Understanding the systemic regulation of haematopoietic stem cell (HSC) populations in the mammalian body has long fascinated scientists, particularly in the context of bone marrow (BM) niche availability. Traditionally, it has been assumed that the BM microenvironment—the niche—is the primary determinant that dictates the number of HSCs maintained within the body. However, groundbreaking research by Takeishi et al. challenges this niche-centered paradigm, unveiling a crucial role for systemic factors in restricting total HSC numbers, even when local niche availability is artificially expanded.
The study addresses a fundamental question in stem cell biology: Are HSC numbers constrained solely by the quantity and quality of BM niches, or does the body employ systemic signaling mechanisms to fine-tune this balance? To probe this, the investigators employed a sophisticated model that involved transplanting multiple wild-type (WT) femurs, loaded with normal HSC numbers, into genetically altered mice with varied expression levels of thrombopoietin (TPO). TPO, a glycoprotein hormone best known for regulating platelet production, also plays a well-established role in HSC maintenance and expansion within the BM niche.
In their first experimental setup, Takeishi et al. transplanted six WT femurs into mouse recipients with three distinct TPO genotypes: normal (Tpo^+/+), heterozygous knockout (Tpo^+/−), and homozygous knockout (Tpo^−/−). This arrangement created an environment where the availability of niches was artificially boosted by the presence of the grafted bone, allowing the researchers to assess whether TPO acts locally at the level of individual femurs or systemically to regulate the total HSC pool. Notably, the researchers hypothesized that if TPO primarily imposed local constraints, HSC numbers in host femurs and grafted femurs of TPO-deficient mice would mirror those of sham-operated controls. Conversely, if systemic regulation is dominant, adjustments in HSC numbers might occur bodywide to maintain a fixed global limit.
The results were striking. As expected, the sham-operated Tpo^+/− mice displayed reduced HSC numbers per femur compared to Tpo^+/+ controls, and this reduction was more pronounced in Tpo^−/− mice, underscoring TPO’s role in sustaining HSC populations under physiological conditions. Yet, in the bone-transplanted Tpo^+/− mice, HSC numbers per host femur and graft were significantly lower than their sham-operated counterparts. Intriguingly, when examining the entire body excluding grafts, a similar trend emerged, indicating that the recipient mice adapted their HSC numbers systemically rather than expanding HSC populations locally in response to increased niches. When summing HSC counts across both host and graft femurs, no significant difference was observed between bone-transplanted and sham-operated mice of the same genotype. This finding strongly supports the notion that TPO defines a systemic ceiling for HSC numbers, preventing unchecked accumulation even when more niches become available.
Further elucidating this systemic impact, the team explored the effect of elevated TPO levels on HSC dynamics by performing a parallel set of experiments in Tpo-transgenic (Tpo-Tg) mice, which overexpress TPO under the control of the albumin promoter. Comparative analysis highlighted that Tpo-Tg mice in the sham-operated state possessed significantly more HSCs per femur compared to wild-type littermates, underpinning the potent role of TPO as an HSC regulator. Upon transplantation of multiple WT femurs into the Tpo-Tg hosts, investigators noted a consistent decline in HSC numbers per host femur compared to sham-operated controls, mirroring observations in the knockout models and reinforcing the premise that TPO does not restrict HSC numbers strictly at the local niche level.
Adding to this, the total HSC content in transplanted Tpo-Tg mice, when considering both host and graft, was significantly higher than that of wild-type hosts. Importantly, the overall HSC numbers did not differ between sham-operated and bone-transplanted Tpo-Tg mice, further confirming that TPO governs a systemic regulation of HSC populations, adjusting the balance across the whole organism rather than expanding or contracting numbers locally in isolated compartments.
The study’s innovative approach—combining genetic modulation of TPO expression with multi-femur transplantation—enables a nuanced dissection of the relationship between niche availability and systemic signaling. The observed homeostatic maintenance of total HSC numbers despite increased niches implicates long-range factors like TPO as fundamental systemic gatekeepers in balancing stem cell reserves. This challenges long-standing views that niche capacity is the dominant limiting factor and opens new vistas into endocrine-like control mechanisms over stem cell populations.
One implication of these findings is that HSC homeostasis involves feedback loops beyond the BM microenvironment, incorporating circulatory signals that inform stem cells and niches of the body’s overall hematopoietic needs. In other words, even with artificially expanded physical niches, the stem cell pool cannot expand uncontrollably if systemic cues signal that supply already meets demand. Such mechanisms could prevent overproliferation of HSCs, minimizing risks of hematologic malignancies or exhaustion due to hyperactivation.
Intriguingly, TPO’s systemic role in limiting HSC numbers complements its well-documented local functions, such as promoting HSC quiescence and survival within niches. This duality in TPO’s action suggests a sophisticated regulatory network wherein local signals and endocrine factors dynamically integrate to calibrate stem cell maintenance and expansion according to physiological context.
These findings also hold potential translational significance. Therapeutic manipulation of TPO signaling might enable tailored expansion of HSCs for transplantation purposes or enhance recovery following myelosuppressive treatments. Conversely, dysregulation of TPO-mediated signals might contribute to hematologic disorders characterized by aberrant stem cell proliferation or deficiency. Thus, understanding this systemic regulation is crucial for designing interventions that respect the body’s intrinsic stem cell number set points.
Moreover, the study invites further exploration into other systemic factors potentially involved in governing stem cell pools across different tissues. It raises compelling questions regarding whether similar systemic constraints govern other adult stem cell compartments, such as neural or epithelial stem cells.
In conclusion, Takeishi et al.’s work compellingly demonstrates that the total number of HSCs within the body is not solely dictated by the availability of local niches but is profoundly influenced by systemic signals such as TPO. This endocrine-like regulation enforces a global limit on stem cell numbers, maintaining hematopoietic homeostasis even amidst expanded niche environments. By integrating local and systemic controls, the body ensures balanced blood cell production and stem cell preservation, highlighting complex multi-level regulation that safeguards organismal health.
Subject of Research: Regulation of haematopoietic stem cell numbers by systemic factors in relation to bone marrow niche availability.
Article Title: Haematopoietic stem cell number is not solely defined by niche availability.
Article References:
Takeishi, S., Marchand, T., Koba, W.R. et al. Haematopoietic stem cell number is not solely defined by niche availability. Nature (2025). https://doi.org/10.1038/s41586-025-09462-5
Image Credits: AI Generated
Tags: bone marrow microenvironmentchallenges to traditional stem cell modelsexperimental models in stem cell biologygenetic alterations in stem cell studieshaematopoietic stem cell regulationHSC population dynamicsniche-centered paradigm in stem cell researchsignaling mechanisms in stem cell regulationsystemic factors in stem cell biologythrombopoietin role in HSC maintenanceTPO genotypes and HSC numbersunderstanding stem cell niche interactions
