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CXCR4 drives lympho-myeloid fate of hematopoietic progenitors via mTOR and mitochondrial metabolic pathways

ABSTRACT: Hematopoietic stem and progenitor cells (HSPCs), including the multipotent progenitors (MPPs), are responsible for replenishing immune cells. They reside in bone marrow (BM) endosteal and (peri)-vascular niches, which provide all cellular and molecular components required for their lifelong maintenance and fate. Among them, the CXCL12 chemokine and one of its receptor, CXCR4, exert a dominant role in promoting HSPC retention and quiescence. These processes are deregulated in the WHIM Syndrome (WS), a rare immunodeficiency caused by inherited heterozygous autosomal gain-of-function CXCR4 mutations that affect homologous desensitization of the receptor. Clinically, WS is notably characterized by severe, chronic circulating lymphopenia whose mechanisms remain to be elucidated. Using a mouse model carrying a naturally occurring WS-linked Cxcr4 mutation, we explored the possibility that the lymphopenia in WS originates from defects at the MPP level in BM. The global strategy consists in performing high-throughput RNA-seq analyses of the different MPP subsets bearing or not the WS-linked Cxcr4 mutation to investigate the impact of the gain-of-Cxcr4-function on the molecular identity of MPP subsets.

ORGANISM(S): Mus musculus

PROVIDER: GSE182992 | GEO | 2021/09/02

REPOSITORIES: GEO

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Bone marrow lympho-myeloid malfunction in obesity requires precursor cell-autonomous TLR4

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2016-08-03 | E-GEOD-73143 | biostudies-arrayexpress

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Location of indigenous human HSCs reveals functional properties of HSCs that are dictated by anatomic and cellular architecture of bone marrow II

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Project description:MYSM1 is a transcriptional regulator essential for HSC function and hematopoiesis. We established that p53 activation is a common mechanism mediating HSC dysfunction, MPP depletion, and lymphopenia in Mysm1-deficiency, however, the specific p53-induced effectors that trigger dysfunction in Mysm1-deficient HSPCs remain unknown. Here, we performed RNA-Seq of Lin-cKit+Sca1+CD150+ and CD150- HSPCs from Mysm1-/-Puma-/-, Mysm1-/-Puma+/-, Puma-/-, and wild-type mice; (Mysm1-/-Puma+/- phenocopies Mysm1-/-). We showed that Bbc3/PUMA is the primary non-redundant mediator of MPP depletion in Mysm1-deficiency and contributes to HSC dysfunction, whereas depletion of lymphoid-lineage cells involves PUMA-independent p53 activities. We also identified a broad downregulation of genes encoding protein components of the ribosome (RP-genes) and other regulators of translation in Mysm1-deficiency, and the downregulation persisted in Mysm1-/-Puma-/-.

2020-07-22 | GSE150665 | GEO

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