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MAT mediates metabolic stress in HSPC
compensation from SCF or other factors secreted by non- adipose cells. Determining additional sources of SCF in regulating systemic metabolism is warranted in future studies.
In the BM, SCF is secreted by endothelial cells,22 stro- mal cells that can be labeled by LEPR,6,59 CXCL12,60 Nestin-GFPlow,60 PDGFRa,62 N-Cadherin,63 and Prx1-Cre,21 and adipocytes.32 Loss of SCF from these niche cells all leads to reduced HSPC numbers.64,65 It is still highly debat- able whether osteoblasts express SCF, but HSC frequency and function were not affected by deleting SCF or CXCL12 from Col2.3+ osteoblasts or ablating Ocn+ osteoblasts cells.21,22,66,67 A recent study by Zhou et al. ele- gantly showed that BM adipocytes proliferate after irradi- ation or chemotherapy, and deleting SCF using Adipoq- Cre/ER inhibits hematopoietic regeneration.32 In this study, using Adipoq-Cre- and Osx1-Cre-mediated knock- out of SCF, we determined that MAT-secreted SCF is essential for HSC maintenance and hematopoiesis also in the steady-state. Zhou et al. did not observe any deficien- cy in HSC frequency in non-irradiated Adipoq- Cre/ER+;KitlGFP/fl mice, probably because they used het- erozygous KitlGFP/fl mice as controls, in which the GFP insert disrupted one allele of the Kitl gene. Haploinsufficiency of the SCF/KIT pathway has been well documented,22,36 and we also observed substantial defects in HSPC in heterozygous Osx1-Cre+;Kitlfl/+ mice. The discrepancies between the results of our studies and those of Zhou et al. could also lie in the different Cre lines used. Adipoq-Cre only labels mature adipocytes, but not bone stroma, adipogenic progenitors, hematopoietic cells, bone lining cells, or osteoblast cells.41 However, Adipoq- CreER also recombines in a subset of LEPR+ stromal cells in the BM.32 On the other hand, the Adipoq-Cre line has its limitations as the Cre expression is not restricted to adult- hood. However, a minimal amount of MAT is present at the age of one week in mice and MAT rapidly expands afterwards.52 We argue that the hematopoietic defects observed in adult Adipoq-Cre+;Kitlfl/fl mice were largely due to SCF excision during adulthood. In the BM of young mice, adipocytes are relatively rare, compared to other cell types that also express SCF. Even though more than half of Kitl mRNA and SCF protein were lost in the BM of Adipoq-Cre+;Kitlfl/fl mice, it is still unclear why such a pro- found effect could be observed when adipose SCF was absent. Note that we cannot rule out the contributions of peripheral adipocytes and other Osx1+ progeny to the hematopoietic defects observed in Adipoq-Cre+;Kitlfl/fl mice and Osx1-Cre+;Kitlfl/fl mice, respectively. Tools that can selectively target MAT are needed to solve this enigma.
There have been a handful of studies that investigated the role of diet and obesity on the composition of the HSPC compartment and blood cell production.9-13,15,16 Despite the inconsistencies seen in these studies, such as the different mouse models, diets, and length of treatment employed, it is generally accepted that diet-induced obesi- ty promotes the immediate expansion of LSK stem cells but push their differentiation skewed toward the myeloid
and lymphoid lineages, which will result in long-term defects in hematopoiesis upon stress and infection. Of note, only male mice were assessed in these studies. Here, we consistently found that HFD activates myelopoiesis and lymphopoiesis in male mice, which may facilitate tis- sue inflammation in obesity. However, HFD in females did not change the ratio of MEP to GMP in the BM or the MkE/GrMo ratio in the peripheral blood. These discrepan- cies may help explain the sexual dimorphism in metabolic dysfunction associated with obesity in animals and humans. It has recently been reported that estrogen signal- ing could control the sexual dimorphism of HSPC devel- opment.44,45 Shown in this study, HFD-induced alterations in the frequency of HSPC populations and the composi- tion of blood cells, despite being divergent between males and females, were both dependent on adipose SCF, under- scoring the fundamental niche function of MAT.
Similar to obesity, aging is also associated with increased HSC numbers but decreased regenerative poten- tial and skewed differentiation toward myeloid cells.54,68,69 Both cell-intrinsic and cell-extrinsic mechanisms are accountable to these aged-related changes. MAT substan- tially expand in aged humans and rodents, and has been proposed as a suppressor of hematopoiesis in aging.70 However, in this study, by deleting SCF from adipose tis- sues, we were able to show that adipose-derived SCF is essential for the expansion of LSK stem cells and all myeloid precursor populations in middle-aged mice. It again supports the notion that MAT provides niche factors for the HSPC, particularly the myeloid compartment. Nevertheless, it is unclear whether such requirement of adipose SCF prevents hematopoietic aging or accelerates the exhaustion of HSPC in the bone marrow. Functional characterization of these HSPC in aged Adipoq-Cre+;Kitlfl/fl mice is required in future experiments.
In summary, we demonstrate that MAT is a functionally important source of SCF in steady-state hematopoiesis and required for HSPC to cope with metabolic stresses in obesity and aging.
Acknowledgments
We thank Dr. Alessandro Bartolomucci, Dr. Maria Razzoli, and Dr. Pilar Ariza Guzman at the Integrative Biology and Physiology Core for EchoMRI analyses and animal housing in temperature-controlled rooms.
Funding
This work was supported by National Key R&D Program of China (2017YFD0500505), Fundamental Research Funds for the Central Universities (KJQN201604), National Natural and Science Foundation of China (31500944), Natural Science Foundation of Jiangsu Province (BK20150687), and China Scholarship Council postdoctoral fellowship (201606855010) to ZH; Natural Science Foundation of Jiangsu Province (BK20170147) to ZZ; National Natural and Science Foundation of China (81770543), American Diabetes Association (18-IBS-167), and NIAID (R01AId139420 and R21AI140109) to H-BR.
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