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Nat Cell Biol. 2019 May;21(5):560-567. doi: 10.1038/s41556-019-0308-3. Epub 2019 Apr 15.

Engineering a haematopoietic stem cell niche by revitalizing mesenchymal stromal cells.

Author information

1
Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, USA.
2
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
3
Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
4
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
5
Center for Epigenomics, Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
6
Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7
Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, USA. paul.frenette@einstein.yu.edu.
8
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA. paul.frenette@einstein.yu.edu.
9
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA. paul.frenette@einstein.yu.edu.

Abstract

Haematopoietic stem cells (HSCs) are maintained by bone marrow niches in vivo1,2, but the ability of niche cells to maintain HSCs ex vivo is markedly diminished. Expression of niche factors by Nestin-GFP+ mesenchymal-derived stromal cells (MSCs) is downregulated upon culture, suggesting that transcriptional rewiring may contribute to this reduced HSC maintenance potential. Using an RNA sequencing screen, we identified five genes encoding transcription factors (Klf7, Ostf1, Xbp1, Irf3 and Irf7) that restored HSC niche function in cultured bone marrow-derived MSCs. These revitalized MSCs (rMSCs) exhibited enhanced synthesis of HSC niche factors while retaining their mesenchymal differentiation capacity. In contrast to HSCs co-cultured with control MSCs, HSCs expanded with rMSCs showed higher repopulation capacity and protected lethally irradiated recipient mice. Competitive reconstitution assays revealed an approximately sevenfold expansion of functional HSCs by rMSCs. rMSCs prevented the accumulation of DNA damage in cultured HSCs, a hallmark of ageing and replication stress. Analysis of the reprogramming mechanisms uncovered a role for myocyte enhancer factor 2c (Mef2c) in the revitalization of MSCs. These results provide insight into the transcriptional regulation of the niche with implications for stem cell-based therapies.

PMID:
30988422
PMCID:
PMC6499646
[Available on 2019-10-15]
DOI:
10.1038/s41556-019-0308-3

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