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Stromal STAT5-mediated trophic activity regulates hematopoietic multipotent progenitor niche factors

ABSTRACT: Signal transducer and activator of transcription 5 (STAT5a and STAT5b) are intrinsically critical for normal hematopoiesis but are also expressed in stromal cells. However, hematopoiesis-supporting stromal function has not been reported. Here, STAT5ab knockout (KO) was generated with a variety of bone marrow hematopoietic and stromal Cre transgenic mouse strains. Pan-hematopoietic deletion with Vav1-Cre was the positive control for loss of multipotent hematopoietic function but surprisingly dysregulated niche factor mRNA expression and deleted STAT5ab in CD45neg cells. Single cell transcriptome analysis of mouse bone marrow from wild-type or Vav1-Cre KO mice showed major changes in hematopoietic stem cell myeloid commitment genes and upregulated protein translation genes throughout myeloid-primed clusters.

ORGANISM(S): Mus musculus

PROVIDER: GSE214857 | GEO | 2023/10/01

REPOSITORIES: GEO

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Project description:Decline in hematopoietic function in aged individuals is associated with expansion of phenotypic hematopoietic stem cells (HSCs) and a shift in their lineage potential toward production of myeloid cells. Both HSC-intrinsic changes, and extrinsic changes in the bone marrow (BM) microenvironment, have been identified in old mice and humans. However, to extend healthy and robust hematopoietic function from youth into older age, we need to understand and effectively target the processes that initiate functional hematopoietic decline. We recently identified decline in Insulin-Like Growth Factor 1 (IGF1) in the BM microenvironment as early as middle age to be an HSC-extrinsic initiating driver of HSC aging (Young et al., Cell Stem Cell 2021). As systemic IGF1 administration has significant undesirable side effects, we sought to comprehensively interrogate the cell population(s) in the BM microenvironment that are responsible for IGF1 decline, towards the goal of cell type-specific targeted therapy. We performed single cell RNA-seq to comprehensively profile hematopoietic and non-hematopoietic fractions of the BM in young (2-4mo; n = 5 biological replicates) and middle-aged (12-14mo; n = 10) mice. In young mice, we find Igf1 to be nearly entirely detected in the mesenchymal stromal cell populations Adipo-CAR and Osteo-CAR, and Igf1 is significantly reduced in expression in both populations in middle-aged mice. Using two independent mesenchymal stromal cell Cre mouse lines, Lepr-Cre and Prx1-CreERT2, we found that knockout of Igf1 resulted in myeloid-biased hematopoiesis that replicated aging phenotypes. This result was similar to our published work showing that knockout of Igf1 using Nestin-CreER causes myeloid-biased hematopoiesis. While these Cre models generally do not mark similar cell types, it has been shown that Lepr-Cre-expressing perisinusoidal stromal cells include cells that express certain Nestin transgenes. Using fluorescent reporters, we find that all three lines (Lepr-Cre, Prx1-CreERT2, and Nestin-CreER) overlap in expression in the CAR populations that abundantly express Igf1 in young mice. Taken together, our work identifies a new role for Cxcl12-abundant reticular cells in sustaining hematopoietic function through local IGF1 production and suggests that specifically targeting CAR cells to maintain or restore Igf1 expression during aging will have beneficial effects on lymphoid cell production and adaptive immunity.

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Stromal STAT5-mediated trophic activity regulates hematopoietic multipotent progenitor niche factors

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