Enhanced homing of mesenchymal stem cells for in situ niche remodeling and bone regeneration

Mesenchymal stem cells (MSCs) transplantation is a promising strategy for osteoporosis treatment. However, limited sources and poor tissue-homing efficiency limit their clinical capabilities. In this study, we isolated a kind of MSCs from women’s menstrual blood (MenSCs) noninvasively and established a novel MSCs bone marrow-targeted delivery system by utilizing water-in-oil-in-water droplet microfluidics. MenSCs were encapsulated within β-cyclodextrin-functionalized alginate microcapsules loaded with zoledronates, which has a high affinity for bone. With this delivery system, MenSCs could be preferentially delivered to the bone marrow tissues via intravenous infusion, and restored bone mass by remodeling the bone marrow niche in situ in ovariectomized mouse models. Moreover, scRNA-seq analysis demonstrated that those MenSCs homed to the bone marrow recruited CD4⁺FOXP3⁺ natural regulatory T (nT_reg) cells by secreting CCL28. The recruited nT_reg promoted CD8⁺ T cells to secret Wnt family member 10B (WNT10B), activating the Wnt signaling in osteoblasts and thus promoting bone formation in situ in the bone marrow. This study reveals a promising application of MenSCs in postmenopausal osteoporosis treatment and highlights the clinical value of MenSCs by encouraging women to reserve autologous MenSCs before menopause to prevent and alleviate postmenopausal osteoporosis.