Engineering a haematopoietic stem cell niche by revitalizing mesenchymal stromal cells

Fumio Nakahara, Daniel K. Borger, Qiaozhi Wei, Sandra Pinho, Maria Maryanovich, Ali H. Zahalka, Masako Suzuki, Cristian D. Cruz, Zichen Wang, Chunliang Xu, Philip E. Boulais, Avi Ma’ayan, John M. Greally, Paul S. Frenette

Research output: Contribution to journalLetter

15 Scopus citations

Abstract

Haematopoietic stem cells (HSCs) are maintained by bone marrow niches in vivo 1,2 , 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.

Original languageEnglish (US)
Pages (from-to)560-567
Number of pages8
JournalNature Cell Biology
Volume21
Issue number5
DOIs
StatePublished - May 1 2019

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Nakahara, F., Borger, D. K., Wei, Q., Pinho, S., Maryanovich, M., Zahalka, A. H., Suzuki, M., Cruz, C. D., Wang, Z., Xu, C., Boulais, P. E., Ma’ayan, A., Greally, J. M., & Frenette, P. S. (2019). Engineering a haematopoietic stem cell niche by revitalizing mesenchymal stromal cells. Nature Cell Biology, 21(5), 560-567. https://doi.org/10.1038/s41556-019-0308-3