Haematopoietic stem cell number is not solely defined by niche availability

Shoichiro Takeishi (), Tony Marchand, Wade R. Koba, Daniel K. Borger, Chunliang Xu, Chandan Guha, Aviv Bergman, Paul S. Frenette, Kira Gritsman and Ulrich Steidl ()
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Shoichiro Takeishi: Albert Einstein College of Medicine
Tony Marchand: Albert Einstein College of Medicine
Wade R. Koba: Albert Einstein College of Medicine-Montefiore Medical Center
Daniel K. Borger: Albert Einstein College of Medicine
Chunliang Xu: Albert Einstein College of Medicine
Chandan Guha: Albert Einstein College of Medicine-Montefiore Medical Center
Aviv Bergman: Albert Einstein College of Medicine-Montefiore Medical Center
Paul S. Frenette: Albert Einstein College of Medicine
Kira Gritsman: Albert Einstein College of Medicine
Ulrich Steidl: Albert Einstein College of Medicine

Nature, 2025, vol. 646, issue 8085, 687-696

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09462-5

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