Transient expansion and myofibroblast conversion of adipogenic lineage precursors mediate bone marrow repair after radiation
Year: 2022
Type: article
Abstract: Radiation causes a collapse of bone marrow cells and elimination of microvasculature. To understand how bone marrow recovers after radiation, we focused on mesenchymal lineage cells that provide a supportive microenvironment for hematopoiesis and angiogenesis in bone. We recently discovered a nonproliferative subpopulation of marrow adipogenic lineage precursors (MALPs) that express adipogenic markers with no lipid accumulation. Single-cell transcriptomic analysis revealed that MALPs acquire proliferation and myofibroblast features shortly after radiation. Using an adipocyte-specific Adipoq-Cre, we validated that MALPs rapidly and transiently expanded at day 3 after radiation, coinciding with marrow vessel dilation and diminished marrow cellularity. Concurrently, MALPs lost most of their cell processes, became more elongated, and highly expressed myofibroblast-related genes. Radiation activated mTOR signaling in MALPs that is essential for their myofibroblast conversion and subsequent bone marrow recovery at day 14. Ablation of MALPs blocked the recovery of bone marrow vasculature and cellularity, including hematopoietic stem and progenitors. Moreover, VEGFa deficiency in MALPs delayed bone marrow recovery after radiation. Taken together, our research demonstrates a critical role of MALPs in mediating bone marrow repair after radiation injury and sheds light on a cellular target for treating marrow suppression after radiotherapy.
Source: JCI Insight
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: University of Pennsylvania, Harvard University, University of Pittsburgh, National Institutes of Health, Genentech, Perelman School of Medicine, University of Pennsylvania, National Institute on Aging, National Heart, Lung, and Blood Institute, NIH Office of the Director, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Penn Center for Musculoskeletal Disorders
Awards: G1236714046, G2610099111, Mechanism of radiotherapy-induced osteoporosis and its treatment, Lnk Regulatory Functions in Hematopoietic Stem Cells, G643851205, Regulation of Ribosome Biogenesis in Hematopoietic Stem Cells, Dissecting the heterogeneity of bone marrow mesenchymal lineage progenitors, Novel Regulation of Oncogenic NRAS Signaling in Myeloid Malignancies, Overall: Resource-based Center for Musculoskeletal Disorders Research (Overall Application), Control of bone physiology by a novel type of adipose cells
OpenAlex ID: W4223531925