Mesenchymal stem cell-derived exosomes (MSC-exos), with its inherent capacity to modulate cellular behavior, are emerging as a novel cell-free therapy for bone regeneration . Herein, focusing on practical applying problems, the osteoinductivity of MSC-exos produced by different stem cell sources (rBMSCs/rASCs) and culture conditions (osteoinductive/common) were systematically compared to screen out an optimized osteogenic exosome (BMSC-OI-exo). Via bioinformatic analyses by miRNA microarray and in vitro pathway verification by gene silencing and miRNA transfection, we first revealed that the osteoinductivity of BMSC-OI-exo was attributed to multi-component exosomal miRNAs (let-7a-5p, let-7c-5p, miR-328a-5p and miR-31a-5p). These miRNAs targeted Acvr2b/Acvr1 and regulated the competitive balance of Bmpr2/Acvr2b toward Bmpr-elicited Smad1/5/9 phosphorylation. On these bases, lyophilized delivery of BMSC-OI-exo on hierarchical mesoporous bioactive glass (MBG) scaffold was developed to realize bioactivity maintenance and sustained release by entrapment in the surface microporosity of the scaffold. In a rat cranial defect model, the loading of BMSC-OI-exo efficiently enhanced the bone forming capacity of the scaffold and induced rapid initiation of bone regeneration. This paper could provide empirical bases of MSC-exo-based therapy for bone regeneration and theoretical bases of MSC-exo-induced osteogenesis mechanism. The BMSC-OI-exo-loaded MBG scaffold developed here represented a promising bone repairing strategy for future clinical application.
Xi Yu,Dan Zhu,Yan Zhao,Yueyang Song,Zejun Zhao,Weisheng Li,Juan Wang,Jinxing Lv,Miao Sun
The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that exposure to adverse environmental factors during pregnancy not only disturbs intrauterine fetal development but also exerts profound negative consequences on offspring. Previous studies have primarily focused on the health risks associated with direct individual exposure to fluoride (a common environmental exposure factor), while the effects of fluoride exposure on offspring during pregnancy have received little attention. In this study, we established the prenatal NaF exposure model by administering drinking water containing 100 mg/L sodium fluoride (NaF) to pregnant dams throughout gestation. We found that prenatal NaF exposure induced intrauterine hyper-osteogenesis and led to an abnormal and sustained, high bone mass phenotype in male offspring. Mechanistically, NaF exposure significantly upregulated osteomodulin (OMD) expression, which subsequently driven the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) via the activation of bone morphogenetic protein receptor type 2 (BMPR2). Notably, pharmacological intervention with CDD−1653, a selective BMPR2 inhibitor, effectively rescued the NaF-induced excessive BMSC osteogenesis and attenuated the abnormal bone accumulation in vivo. Taken together, our study demonstrates that prenatal fluoride exposure triggers aberrant activation of osteogenesis in male offspring through the OMD-BMPR2 signaling pathway. These findings uncover the potential molecular mechanisms by which early-life environmental fluoride exposure alters skeletal homeostasis in male offspring and highlight the imperative for public health strategies to mitigate gestational fluoride risks.
Qinghao Zhang,Yuanda Liu,Jie Li,Jing Wang,Changsheng Liu
Exposure to a growth factor abundant milieu has remarkable regenerative and rejuvenating effects on organ diseases, tissue damage, and regeneration, including skeletal system defects and bone regeneration. Although the introduction of candidate growth factors into relevant fields has been reported, their regenerative effects remain unsatisfactory, mainly because of the experimental challenges with limited types of growth factors, elusive dosage adjustment, and asynchronous stem cell activation with cytokine secretion. Here, an innovative hydrogel recapitulating a growth factor-enriched microenvironment (GEM) for regenerative advantage, is reported. This sulfated hydrogel includes bone morphogenetic protein-2 (BMP-2), an essential growth factor in osteogenesis, to direct mesenchymal stem cell (MSC) differentiation, stimulate cell proliferation, and improve bone formation. The semi-synthetic hydrogel, sulfonated gelatin (S-Gelatin), can amplify BMP-2 signaling in mouse MSCs by enhancing the binding between BMP-2 and BMP-2 type II receptors (BMPR2), which are located on MSC nuclei and activated by the hydrogel. Importantly, the dramatically improved cytokine secretion of MSCs throughout regeneration confirms the growth factor-acquiring potential of S-Gelatin/rhBMP-2 hydrogel, leading to the vascularization enhancement. These findings provide a new strategy to achieve an in situ GEM and accelerated bone regeneration by amplifying the regenerative capacity of rhBMP-2 and capturing endogenous growth factors.
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