- https://doi.org/10.62347/irbe1598
The effect of decitabine on human induced pluripotent stem cells (hiPSCs) derived CD34+ cells expansion and the megakaryocytes generation and maturation.
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Take Notes Epigenetic modifiers play an important role in regulating the fate of hematopoietic stem cells (HSCs). The chromatin-modifying agents (CMA) have previously been shown to expand HSCs from cord blood (CB) and bone marrow (BM) CD34+ cells. Meanwhile, DNA methylation maintains persistent cellular memories and is thought to be the primary epigenetic barrier to reprogramming. The DNA hypomethylation drug decitabine is one of the CMA that could alter gene expression and HSC self-renewal. It has been reported that decitabine could promote platelets generation in ITP patients. It's unknown if decitabine could affect CD34+ cells and megakaryocytes generation and maturation from human induced pluripotent stem cells (hiPSCs). We utilized serum free, exon free and feeder free differentiation system to generate CD34+ from hiPSCs and induced them differentiation into megakaryocytes. Different concentrations of decitabine were added at different stages and analyzed these cells by RT-PCR, flow cytometry analysis, cell counting and other regular experimental methods. The proliferation and function of CD34+ cells in vitro were significantly suspended after exposure to decitabine. Low concentration of decitabine could maintain the CD34+ function. In addition, we found that decitabine did not have any effect on the megakaryocyte generation, but it prevented megakaryocyte maturation. The DNA methyltransferases (DNMTs) changed a lot not only in CD34+ stage but also in the megakaryocyte generation and maturation due to decitabine addition. These results suggested that the effect of decitabine on CD34+ cells from hiPSCs was very different from CB, PB and BM CD34+ cells and the epigenetic changes may play an important role in the CD34+ expansion and megakaryocytes maturation. It may provide a potential mechanism of studying hiPSCs derived HSCs and megakaryocytes maturation in the future.
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BackgroundMigration, proliferation, and differentiation of hematopoietic stem cells (HSCs) are dependent upon a complex three-dimensional (3D) bone marrow microenvironment. Although osteoblasts control the HSC pool, the subendosteal niche is complex and its cellular composition and the role of each cell population in HSC fate have not been established. In vivo models are complex and involve subtle species-specific differences, while bidimensional cultures do not reflect the 3D tissue organization. The aim of this study was to investigate in vitro the role of human bone marrow–derived mesenchymal stromal cells (BMSC) and active osteoblasts in control of migration, lodgment, and proliferation of HSCs.Methodology/Principal FindingsA complex mixed multicellular spheroid in vitro model was developed with human BMSC, undifferentiated or induced for one week into osteoblasts. A clear limit between the two stromal cells was established, and deposition of extracellular matrix proteins fibronectin, collagens I and IV, laminin, and osteopontin was similar to the observed in vivo. Noninduced BMSC cultured as spheroid expressed higher levels of mRNA for the chemokine CXCL12, and the growth factors Wnt5a and Kit ligand. Cord blood and bone marrow CD34+ cells moved in and out the spheroids, and some lodged at the interface of the two stromal cells. Myeloid colony-forming cells were maintained after seven days of coculture with mixed spheroids, and the frequency of cycling CD34+ cells was decreased.Conclusions/SignificanceUndifferentiated and one-week osteo-induced BMSC self-assembled in a 3D spheroid and formed a microenvironment that is informative for hematopoietic progenitor cells, allowing their lodgment and controlling their proliferation.
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