Stem cells play a crucial role in re-establishing homeostasis in the body, and the search for mechanisms by which they interact with the host to exert their therapeutic effects remains a key question currently being addressed. Considering their significant regenerative/therapeutic potential, research on mesenchymal stem cells (MSCs) has experienced an unprecedented advance in recent years, becoming the focus of extensive works worldwide to develop cell-based approaches for a variety of diseases. Initial evidence for the effectiveness of MSCs therapy comes from the restoration of dynamic microenvironmental homeostasis and endogenous stem cell function in recipient tissues by systemically delivered MSCs. The specific mechanisms by which the effects are exerted remain to be investigated in depth. Importantly, the profound cell-host interplay leaves persistent therapeutic benefits that remain detectable long after the disappearance of transplanted MSCs. In this review, we summarize recent advances on the role of MSCs in multiple disease models, provide insights into the mechanisms by which MSCs interact with endogenous stem cells to exert therapeutic effects, and refine the interconnections between MSCs and cells fused to damaged sites or differentiated into functional cells early in therapy.

Peri-implantitis is characterized by inflammatory cell infiltration and hyperactivation of the osteoclasts surrounding dental implants which can result in bone resorption and ultimately implant failure. Therefore, coordinating the activity of inflammatory response and bone-resorbing osteoclasts is crucial for the prevention of peri-implantitis. Asperuloside (ASP), an iridoid glycoside, has significant anti-inflammatory activities, suggesting the great potential in attenuating peri-implantitis bone resorption. A ligature-induced peri-implantitis model in the maxilla of rats was established, and the effects of ASP on preventing peri-implantitis were evaluated after four weeks of ligation using micro-CT and histological staining. RT-PCR, western blotting, tartrate-resistant acid phosphatase (TRAP), and immunofluorescent staining were conducted on osteoclasts to confirm the mechanisms of ASP on osteoclastogenesis. The results show that ASP could lead to attenuation of alveolar bone resorption in peri-implantitis by inhibiting osteoclast formation and decreasing pro-inflammatory cytokine levels in vivo. Furthermore, ASP could inhibit osteoclastogenesis by downregulating expression levels of transcription factors nuclear factor of activated T-cell (NFATc1) via restraining the activations of nuclear factor kappa beta (NF-κB) and the phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2). In conclusion, ASP could significantly attenuate bone resorption in peri-implantitis via inhibition of osteoclastogenesis by suppressing NF-κB and ERK1/2 signaling pathways activations.

Psychological stress has been associated with the onset of several diseases, including osteoporosis. However, the underlying pathogenic mechanism remains unknown, and effective therapeutic strategies are still unavailable. Growing evidence suggests that the sympathetic nervous system regulates bone homeostasis and vascular function under psychological stress, as well as the coupling of osteogenesis and angiogenesis in bone development, remodeling, and regeneration. Furthermore, extracellular vesicles (EVs), particularly mesenchymal stem cell extracellular vesicles (MSC–EVs), have emerged as prospecting therapies for stimulating angiogenesis and bone regeneration. We summarize the role of sympathetic regulation in bone homeostasis and vascular function in response to psychological stress and emphasize the relationship between vessels and bone. Finally, we suggest using MSC–EVs as a promising therapeutic method for treating osteoporosis in psychological stress.

Rationale: Mesenchymal stem cells (MSCs) possess potent immunomodulatory capability, but occasionally, clinical application of MSCs is hindered by compromised cell functionality and insufficient therapeutic efficacy.

Introduction: The dental follicle localizes the surrounding enamel organ and dental papilla of the developing tooth germ during the embryonic stage. It can differentiate and develop to form the periodontal ligament, cementum, and alveolar bone tissues. Postnatally, the dental follicle gradually degenerates, but some parts of the dental follicle remain around the impacted tooth. However, the specific cellular components and the intricate regulatory mechanisms governing the postnatal development and biological function of the dental follicle have not been completely understood.Methods: We analyzed dental follicles with single-cell RNA sequencing (scRNA-seq) to reveal their cellular constitution molecular signatures by cell cycle analysis, scenic analysis, gene enrichment analysis, and cell communication analysis.Results: Ten cell clusters were identified with differential characteristics, among which immune and vessel-related cells, as well as a stem cell population, were revealed as the main cell types. Gene regulatory networks (GRNs) were established and defined four regulon modules underlying dental tissue development and microenvironmental regulation, including vascular and immune responses. Cell–cell communication analysis unraveled crosstalk between vascular and immune cell components in orchestrating dental follicle biological activities, potentially based on COLLAGAN-CD44 ligand–receptor pairs, as well as ANGPTL1-ITGA/ITGB ligand–receptor pairs.Conclusion: We establish a landscape of cell regulatory and communication networks in the human dental follicle, providing mechanistic insights into the cellular regulation and interactions in the complex dental follicle tissue microenvironment.

Rapid and stable regeneration of bone defects remains a pressing clinical challenge. We previously fabricated stem cell aggregates (CA) by mimicking developmental condensation and demonstrated their efficacy in promoting bone defect repair. Endogenous Gli1⁺ skeletal stromal/progenitor cells (SSPCs) are a pivotal SSPC subtype known to maintain bone homeostasis and enhance bone regeneration; however, the functional properties and translational potential of CA derived from these cells (Gli1⁺ CA) remain largely elusive. Single-cell RNA sequencing was performed to characterize differential gene expression profiles between Gli1^high and Gli1^low SSPCs. The spatial relationship among Gli1⁺ cells, RUNX2⁺ cells, and type H vessels in vivo was further validated. Gli1-CreER^T2;mT/mG transgenic mice were generated to enable the isolation of Gli1⁺ SSPCs and the subsequent fabrication of Gli1⁺ CA. The pro-angiogenic potential of Gli1⁺ CA was assessed in vitro, and the underlying regulatory mechanisms were further explored. Finally, Gli1⁺ CA were implanted into a mouse femoral defect model, and bone regenerative efficacy was evaluated by micro-CT and immunofluorescence staining. Single-cell RNA sequencing revealed that, compared with Gli1^low SSPCs, Gli1^high SSPCs highly expressed genes associated with osteogenesis, angiogenesis, and extracellular matrix synthesis. In vivo validation demonstrated robust enrichment of Gli1⁺ cells in the metaphysis; these cells exhibited a tight spatial correlation with the osteogenic master transcription factor RUNX2 and type H vessels. We subsequently sorted Gli1⁺ SSPCs via flow cytometry and fabricated CA, and in vitro analysis confirmed that their expression profiles were consistent with the sequencing data. Functional assays further revealed that Gli1⁺ CA promoted endothelial tube formation through paracrine signaling. Ultimately, Gli1⁺ CA markedly accelerated bone regeneration in a mouse femoral defect model compared with unsorted CA and Gli1⁻ CA, likely by inducing type H vessel formation. This study not only addresses a critical knowledge gap in Gli1⁺ CA-mediated bone regeneration, but also proposes a novel strategy termed "precision screening of endogenous SSPC subsets coupled with targeted aggregate fabrication". This approach offers a more precise therapeutic direction for the regenerative treatment of bone defects.