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 language | English (US) |
|---|---|
| Pages (from-to) | 560-567 |
| Number of pages | 8 |
| Journal | Nature Cell Biology |
| Volume | 21 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2019 |
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ASJC Scopus subject areas
- Cell Biology
Cite this
Engineering a haematopoietic stem cell niche by revitalizing mesenchymal stromal cells. / Nakahara, Fumio; Borger, Daniel K.; Wei, Qiaozhi; Pinho, Sandra I.; Maryanovich, Maria; Zahalka, Ali H.; Suzuki, Masako; Cruz, Cristian D.; Wang, Zichen; Xu, Chunliang; Boulais, Philip E.; Ma’ayan, Avi; Greally, John M.; Frenette, Paul S.
In: Nature Cell Biology, Vol. 21, No. 5, 01.05.2019, p. 560-567.Research output: Contribution to journal › Letter
}
TY - JOUR
T1 - Engineering a haematopoietic stem cell niche by revitalizing mesenchymal stromal cells
AU - Nakahara, Fumio
AU - Borger, Daniel K.
AU - Wei, Qiaozhi
AU - Pinho, Sandra I.
AU - Maryanovich, Maria
AU - Zahalka, Ali H.
AU - Suzuki, Masako
AU - Cruz, Cristian D.
AU - Wang, Zichen
AU - Xu, Chunliang
AU - Boulais, Philip E.
AU - Ma’ayan, Avi
AU - Greally, John M.
AU - Frenette, Paul S.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85064533741&partnerID=8YFLogxK
U2 - 10.1038/s41556-019-0308-3
DO - 10.1038/s41556-019-0308-3
M3 - Letter
VL - 21
SP - 560
EP - 567
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 5
ER -