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Stem cell factor: the bridge between bone marrow adipocytes and hematopoietic cells
Ziru Li and Ormond A. MacDougald
Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA. E-mail: ZIRU LI - liziru@umich.edu
doi:10.3324/haematol.2019.224188
White adipocytes serve as an energy reservoir to store excessive calories in the form of lipid droplets and protect other tissues or organs from ectopic lipid accumulation. Brown adipocytes express uncoupling protein 1 and are integral to adaptive thermoge- nesis. Whereas the functions of adipocytes in either white or brown adipose tissues are well documented, our knowledge of bone marrow adipocytes (BMA) remains in its infancy. Bone marrow adipose tissue (BMAT) occupies approximate- ly 50-70% of the bone marrow volume in human adults.1 It is a dynamic tissue and responds to multiple metabolic con- ditions. For example, BMAT increases with obesity, aging, diabetes, caloric restriction, and irradiation.2 Although the significance of BMAT expansion under these conditions is still largely unknown, BMA interact locally with hematopoi- etic and bone cells, and contribute to global metabolism through secretion of adiponectin, leptin, stem cell factor (SCF), and other functional factors. For example, A-ZIP/F1 mice, which lack adipose tissues throughout the body, including BMAT, have delayed hematopoietic regeneration in long bones after irradiation.3 Our latest work also observed that depletion of BMA by bariatric surgery is asso- ciated with a decrease in bone marrow erythroid cells and anemia.4 The importance of BMA and the derived factors on hematopoiesis is further enhanced by a study in this issue of the Journal, in which Zhang et al.5 demonstrate that BMAT- derived SCF mediates metabolic regulation of hematopoiesis.
Stem cell factor, also known as Kit ligand (Kitl), is a hematopoietic cytokine expressed in fibroblasts and endothelial cells, as well as in BMA.3 Together with its recep- tor, c-Kit, SCF plays important roles in the maintenance of hematopoietic stem cells (HSC) and hematopoiesis. Blockade of the interaction between c-Kit and SCF with anti- c-Kit antibody promotes the clearance of HSC, which indi- cates the importance of Kitl/c-Kit signaling in HSC self- renewal.6 Loss-of-function mutations in c-Kit cause macro- cytic anemia, or even embryonic lethality under some severe mutations.7 Inversely, mice with c-Kit gain-of-function mutations developed erythrocytosis compatible with myelo- proliferative disorders.8 Analyses of multiple cell populations isolated from bone marrow and adipose tissue have demon- strated that BMA and LepR-positive (+) stromal cells are the primary sources of SCF, which is required for the regenera- tion of HSC and hematopoiesis after irradiation.3 Zhang et al. report that BMA-derived SCF is important for hematopoietic homeostasis under basal (Figure 1), obese and aging condi- tions, and in response to β3-adrenergic agonists.5
Knockout of SCF in adipocytes with an adiponectin driver does not influence circulating SCF concentrations or pheno- types of the peripheral adipose depots, which is perhaps due to compensatory expression of SCF from other sources, such as endothelial cells, fibroblasts and stromal cells. Interestingly, Zhang et al. observed a significant loss of SCF
in the bone marrow supernatant, which indicates that BMAT is a primary source of SCF in bone marrow.5 Deficiency of SCF in BMAT reduces the bone marrow cellu- larity, hematopoietic stem and progenitor cells (HSPC), com- mon myeloid progenitors (CMP), megakaryocyte-erythro- cyte progenitor (MEP) and granulocyte-monocyte progeni- tors (GMP) under steady-state condition. Consistent with these changes in the progenitor cells of bone marrow, mice deficient for adipocyte SCF develop macrocytic anemia and reduction of neutrophils, monocytes and lymphocytes in cir- culation. In contrast to results in this study, Zhou et al. reported that the conditional deficiency of SCF in adipocytes driven by adiponectin-Cre/ER had no effect on hematopoiesis under basal conditions.3 Although further investigation is necessary, the discrepancy between these two studies might be due to the time-frame of SCF deletion, tamoxifen injection and/or animal lines. Of note, the dele- tion of SCF has no effect on the proliferation of HSPC evi- denced by colony-forming assays, which suggests that defects in BMAT-derived SCF influences the bone marrow microenvironment rather than the intrinsic function of HSPC.
Since adiponectin-Cre is expressed in both peripheral adipocytes and BMA, it is possible that there might be effects on hematopoiesis that are independent of BMAT. To more specifically study effects of BMA on the bone marrow niche and hematopoiesis, Zhang et al. also deleted the Kitl using osterix promoter, which traces BMA but not the other adipocytes. Again, knockout of Kitl from the osterix-positive (+) cells reduced bone marrow cellularity, hematopoietic pro- genitor populations and mature blood cells including red blood cells (RBC), neutrophils and monocytes, which is con- sistent with the phenotypes from mice lacking adipocytic Kitl. Of note, in addition to BMA, osterix+ progenitors also trace to osteoblasts.9,10 Mesenchymal and osteoblast lineage cells are involved in the maintenance and regulation of the supportive microenvironments necessary for quiescence, self-renewal and differentiation of HSC.11,12 However, the SCF from osteoblasts is not required for HSC maintenance in adult bone marrow under steady-state conditions.13 Although the possible effects of SCF derived from osterix+ progenitors on hematopoiesis could not be excluded and the bone phenotypes were not explored in this mouse model, it should be appreciated that authors used both adiponectin- and osterix-driven Cre enzyme to confirm the phenotypes of SCF-deficiency on hematopoiesis. These results strongly point to BMA as an important source of SCF since the com- mon cell type traced by adiponectin and osterix drivers is the BMA; however, development of BMA-specific transgenic mouse tools will be required to truly confirm these observa- tions of BMA and the roles of SCF in the bone marrow niche homeostasis and hematopoiesis.
The authors also investigated whether BMA-derived SCF is required for hematopoietic adaptation to aging or high fat
haematologica | 2019; 104(9)
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