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PEAR1 is a potential regulator of early hematopoiesis of human pluripotent stem cells

ABSTRACT: Human pluripotent stem cells (hPSCs) provide a potential resource for the generation of functional blood cells in vitro. However, it remains largely unknown about the mechanism underlying hPSC-derived hematopoiesis. Here, we identified platelet endothelial aggregation receptor-1 (PEAR1) as a potential regulator of early hematopoietic development of hPSCs. We found that the expression of PEAR1 was gradually increased during endothelial and hematopoietic development. The hematopoietic potential was enriched in PEAR1+ population and PEAR1 could be used as a potential marker to enrich hemogenic endothelium. Moreover, knockout of PEAR1 impaired the hematopoietic potential of hPSCs. Collectively, our findings demonstrate that PEAR1 is required for early hematopoiesis and can be potentially used for establishing new strategies to produce more functional blood cells from hPSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198739 | GEO | 2024/03/30

REPOSITORIES: GEO

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Project description:MLL-AF4 is a hallmark genomic aberration which arises prenatally in high-risk infant acute lymphoblastic leukemia (ALL). In human embryonic stem cells (hESCs), MLL-AF4 skewed hemato-endothelial specification but was not sufficient for transformation. Additional cooperating genetic insults seem required for MLL-AF4-mediated leukemogenesis. FLT3 is highly expressed in MLL-AF4+ ALL through activating mutations (FLT3-TKD or FLT3-ITD) or increased transcriptional expression, being therefore considered a potential cooperating event in MLL-AF4+ ALL. Here, we explored the developmental impact of FLT3 activation on its own or in cooperation with MLL-AF4 in the hematopoietic fate of hESCs. FLT3 activation did not impact specification of CD45-CD31+ hemogenic precursors but significantly enhanced the formation of CD45+CD34+ and CD45+ blood cells and blood progenitors with clonogenic potential. Importantly, FLT3 activation through FLT3 mutations or FLT3-WT overexpression completely abrogated hematopoietic differentiation from MLL-AF4-expressing hESCs, indicating that FLT3 activation cooperates with MLL-AF4 to inhibit human embryonic hematopoiesis. Cell cycle/apoptosis analyses suggest that FLT3 activation directly impacts hESC specification rather than selective proliferation/survival of hESC-emerging hematopoietic derivatives. Transcriptional profiling supported the limited impact of FLT3 activation on hESC specification towards CD45-hemogenic precursors and the enhanced hematopoiesis upon FLT3 activation, and inhibited hematopoiesis upon MLL-AF4 expression in FLT3-activated hESCs which was associated to large transcriptional changes and regulation of master early hematopoietic genes. Also, although FLT3 activation and MLL-AF4 cooperate to inhibit embryonic hematopoiesis the underlying molecular/genetic mechanisms differ depending on how FLT3 activation is achieved. Finally, FLT3 activation did not cooperate with MLL-AF4 to immortalize/transform hESC-derived hematopoietic cells. 18 samples were analyzed. CD45- hemogenic precursors EV, 2 biological rep CD45- hemogenic precursors FLT3-TKD, 2 biological rep CD45- hemogenic precursors FLT3-WT, 2 biological rep CD45- hemogenic precursors FLT3-TKD/MLLAF4, 2 biological rep CD45- hemogenic precursors FLT3-WT/MLLAF4, 2 biological rep CD45+ blood cells EV, 1 biological rep CD45+ blood cells FLT3-TKD, 2 biological rep CD45+ blood cells FLT3-WT, 2 biological rep CD45+ blood cells FLT3-TKD/MLLAF4, 2 biological rep CD45+ blood cells FLT3-WT/MLLAF4, 1 biological rep

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PEAR1 is a potential regulator of early hematopoiesis of human pluripotent stem cells

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