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Hematopoiesis
Bone marrow adipose tissue-derived stem cell factor mediates metabolic regulation
of hematopoiesis
Zengdi Zhang,1* Zan Huang,1,2,3* Brianna Ong,1 Chinmayi Sahu,1 Hu Zeng,4,5 and Hai-Bin Ruan1,6
*These authors contributed equally.
ABSTRACT
Hematopoiesis is dynamically regulated by metabolic cues in homeostatic and stressed conditions; however, the cellular and molecular mechanisms mediating the metabolic sensing and reg- ulation remain largely obscure. Bone marrow adipose tissue remodels in various metabolic conditions and has been recently proposed as a niche for hematopoietic stem cells after irradiation. Here, we investigated the role of marrow adipose tissue-derived hematopoietic cytokine stem cell factor in unperturbed hematopoiesis by selectively ablating the Kitl gene from adipocytes and bone marrow stroma cells using Adipoq-Cre and Osx1-Cre, respectively. We found that both Adipoq-Kitl knockout (KO) and Osx1-Kitl KO mice diminished hematopoietic stem and progenitor cells and myeloid progenitors in the bone marrow and developed macro- cytic anemia at the steady-state. The composition and differentiation of hematopoietic progenitor cells in the bone marrow dynamically responded to metabolic challenges including high fat diet, β3-adrenergic activation, thermoneutrality, and aging. However, such responses, par- ticularly within the myeloid compartment, were largely impaired in Adipoq-Kitl KO mice. Our data demonstrate that marrow adipose tissue provides stem cell factor essentially for hematopoiesis both at the steady state and upon metabolic stresses.
Introduction
The metabolic and hematopoietic systems demonstrate dynamic and complex interplays in health and disease. On the one hand, a plethora of blood cells includ- ing granulocytes, monocytes and macrophages, mast cells, and lymphocytes con- tribute to the physiological and pathological regulation of energy intake and expenditure, glucose and lipid metabolism, bone remodeling, and the aging process.1-4 On the other hand, hematopoietic stem cells (HSC), myeloid and lym- phoid progenitors, and their mature progeny not only impose different bioener- getic demands during development,5-8 but also show flexibility and plasticity in their maintenance, differentiation, and function in response to various metabolic disturbances, such as obesity, hyperglycemia, and aging.9-16 A large body of evi- dence indicates that both intrinsic and extrinsic factors drive the hematopoietic process; however, the cellular and molecular mechanisms underlying the metabolic regulation of hematopoiesis remain for the most part elusive.
In adults, the bone marrow (BM) microenvironment provides niches that sup- port the renewal, quiescence, and differentiation of hematopoietic stem and pro- genitor cells (HSPC).17-19
Recent studies have started to unveil the complexity and heterogeneity of niche cell types, niche factors, and their actions. BM mesenchymal stem cells [BMSC,
Ferrata Storti Foundation
1Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USA; 2Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agriculture University, Nanjing, Jiangsu, China; 3National Center for International Research on Animal Gut Nutrition, Nanjing Agriculture University, Nanjing, Jiangsu, China; 4Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA; 5Department of Immunology, Mayo Clinic, Rochester, MN, USA and 6Center for Immunology, University of Minnesota, Minneapolis, MN, USA
Haematologica 2019 Volume 104(9):1731-1743
Correspondence:
RUAN HAI-BIN
hruan@umn.edu
Received: September 3, 2018. Accepted: February 18, 2019. Pre-published: February 21, 2019.
doi:10.3324/haematol.2018.205856
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/9/1731
©2019 Ferrata Storti Foundation
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