Apoptotic vesicles rescue impaired mesenchymal stem cells and their therapeutic capacity for osteoporosis by restoring miR-145a-5p deficiency.

ABSTRACT

Apoptotic vesicles (apoVs) play a vital role in various pathological conditions; however, we have yet to fully understand their precise biological effects in rescuing impaired mesenchymal stem cells (MSCs) and regulating tissue homeostasis. Here, we proved that systemic infusion of bone marrow MSCs derived from wild-type (WT) mice effectively improved the osteopenia phenotype and hyperimmune state in ovariectomized (OVX) mice. Importantly, the WT MSCs rescued the impairment of OVX MSCs both in vivo and in vitro, whereas OVX MSCs did not show the same efficacy. Interestingly, treatment with apoVs derived from WT MSCs (WT apoVs) restored the impaired biological function of OVX MSCs and their ability to improve osteoporosis. This effect was not observed with OVX MSCs-derived apoVs (OVX apoVs) treatment. Mechanistically, the reduced miR-145a-5p expression hindered the osteogenic differentiation and immunomodulatory capacity of OVX MSCs by affecting the TGF-ß/Smad 2/3-Wnt/ß-catenin signaling axis, resulting in the development of osteoporosis. WT apoVs directly transferred miR-145a-5p to OVX MSCs, which were then reused to restore their impaired biological functions. Conversely, treatment with OVX apoVs did not produce significant effects due to their limited expression of miR-145a-5p. Overall, our findings unveil the remarkable potential of apoVs in rescuing the biological function and therapeutic capability of MSCs derived from individuals with diseases. This discovery offers a new avenue for exploring apoVs-based MSC engineering and expands the application scope of stem cell therapy, contributing to the maintenance of bone homeostasis through a previously unrecognized mechanism.