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Identification of a common mesenchymal stromal progenitor for the adult haematopoietic niche.

ABSTRACT: Microenvironment cues received by haematopoietic stem cells (HSC) are important in regulating the choice between self-renewal and differentiation. On the basis of the differential expression of cell-surface markers, here we identify a mesenchymal stromal progenitor hierarchy, where CD45(-)Ter119(-)CD31(-)CD166(-)CD146(-)Sca1(+)(Sca1(+)) progenitors give rise to CD45(-)Ter119(-)CD31(-)CD166(-)CD146(+)(CD146(+)) intermediate and CD45(-)Ter119(-)CD31(-)CD166(+)CD146(-)(CD166(+)) mature osteo-progenitors. All three progenitors preserve HSC long-term multi-lineage reconstitution capability in vitro; however, their in vivo fates are different. Post-transplantation, CD146(+) and CD166(+) progenitors form bone only. While Sca1(+) progenitors produce CD146(+), CD166(+) progenitors, osteocytes and CXCL12-producing stromal cells. Only Sca1(+) progenitors are capable of homing back to the marrow post-intravenous infusion. Ablation of Sca1(+) progenitors results in a decrease of all three progenitor populations as well as haematopoietic stem/progenitor cells. Moreover, suppressing production of KIT-ligand in Sca1(+) progenitors inhibits their ability to support HSCs. Our results indicate that Sca1(+) progenitors, through the generation of both osteogenic and stromal cells, provide a supportive environment for hematopoiesis.

SUBMITTER: Hu X

PROVIDER: S-EPMC5062560 | biostudies-other | 2016 Oct

REPOSITORIES: biostudies-other

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Identification of a common mesenchymal stromal progenitor for the adult haematopoietic niche.

Hu Xingbin X Garcia Mayra M Weng Lihong L Jung Xiaoman X Murakami Jodi L JL Kumar Bijender B Warden Charles D CD Todorov Ivan I Chen Ching-Cheng CC

Nature communications 20161010

Microenvironment cues received by haematopoietic stem cells (HSC) are important in regulating the choice between self-renewal and differentiation. On the basis of the differential expression of cell-surface markers, here we identify a mesenchymal stromal progenitor hierarchy, where CD45-Ter119-CD31-CD166-CD146-Sca1+(Sca1+) progenitors give rise to CD45-Ter119-CD31-CD166-CD146< ...[more]

PMID: 27721421

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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.

Dataset Information

Identification of a common mesenchymal stromal progenitor for the adult haematopoietic niche.

Publications

Identification of a common mesenchymal stromal progenitor for the adult haematopoietic niche.

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