Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF

Abstract

Endothelial cells and Leptin Receptor+ (LepR+) stromal cells are critical sources of haematopoietic stem cell (HSC) niche factors, including Stem Cell Factor (SCF), in bone marrow. After irradiation or chemotherapy, these cells are depleted while adipocytes become abundant. We discovered that bone marrow adipocytes synthesize SCF. They arise from Adipoq-Cre/ER+ progenitors, which represent ~5% of LepR+ cells, and proliferate after irradiation. Scf deletion using Adipoq-Cre/ER inhibited hematopoietic regeneration after irradiation or 5-fluorouracil treatment, depleting HSCs and reducing mouse survival. Scf from LepR+ cells, but not endothelial, hematopoietic, or osteoblastic cells, also promoted regeneration. In non-irradiated mice, Scf deletion using Adipoq-Cre/ER did not affect HSC frequency in long bones, which have few adipocytes, but depleted HSCs in tail vertebrae, which have abundant adipocytes. A-ZIP/F1 ‘fatless” mice exhibited delayed hematopoietic regeneration in long bones but not in tail vertebrae, where adipocytes inhibited vascularization. Adipocytes are a niche component that promotes hematopoietic regeneration.

Adipocytes role in the bone marrow niche

“…Zhou and colleagues revealed that adipocyte derived-stem cell factor is important for hematopoiesis (19). Stem cell factor is expressed by a number of bone marrow cell types as several other cytokines that bind to receptors on hematopoietic stem cells.…”

“…This growing evidence highlight the need for further investigation of the adipocyte derived signals involved in the bone marrow fat tissue influence on leukemia cell survival, progression, and spread. While Zhou and colleagues reveal that adipocyte-derived stem cell factor is an essential factor for hematopoietic stem cell regulation (19), its role in the modulation of tumor burden still needs to be explored. The mechanistic understanding of leukemic stem cells protection, through modulation of local concentrations of chemotherapy, support of tumor cells in a dormant state, or stimulation of overt anti-apoptotic signaling cascades is essential to the development of novel therapeutic strategies to blunt residual disease.…”

“…These works indicate that bone marrow fat cells inhibit hematopoietic stem cell function, repressing their growth and differentiation (14). However, in a recent article in Nature Cell Biology, Zhou and colleagues challenge the current view of adipocytes as negative regulators of the hematopoietic stem cells niche in the bone marrow (19). The authors demonstrated that fat cells promote increased hematopoiesis in response to myeloablation (19) (Figure 1).…”

“…However, in a recent article in Nature Cell Biology, Zhou and colleagues challenge the current view of adipocytes as negative regulators of the hematopoietic stem cells niche in the bone marrow (19). The authors demonstrated that fat cells promote increased hematopoiesis in response to myeloablation (19) (Figure 1). Zhou and colleagues investigated the role of bone marrow adipocytes as hematopoietic stem cell niche components by using state-of-the-art techniques, including sophisticated Cre/loxP technologies, confocal microscopy, in vivo lineage-tracing, and bone marrow transplantation.…”

Identification of a murine CD45−F4/80lo HSC-derived marrow endosteal cell associated with donor stem cell engraftment

“…Adipocytes have also been investigated for their role in hematopoiesis, although their role is unclear at this time. 7,8 The adaptive potential of these cellular microenvironments to respond to both pathological and physiological changes highlights the complex and vital interactions of the cellular constituents of the niche as well the important differences between homeostasis and postablated marrow niches. Successful hematopoietic reconstitution of donor HSC after HCT is dependent on a number of intricate cellular interactions, including recovery of the sinusoidal endothelium, 1,9-11 migration of megakaryocytes to the endosteal space, and osteoblast proliferation.…”