Engineering a haematopoietic stem cell niche by revitalizing mesenchymal stromal cells
Open accessAbstract
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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A screen identified five transcription factors (including KLF7 and XBP1) that, when expressed in niche cells ex vivo, sustain HSC function for subsequent competitive reconstitution assays.
“With use of this system, a screen identified five transcription factors (including KLF7 and XBP1) that, when expressed in niche cells ex vivo, sustain HSC function for subsequent competitive reconstitution assays235.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [235]
Expression of these transcription factors prevents the accumulation of DNA damage in HSCs ex vivo.
“Indeed, expression of these transcription factors prevents the accumulation of DNA damage, as occurs during ageing in vivo, in HSCs ex vivo.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [235]
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- Authors
- 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.
- Affiliations
- Albert Einstein College of Medicine (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Frenette, Paul S.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2019-04-15
- Volume
- 21
- Issue
- 5
- Pages
- 560-567
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC6499646
- OpenAlex
- W2937317283
- Cited by
- 99
- References
- 42
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 10 · 2023: 15 · 2022: 16 · 2021: 15 · 2020: 19 · 2019: 9
- FWCI
- 10.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Vector Institute
- National Heart, Lung, and Blood Institute (U54HL127624, R01HL069438)
- National Cancer Institute (U24CA224260, F30CA203446)
- National Institute of General Medical Sciences (T32GM007491, T32GM007288)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK112976, R01DK056638, U01DK116312)
- National Institute of Neurological Disorders and Stroke (T32NS007098)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- hematopoietic stem cells, bone marrow microenvironment, mesenchymal stem cells, transcriptional reprogramming, KLF7, XBP1, IRF3, IRF7, MEF2C, HSC expansion, DNA damage, stem cell therapy
- MeSH terms
- X-Box Binding Protein 1, Animals, Bone Marrow Cells, Cell Differentiation, Gene Expression Regulation, Hematopoietic Stem Cells, Humans, Mice, Transgenic, Peptides, Sequence Analysis, RNA, Intracellular Signaling Peptides and Proteins, Interferon Regulatory Factor-3, Mice, Kruppel-Like Transcription Factors, Stem Cell Niche, Mesenchymal Stem Cells, Cell Engineering, Nestin
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