Direct chemical reprogramming of human cord blood erythroblasts to induced megakaryocytes that produce platelets
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PROVIDER: PRJNA856626 | ENA |
REPOSITORIES: ENA
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Project description:The shortage of platelets is becoming increasingly prominent owing to their short shelf life, limited supply, and increasing demand in response to public health incidents. It is an attractive idea to obtain large numbers of transfusible megakaryocytes (MKs) and platelets from somatic cells via cell lineage reprogramming. However, generating human MKs from somatic cells using a pharmacological reprogramming approach has not been widely explored. Here, we report the successful generation of human induced MKs (iMKs) from cord blood erythroblasts (EBs) using a chemical reprogramming strategy with a combination of four small molecules (4M): Bix01294, RG108, VPA, and PD0325901. The iMKs exhibited the ability to produce proplatelets and release vital functional platelets in vitro, demonstrating their similarity to natural MKs. Importantly, after injection into mice, iMKs were able to mature and give rise to functional platelets that were incorporated into newly formed thrombi. The reprogramming process was carefully examined using single-cell RNA sequencing, which revealed an efficient, rapid, and successful cell fate conversion of EBs to iMKs by 4M via the intermediate state of bipotent precursors. Assay for transposase-accessible chromatin sequencing results indicated that 4M induced genome-wide chromatin remodeling during MK reprogramming from EBs. 4M drove the transition of the transcription factor gene network by downregulating the key erythroid transcription factor genes KLF1 and MYB and subsequently upregulating MK development-associated transcription factor genes, including FLI1 and MEIS1. This process eventually led human cord blood EBs to acquire the MK fate. Thus, our chemical reprogramming of cord blood EBs to iMKs provides a simple and efficient approach to generating clinically transfusible MKs and platelets.
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Project description:We developed a novel differentiation system that directionally induces hESCs into megakaryocytes and functional platelet in vitro by highly mimicking the in vivo developmental process of megakaryocytes and platelets. We then performed gene expression profiling analysis using data obtained by RNA-seq at different stages of differentiation during the differentiation of hESCs into megakaryocyte lineages.
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Project description:Megakaryocytes and erythroblasts derive from the same progenitor cell type but carry out very different functions. In order to understand how the different functional phenotypes arise we have characterised the epigenetic landscape of these cells.
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Project description:Maps of open chromatin in three primary human blood cell types of the myeloid lineage (megakaryocytes, erythroblasts and monocytes) using the formaldehyde-assisted isolation of regulatory elements method followed by next-generation sequencing (FAIRE-seq). We also generated FAIRE-seq data in the megakaryocytic cell line CHRF-288-11. In addition to our data sets, we retrieved FAIRE-seq data for the erythroblastoid cell line K562 (ENCODE Project Consortium 2012) and pancreatic islets (Gaulton et al. 2010), and reanalyzed these data sets using the same methodology.
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Project description:Platelet-rich plasma (PRP), which is prepared by concentrating platelets in autologous blood, shows efficacy in chronic skin wounds via multiple growth factors. However, it exhibits heterogeneity across patients, leading to unstable therapeutic efficacy. Human induced pluripotent stem cell-derived megakaryocytes and platelets (iMPs) are capable of providing a stable supply, holding promise as materials for novel therapies. Thus, we evaluated the effect of iMPs on wound healing in vitro. iMPs specifically released FGF2 and exhibited superior enhancement on HUVEC proliferation compared to PRP. RNA-seq revealed that iMPs induce polarization to stalk cells and enhance ANGPTL4 gene expression in HUVECs. These mechanisms were suggested to provide the superior effects of iMPs.
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Project description:Circulating nucleic acids are present in plasma and are derived from a range of cell types, mainly cells of hematopoietic origin, enabling their use as biomarkers for diseases involving these cell types. Using cell type-specific methylation markers, we determined that megakaryocytes are major contributors to cfDNA (~26%), while erythroblasts contribute 1-4% of cfDNA in healthy individuals. Additionally, we identified megakaryocyte-derived DNA within platelets, providing non-invasive access to the megakaryocyte genome and epigenome. Analysis of cfDNA in women who have received male platelet transfusions indicates that megakaryocyte-derived cfDNA does not originate from platelets but is rather released directly from megakaryocytes. The concentration of megakaryocyte-derived cfDNA is elevated in individuals with pathologies involving increased platelet production (Essential Thrombocythemia, Idiopathic Thrombocytopenic Purpura) and decreased by bone marrow suppression (due to chemotherapy), while erythrocyte progenitor cfDNA is elevated in patients with Thalassemia. Megakaryocyte- and erythroblast-specific DNA methylation patterns may serve as novel biomarkers for pathologies involving increased or decreased thrombopoiesis and erythropoiesis.
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Project description:Dominant-negative mutations in transcription factor Growth Factor Independence-1B (GFI1B) cause a bleeding disorder characterized by a plethora of megakaryocyte and platelet abnormalities. The deregulated molecular mechanisms and pathways are unknown. Here we show that normal and mutant GFI1B interacted most strongly with the LSD1-RCOR-HDAC corepressor complex in megakaryoblasts. Sequestration of this complex by mutant GFI1B and chemical separation of GFI1B from LSD1 induced abnormalities in normal megakaryocytes comparable to those seen in patients. Megakaryocytes derived from GFI1B-mutant induced pluripotent stem cells (iPSC) also phenocopied abnormalities seen in patients. Proteome studies on normal and mutant iPSC-derived megakaryocytes identified a multitude of deregulated pathways downstream of mutant GFI1B. Proteome studies on primary normal and GFI1B-mutant platelets showed reduced expression of proteins implicated in platelet function, and sustained expression of proteins normally downregulated during megakaryocyte differentiation. Thus, GFI1B regulates a broad developmental program during megakaryopoiesis. Mutant GFI1B deregulates this program through LSD1-RCOR-HDAC sequestering.
2019-01-25 | PXD009020 | Pride
Project description:Thrombopoietin (TPO) acting via its receptor Mpl is the major cytokine regulator of platelet number. To precisely define the role of specific hematopoietic cells in TPO dependent hematopoiesis, we generated mice that express the Mpl receptor normally on stem/progenitor cells but lack expression on megakaryocytes and platelets (MplPF4cre/PF4cre). MplPF4cre/PF4cre mice displayed profound megakaryocytosis and thrombocytosis with a remarkable expansion of megakaryocyte-committed and multipotential progenitor cells, the latter displaying biological responses and a gene expression signature indicative of chronic TPO over-stimulation as the underlying causative mechanism, despite a normal circulating TPO level. Thus, TPO signaling in megakaryocytes is dispensable for platelet production; its key role in control of platelet number is via generation and stimulation of the bipotential megakaryocyte precursors. Nevertheless, Mpl expression on megakaryocytes and platelets is essential to prevent megakaryocytosis and myeloproliferation by restricting the amount of TPO available to stimulate the production of megakaryocytes from the progenitor cell pool.
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