Control of bone physiology by a novel type of adipose cells

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Project Summary Osteoporosis and low bone mass are common chronic disorders associated with significant morbidity and substantial healthcare costs. Bone is a dynamic tissue that constantly undergoes coupled remodeling by osteoblasts and osteoclasts. Bone marrow (BM) adipocytes, arising from the same mesenchymal stem cells (MSCs) as osteoblasts, also play a crucial role in bone homeostasis. Therefore, advancing our knowledge on mesenchymal populations in bone and understanding their functions will reveal novel targets that address the unmet clinical need for improved treatments for skeletal diseases. By carrying out large scale single cell transcriptome analysis, we recently computationally defined the hierarchy of BM mesenchymal lineage cells and delineated the in vivo differentiation process of MSCs through multiple intermediate subpopulations. Interestingly, we identified a new subpopulation situated after proliferative mesenchymal progenitors and before classic lipid-laden adipocytes (LiLAs) along the adipogenic differentiation route, and thus named those cells marrow adipogenic lineage precursors (MALPs). These non-proliferative cells express mature adipocyte markers, including Adiponectin (Adipoq), but do not accumulate lipid. In young mice, MALPs, genetically labelled by Adipoq-Cre(ER), exist abundantly as BM stromal cells and capillary pericytes. Morphologically, they display many long cell processes that make contacts among themselves and with surrounding cells, as well as the bone surface, to establish a ubiquitous 3D network inside BM cavity. Cell ablation revealed that these Adipoq+ cells play critical roles in maintaining BM vasculature and in suppressing bone formation. Strikingly, MALPs are rapidly and transiently expanded after focal radiation, implying a reparative role during injury response. One important feature of MALPs is that they highly express many secreted factors, such as VEGFa, RANKL (Tnfsf11), CSF1, Cxcl12 etc, indicating regulatory actions on surrounding cells. These data lead to our central hypothesis that MALPs represent a novel adipose cell type with pivotal roles in regulating their BM environment during skeletal development, homeostasis, aging, and injury repair. Bone marrow adipose tissue (MAT) normally refers to LiLAs, and current MAT research centers on their energy and lipid-related roles. This proposal will expand the concept of MAT to include MALPs, a much more abundant cell population, and its non-lipid-associated actions. Our aims are to: 1) determine the in vivo fate and properties of MALPs; 2) elucidate the role of MALPs in regulating bone marrow vasculature; 3) determine the regulatory actions of MALPs on bone resorption. Innovative approaches, such as single nucleus RNA-sequencing (snRNA-seq), confocal 3D imaging, RNA FISH, genetically modified and reporter animal models, will be used throughout the proposal. Our project will comprehensively characterize a novel mesenchymal subpopulation and its multifaceted regulatory roles in bone. The data we gather here will shed new light on bone, adipose, and vascular biology and identify new targets of intervention on osteoporosis and bone repair.