Transient expansion and myofibroblast conversion of adipogenic lineage precursors mediate bone marrow repair after radiation
Leilei Zhong, … , Wei Tong, Ling Qin
Leilei Zhong, … , Wei Tong, Ling Qin
Published April 8, 2022
Citation Information: JCI Insight. 2022;7(7):e150323. https://doi.org/10.1172/jci.insight.150323.
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Research Article Bone biology Vascular biology

Transient expansion and myofibroblast conversion of adipogenic lineage precursors mediate bone marrow repair after radiation

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.

Authors

Leilei Zhong, Lutian Yao, Nicholas Holdreith, Wei Yu, Tao Gui, Zhen Miao, Yehuda Elkaim, Mingyao Li, Yanqing Gong, Maurizio Pacifici, Amit Maity, Theresa M. Busch, Kyu Sang Joeng, Keith Cengel, Patrick Seale, Wei Tong, Ling Qin

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Figure 6

MALP ablation blocks bone marrow recovery after radiation.

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MALP ablation blocks bone marrow recovery after radiation. (A) Represent...
(A) Representative fluorescence images of Td+ cells, Perilipin+ LiLAs, and CD45+ hematopoietic cells in femoral bone marrow of Adipoq/Td/DTR mice after receiving 2 weeks of vehicle (Veh) or DT injections with or without prior radiation. Scale bar: 20 μm (top), 100 μm (middle), and 20 μm (bottom). (B) Quantification of CD45+ cells per bone marrow area. n = 3–6 mice/group. (C) Bone marrow cells were flushed from femurs and counted. n = 3–8 mice/group. (D) Cell counts of hematopoietic lineage cells in the bone marrow. n = 3–11 mice/group. B cells = B220+, T cells = CD3+, myeloid cells = Gr1+ and/or Mac1+. (E) Cell counts of HSPCs. n = 3–11 mice/group. LK, Lineage–cKit+, LSK, Lineage–Sca1+cKit+, SLAM LSK, Lineage–Sca1+cKit+CD48–CD150+, MPP, Lineage–Sca1+cKit+CD48+CD150–. (F) Representative fluorescence images of Adipoq/Td/DTR femoral bone marrow with Emcn staining (vessels). Arrows point to Td+ pericytes. Scale bar: 20 μm. (G) Quantification of bone marrow vessel diameter, density, and area. (H) The number of pericytes per vessel length (VL) was measured. n = 3–4 mice/group. (I) The percentage of Emcn+ endothelial cells in bone marrow was measured by flow cytometry. n = 3–4 mice/group. (J) qRT-PCR analysis of hematopoietic and angiogenic factors in sorted Td– and Td+ cells from bone marrow before and after radiation. n = 4 mice/group. Statistical analysis was performed using 1-way ANOVA with Tukey’s multiple-comparison analysis. *: P < 0.05; **: P < 0.01; ***: P < 0.001.