Haematopoietic stem cell number is not solely defined by niche availability
- PMID: 40866696
- DOI: 10.1038/s41586-025-09462-5
Haematopoietic stem cell number is not solely defined by niche availability
Abstract
Haematopoietic stem cells (HSCs) reside in specialized microenvironments, referred to as niches, and the classical model suggests that HSC numbers are predominantly determined by the niche size1-5. However, the vast excess of niche cells relative to HSCs challenges this perspective. To rigorously define the role of niche size in regulating HSC numbers, we developed a femur-transplantation system, enabling us to increase available HSC niches. Notably, the addition of niches did not alter the total HSC numbers in the body, suggesting the presence of a systemic mechanism that limits HSC numbers. Additionally, HSC numbers in transplanted wild-type femurs did not exceed physiological levels when HSCs were mobilized from defective endogenous niches to the periphery, indicating that HSC numbers are constrained at the local level as well. The notion of dual restrictions at systemic and local levels was further supported by other experimental approaches, including parabiosis and non-conditioned transfer of HSCs after bone transplantation. Moreover, we found that thrombopoietin has a pivotal role in determining the total number of HSCs in the body, even in the context of increased niche availability. Our study redefines key principles underlying HSC number regulation, providing insights into this critical biological process.
© 2025. The Author(s).
Conflict of interest statement
Competing interests: T.M. serves as a consultant for Astellas, Jazz Pharmaceuticals, Servier and Sobi, and has received personal fees from Jazz Pharmaceuticals and Servier outside the submitted work. C.G. has received grants and personal fees from Janssen and Varian, and grants from Celldex outside the submitted work. P.S.F. served as a consultant for Pfizer, received research funding from Ironwood Pharmaceuticals outside the submitted work, and was a shareholder of Cygnal Therapeutics. K.G. has received research funding from ADC Therapeutics and iOnctura outside the submitted work. U.S. has received grants from GlaxoSmithKline, Bayer Healthcare, Aileron Therapeutics and Novartis, and personal fees from GlaxoSmithKline, Bayer Healthcare, Celgene, Aileron Therapeutics, Stelexis Therapeutics, Pieris Pharmaceuticals, Trillium and Pfizer outside the submitted work. U.S. has equity ownership in and has served on the board of directors of Stelexis Therapeutics outside the submitted work. U.S. has equity ownership in Roshon Therapeutics outside the submitted work. The other authors declare no competing interests.
Update of
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Haematopoietic stem cell numbers are not solely determined by niche availability.bioRxiv [Preprint]. 2023 Oct 29:2023.10.28.564559. doi: 10.1101/2023.10.28.564559. bioRxiv. 2023. Update in: Nature. 2025 Aug 27. doi: 10.1038/s41586-025-09462-5. PMID: 37961493 Free PMC article. Updated. Preprint.