hESC), TSA has been shown to induce cardiomyocyte differentiation by involving GATA-4 (Kawamura et al., 2005). Additionally, during neural differentiation, an inhibition of HDAC activity by TSA promoted pluripotency maintenance at the initial stage of hESC differentiation, but later inhibited differentiation during the neural commitment stage (Qiao et al., 2015). HDAC1 and HDAC2 deletion in mouse embryonic stem (mESC) cells did not affect ESC proliferation, but led to a marked decrease in ESC differentiation, i.e., embryoid body (EB) formation (Dovey et al., 2010). Further, HDAC1-deficient EBs were significantly smaller, showed spontaneous rhythmic contraction, and increased expression of both cardiomyocyte and neuronal markers (Dovey et al., 2010). Although the role of HDAC inhibition on stem cell differentiation has been explored extensively, its role on stem cell proliferation is limited. Wilting et al., have revealed the overlapping roles of HDAC1 and HDAC2 in hematopoiesis and cell cycle regulation by dual inactivation of both HDAC1 and HDAC2, which led to apoptosis of megakaryocytes and thrombocytopenia (Wilting et al., 2010). Zupkowitz and colleagues demonstrated the essential requirement of HDAC1 for mouse development which is to regulate cellular proliferation and represses the CKI, p21 (Zupkovitz et al., 2010). In addition, studies also suggested that loss of HDAC1 in T cells led to increased proliferation, indicating that the role of HDACs on proliferation is cell type-dependent. These HDACs are known to regulate different sets of target genes that govern the outcome of cellular proliferation in a particular cell type. Our analysis also revealed a higher expression of both HDAC1 and HDAC2 in BMSCs as compared with HSPCs, suggesting their role in regulating the cell cycle. HDAC3, another class I HDAC, has been shown to control G1-S transition in resting T cells by repressing Skp2 transcription, leading to increased levels of p27 and consequently halting the cell cycle in the G0/G1 phase (Zhang et al., 2008). Similarly, HSPCs expressed a higher level of HDAC3 in our study, which implies its indirect role in regulating p27-mediated low proliferative state. Thus, HDACs participate in maintenance of wide physiological functions in the adult stem cells. Pharmacological inhibition of HDACs with small molecule inhibitors will provide further insight into the molecular functioning of this highly important class of enzymes.