Bone marrow stromal cells lose their capacity to regenerate bone after repeated injuries, shifting instead toward fat production, according to research published in Nature Communications.
Researchers tracked leptin receptor-positive and C-X-C motif chemokine ligand 12-positive reticular stromal cells in mouse models. While a single bone marrow injury prompted these cells to generate reparative bone, repeated injuries caused them to enter a state of stromal exhaustion. In this exhausted state, the cells showed lower proliferation in colony-forming unit assays and failed to produce normal numbers of osteoblasts.
Lineage Switching and Signaling
Exhausted stromal cells exhibited distinct metabolic abnormalities, chronic inflammation linked to stress responses, and reduced regenerative plasticity. Tests for cellular senescence revealed that markers such as p16INK4a and SA-beta-gal appeared primarily in perilipin-positive marrow adipocytes rather than inside the stromal cells themselves.
The study linked this functional failure to altered molecular pathways. Deleting beta-catenin during tissue repair triggered adipogenesis through lineage switching, whereas activating Wnt and beta-catenin signaling through genetic or pharmacological methods partially rescued osteogenesis in damaged tissue.
A 12-week recovery interval between surgeries demonstrated that the impairment persisted over time. Although marrow fat levels subsided and the marrow cavity appeared histologically normal before the second procedure, re-challenging the bone with a second injury still produced defective bone formation and stimulated adipocyte differentiation.
