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Circulating Hematopoietic Stem/Progenitor Cell subsets contribute to human hematopoietic homeostasis

ABSTRACT: In physiological conditions, few circulating hematopoietic stem/progenitor cells (cHSPC) are present in peripheral blood (PB) and their role remain unsolved. By integrating advanced immunophenotyping, high-throughput transcriptome profiling and functional assays we characterized the biological properties of human cHSPC. We found distinct composition but comparable bone marrow (BM) homing and differentiation potential after xenotransplantation of cHSPC with respect to their BM counterpart. Trafficking HSPC are in a low-cycling pre-activated state with primitive and committed progenitors being transcriptionally and functionally skewed towards erythroid differentiation. Moreover, a subset of circulating lymphoid progenitors are primed for seeding lymphoid organs and can actively contribute to T-cell production in patients treated with gene therapy. In case of hematopoietic impairment, cHSPC content and composition correlate with BM-HSPC state. Altogether, our data unveiled the cHSPC contribution to steady-state hematopoiesis, with a key function in sustaining extramedullary lympho- and erythro-poiesis, and supported their clinical exploitation as biomarker for BM-HSPC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253485 | GEO | 2024/03/26

REPOSITORIES: GEO

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Project description:Epigenetic modifications must underlie lineage-specific differentiation since terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Hematopoiesis provides a well-defined model of progressive differentiation in which to study the role of epigenetic modifications in cell fate decisions. Multi-potent progenitors (MPPs) can differentiate into all blood cell lineages, while downstream progenitors commit to either myeloerythroid or lymphoid lineages. While DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs {Broske, 2009 #6}, a comprehensive DNA methylation map of hematopoietic progenitors, or of any cell lineage, does not exist. Here we have generated a mouse DNA methylation map, examining 4.6 million CpG sites throughout the genome including all CpG islands and shores, examining MPPs, all lymphoid progenitors (ALPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Interestingly, differentiation towards the myeloid lineage corresponds with a net decrease in DNA methylation, while lymphoid commitment involves a net increase in DNA methylation, but both show substantial dynamic changes consistent with epigenetic plasticity during development. By comparing lineage-specific DNA methylation to gene expression array data, we find many examples of genes and pathways not previously known to be involved in lymphoid/myeloid differentiation, such as Gcnt2, Arl4c, Gadd45α, and Jdp2. Several transcription factors, including Meis1 and Prdm16 were methylated and silenced during differentiation, suggesting a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome appears to be important in hematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation, often correlating with gene expression changes, and define a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions. mRNA expression of 8 hematopoietic progenitor populations [MPPFL-(5), MPPFL+(3), CMP(3), GMP(3), CLP(3), DN1(3), DN2(3), DN3(3)] were compared

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Circulating Hematopoietic Stem/Progenitor Cell subsets contribute to human hematopoietic homeostasis

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