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Microenvironmental Control of Hematopoietic Niche Capacity via CXCL8 and Protein Kinase C

ABSTRACT: Altered hematopoietic stem cell (HSC) fate underlies primary blood disorders but microenvironmental factors controlling HSC fate are poorly understood. Genetically barcoded GESTALT zebrafish were used to screen for factors expressed by the sinusoidal vascular niche that alter the phylogenetic distribution of the HSC pool under native conditions. Dysregulated expression of protein kinase C delta (PKC-d, encoded by prkcda) increased the number of HSC clones by approximately 50% and expanded polyclonal populations of immature neutrophil and erythroid precursors. PKC agonists such as cxcl8 augmented HSC competition for residency within the niche and expanded defined niche populations. Cxcl8 induced association of PKC-d with the focal adhesion complex, activating MEK/ERK signaling and expression of niche factors in human endothelial cells. Our findings demonstrate the existence of reserve capacity within the niche which is controlled by PKC and has significant impact on HSC phylogenetic and phenotypic fate.

ORGANISM(S): Danio rerio Homo sapiens

PROVIDER: GSE191029 | GEO | 2023/05/15

REPOSITORIES: GEO

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Project description:Haematopoietic stem cells (HSCs) reside in bone marrow (BM) niches where they are maintained to replenish all blood cell lineages throughout life. Among the constituents of the murine HSC niches, various cell types such as CXCL12-abundant reticular (CAR) cells, Nestin-GFP+ perivascular cells, leptin receptor (LepR)+ cells, endothelial cells, osteoblasts, sympathetic nerves, macrophages and megakaryocytes in the BM have been proposed to contribute to HSC niche activity. When niche cells are removed from their natural habitat, the ability to maintain HSCs ex vivo is markedly diminished. Mesenchymal-derived stromal cells (MSCs) identified by Nestin-GFP express high levels of niche factors in vivo, but their expression is downregulated rapidly upon culture, suggesting that alterations in transcriptional rewiring may contribute to the reduced HSC maintenance potential. We found that the enforced expression of 5 genes (Klf7, Ostf1, Xbp1, Irf3 and Irf7) markedly restored HSC niche function in cultured BM-derived MSCs. These revitalized MSCs (rMSCs) exhibited boosted synthesis of HSC niche factors while retaining their mesenchymal lineage differentiation capacity. By contrast to HSCs co-cultured with control MSCs, HSCs expanded with rMSCs showed significantly higher repopulation capacity. To evaluate to what extent rMSCs are reprogrammed toward freshly isolated MSCs, we compared, by RNA-seq analysis, the transcriptome of freshly sorted CD45(-) Ter119(-) CD31(-) Scf-GFP(-) cells, CD45(-) Ter119(-) CD31(-) Scf-GFP(+) cells, rMSCs and control vector-transduced stroma. HSC niche-associated genes were highly expressed in both native Scf-GFP(+) stromal cells and rMSCs compared to the Scf-GFP cell fraction and control MSCs. With the motif analysis of ATAC-seq data, we found that myocyte enhancer factor 2c (Mef2c) is one of the key factor in the revitalization of MSCs. These results suggest that rMSC may provide a promising platform for curative transplantation therapies.

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Microenvironmental Control of Hematopoietic Niche Capacity via CXCL8 and Protein Kinase C

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