Abstract
Bone marrow mesenchymal lineage cells are a heterogeneous cell population involved in bone homeostasis and diseases such as osteoporosis. While it is long postulated that they originate from mesenchymal stem cells, the true identity of progenitors and their in vivo bifurcated differentiation routes into osteoblasts and adipocytes remain poorly understood. Here, by employing large scale single cell transcriptome analysis, we computationally defined mesenchymal progenitors at different stages and delineated their bi-lineage differentiation paths in young, adult and aging mice. One identified subpopulation is a unique cell type that expresses adipocyte markers but contains no lipid droplets. As non-proliferative precursors for adipocytes, they exist abundantly as pericytes and stromal cells that form a ubiquitous 3D network inside the marrow cavity. Functionally they play critical roles in maintaining marrow vasculature and suppressing bone formation. Therefore, we name them marrow adipogenic lineage precursors (MALPs) and conclude that they are a newly identified component of marrow adipose tissue.
Highlights
Osteoporosis is a silently progressive disease characterized by excessive bone loss and structural deterioration until it clinically presents as bone fragility and fracture
In contrast to the wealth of knowledge regarding hematopoiesis from hematopoietic stem cells (HSCs) (Orkin and Zon, 2008), our in vivo knowledge of mesenchymal stem cells (MSCs) and their descendants are largely incomplete, which has greatly limited advances in treating clinical disorders of bone loss. It is well-accepted that bone marrow mesenchymal progenitors are heterogeneous, including MSCs and their descendants at various differentiation stages before they reach the terminal states as osteoblasts, osteocytes, and adipocytes
Based on previous studies that leptin receptor (Lepr) marks adult bone marrow MSCs (Zhou et al, 2014) and Lepr+ cells serve as niche for hematopoietic progenitors (Comazzetto et al, 2019), one study used Lepr-Cre to label mesenchymal stromal cells and Col1a-Cre to label osteoblasts for analyzing HSC niches (Tikhonova et al, 2019)
Summary
Osteoporosis is a silently progressive disease characterized by excessive bone loss and structural deterioration until it clinically presents as bone fragility and fracture. In contrast to the wealth of knowledge regarding hematopoiesis from hematopoietic stem cells (HSCs) (Orkin and Zon, 2008), our in vivo knowledge of MSCs and their descendants are largely incomplete, which has greatly limited advances in treating clinical disorders of bone loss It is well-accepted that bone marrow mesenchymal progenitors are heterogeneous, including MSCs and their descendants at various differentiation stages before they reach the terminal states as osteoblasts, osteocytes, and adipocytes. Based on previous studies that leptin receptor (Lepr) marks adult bone marrow MSCs (Zhou et al, 2014) and Lepr+ cells serve as niche for hematopoietic progenitors (Comazzetto et al, 2019), one study used Lepr-Cre to label mesenchymal stromal cells and Col1a-Cre to label osteoblasts for analyzing HSC niches (Tikhonova et al, 2019). Among newly identified mesenchymal subpopulations, a new type of adipose lineage cells is subsequently validated and investigated for their critical actions in regulating bone marrow vasculature and bone homeostasis
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