Competition between hematopoietic stem and progenitor cells controls hematopoietic stem cell compartment size

Abstract

Cellular competition for limiting hematopoietic factors is a physiologically regulated but poorly understood process. Here, we studied this phenomenon by hampering hematopoietic progenitor access to Leptin receptor+ mesenchymal stem/progenitor cells (MSPCs) and endothelial cells (ECs). We show that HSC numbers increase by 2-fold when multipotent and lineage-restricted progenitors fail to respond to CXCL12 produced by MSPCs and ECs. HSCs are qualitatively normal, and HSC expansion only occurs when early hematopoietic progenitors but not differentiated hematopoietic cells lack CXCR4. Furthermore, the MSPC and EC transcriptomic heterogeneity is stable, suggesting that it is impervious to major changes in hematopoietic progenitor interactions. Instead, HSC expansion correlates with increased availability of membrane-bound stem cell factor (mSCF) on MSPCs and ECs presumably due to reduced consumption by cKit-expressing hematopoietic progenitors. These studies suggest that an intricate homeostatic balance between HSCs and proximal hematopoietic progenitors is regulated by cell competition for limited amounts of mSCF.

Stromal STAT5-mediated trophic activity regulates hematopoietic multipotent progenitor niche factors

“…4B ) as determined by flow cytometry. This result is consistent with a recent publication showing how competition between hematopoietic stem and progenitor cells controls HSC compartment size(30). Therefore, Lepr + cells utilize STAT5ab in a manner that promotes lymphoid lineage priming.…”

Serum Amyloid A proteins reduce bone mass during mycobacterial infections

“…S1F ). LEPR + MSC were described as the major source of osteoblasts and adipocytes in the adult bone marrow (Zhou et al 2014) and nurse hematopoietic maintenance and differentiation (Cordeiro Gomes et al 2016, Miao et al 2022), reinforcing the close relationship between hematopoiesis and the bone (Tsumura et al 2022).…”

“…S1F). LEPR + MSC were described as the major source of osteoblasts and adipocytes in the adult bone marrow (Zhou et al 2014) and nurse hematopoietic maintenance and differentiation (Cordeiro Gomes et al 2016, Miao et al 2022, reinforcing the close relationship between hematopoiesis and the bone (Tsumura et al 2022). Disseminated M. avium infection leads to the colonization of macrophages within the bone marrow parenchyma (Gomes et al 2019) instead of a direct colonization of bone cells (Fig.…”

Cell circuits between leukemic cells and mesenchymal stem cells block lymphopoiesis by activating lymphotoxin beta receptor signaling

“…Other cytokines, such as SCF (encoded by Kitl ), M-CSF (encoded by Csf1 ), IL34, FLT3L, etc., are also downregulated but in an LTβR-independent manner. Of note, SCF is a critical cytokine for the survival and expansion of myelo-erythroid lineage progenitors ( Miao et al, 2020 ; Broudy et al, 1995 ; Broudy, 1997 ; Munugalavadla and Kapur, 2005 ), and its consumption in vivo is under competition between hematopoietic stem and progenitor cells ( Miao et al, 2022 ). The fact that SCF production is insensitive to LTβR signaling may contribute to explain why myelopoiesis and erythropoiesis are not restored when LTβR signaling is blocked.…”