Marrow adipogenic lineage precursors (MALPs) facilitate bone marrow recovery after chemotherapy

Abstract

Chemotherapy-induced hematopoietic toxicity is a multifactorial challenge in the treatment of oncology patients. The resultant bone marrow suppression is a major dose-limiting side effect. In this study, we utilized 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, to investigate the mechanisms underlying bone marrow recovery following chemotherapy. A single injection of 5-FU did not alter mouse bone structure but caused acute damage to bone marrow cellularity and vasculature. Single-cell RNA-sequencing of bone marrow mesenchymal lineage cells revealed a substantial reduction in early mesenchymal progenitors and a marked expansion of marrow adipogenic lineage precursors (MALPs) five days post-treatment. Furthermore, 5-FU upregulated the expression of myofibroblast markers in MALPs, indicating a myofibroblast transformation. Using Adipoq-Cre to label MALPs in vivo, we observed that 5-FU transiently increases the number of MALPs in the bone marrow by promoting their proliferation. Immunostaining confirmed the elevated expression of myofibroblast markers in MALPs. By day 14 after 5-FU injection, bone marrow cellularity and vasculature were largely restored; however, the ablation of MALPs significantly impaired this recovery. Taken together, our study uncovers the critical role of MALPs in facilitating bone marrow repair following chemotherapy-induced injury and identifies them as a potential cellular target for treating chemotherapy-induced myelosuppression.