Cell fate determination is controlled by a complex network of cell signalling pathways. The process of osteoblasts transforming into osteocytes can be described as several distinct stages: from osteoblasts to early osteocytes, then to mature osteocytes, deeply embedded in the bone matrix within spaces called lacunae and canaliculi. During this transition, the committed osteoblast undergoes significant changes, including loss of proliferative capacity, the extension of multiple slender processes, and the secretion of minerals onto the collagenous scaffold. These osteocytes are arranged in an ordered manner with respect to neighbouring cells, suggesting that osteoblast-to-osteocyte transition is a tightly regulated developmental event. In this review, we summarise recent findings on Notch expression during osteoblast-to-osteocyte transition and propose a regulatory role for Notch in coordinating adjacent osteoblast activity during this process. We further discuss the implications of Notch signalling in the alveolar bone, as emerging data indicate that Notch participates in the osteogenic commitment of periodontal and alveolar progenitor cells, modulates force-driven remodelling, contributes to inflammatory osteolysis in periodontitis, and presents opportunities for biomaterial-guided alveolar bone regeneration and improved osseointegration around dental implants. This review highlights Notch as a potential master regulator of alveolar bone biology, suggesting that precise spatial and temporal control of Notch signalling may offer new therapeutic avenues to maintain alveolar bone homeostasis.
Diabetic periodontitis is a refractory complication of diabetes with limited therapeutic options. Here, we identify excessive fibrin deposition as a key perpetuator of chronic inflammation in diabetic periodontitis. Through single-cell transcriptomics and functional studies, we demonstrate that fibrin-Mac-1 interaction promotes M1 macrophage polarization via the NF-κB pathway, amplifying gamma delta T (γδ T) cell-derived IL-17A production and disrupting epithelial barrier integrity. Targeting this axis with a novel fibrin-blocking peptide (377 P) suppressed M1 macrophage and IL-17A signaling, restored claudin-1–dependent tight junctions, and promoted periodontal bone healing in diabetic mice. Clinical validation in human periodontal tissues revealed fibrin-M1 macrophage co-localization correlating with disease severity. Our findings establish fibrin as a druggable target for diabetic complications and propose 377 P as a translatable therapy to resolve chronic mucosal inflammation.
Homeostatic Medicine is an emerging integrative discipline that focuses on decoding the pivotal role of homeostasis in health and diseases and exploring strategies to restore inherent homeostasis for disease treatment and prevention. It not only provides a transformative theoretical framework, but also novel therapeutic strategies that may potentially revolutionize medical research and clinical practice. In this review, we first introduce the development, fundamental concepts, and core principles of Homeostatic Medicine. Then, we delve into two key regulatory systems as examples of homeostatic control: the nitrate-nitrite-nitric oxide (NO) pathway, mediated by the transporter Sialin, and the multifaceted regulation of oral stem cell (OSC) homeostasis, which encompasses metabolic flexibility, epigenetic programming, signaling networks, and immune-stem cell crosstalk. Under the framework of Homeostatic Medicine, we investigate the mechanisms of homeostatic dysregulation across a spectrum of diseases, including oral diseases, cancer, and cardiovascular and metabolic disorders. Subsequently, we leverage these insights to propose novel therapeutic strategies. Lastly, by synthesizing current knowledge, we outline the future research directions and translational pathways, emphasizing the importance of deep interdisciplinary collaboration in the development of Homeostatic Medicine.
The aim of this study is to compare the caries-preventive effect of 5% sodium fluoride (NaF) varnish with and without functionalized tricalcium phosphate (fTCP) on young children with untreated active caries. This 24-month, double-blind, parallel-designed, randomised controlled trial recruited 408 three-year-old children with untreated active carious lesion. Dental caries was diagnosed at the cavitation level according to WHO criteria, with carious lesions categorized as active if gentle probing revealed softness. A tooth surface was scored as sound in the absence of treated or untreated clinical dental caries. Recruited children were block-randomized into two intervention groups based on caries status (dmfs=1–3 or > 3). Group A received semi-annual application of a NaF varnish on all tooth surfaces. Group B received semi-annual application of a NaF varnish with fTCP on all tooth surfaces. Silver nitrate was applied on carious tooth surface before varnish application to promote caries arrest. Per protocol analysis was performed. At the 24-month evaluation, 356 children (87%) and 29,628 tooth surfaces (87%) were assessed. No significant difference was found in the attrition rate between groups (p = 0.30). At child level, no significant difference was found in the incidence rate of dental caries (86% vs. 82%, p = 0.38), the increment of mean dmft score (2.7 vs. 2.5, p = 0.50) and mean dmfs scores (4.8 vs. 4.3, p = 0.37) between groups. At tooth surface level, Group A had more sound tooth-surface becoming carious (865 vs. 742; 5.7% vs. 5.1%; p = 0.035). However, results of the generalized estimating equation model indicated treatment protocols were not significant related to the incidence of carious surfaces (p = 0.197) after adjusting clustering effect and confounding factors. When applied semi-annually to children with active caries, the 5% NaF varnish with fTCP and the conventional NaF varnish showed equivalent preventive efficacy in children with active caries.
Lymphatic dysfunction, clinically presenting as secondary lymphedema and chronic inflammatory conditions, remains a significant clinical challenge following oncologic therapy and tissue trauma. Current therapeutic strategies offer limited long-term efficacy, and cell-based regenerative approaches are constrained by safety concerns and scalability limitations. Within this therapeutic landscape, exosomes have emerged as promising mediators of lymphatic vessel repair. However, their specific role in lymphatic regeneration has not yet been fully elucidated. These nanovesicles, derived from diverse cellular sources, carry diverse molecular constituents that precisely modulate cellular processes critical for lymphangiogenesis. Compelling evidence highlights the essential role of exosome-mediated networks in lymphangiogenic processes. Exosomes influence lymphatic endothelial cell behavior by engaging multiple canonical signaling pathways. Current reviews predominantly address exosome biology or lymphatic pathophysiology in isolation, lacking a systematic analysis of exosomal regulatory mechanisms. This review aims to delineate the multifunctional role of exosomes as modulators of the lymphatic regenerative niche. We further discuss current tissue engineering strategies that utilize exosomes to promote lymphatic vessel regeneration, identify persistent gaps, and seek to establish a theoretical foundation for exosome-based lymphatic regeneration.
Enzyme-mediated mineralization offers a versatile strategy for developing advanced composite biomaterials, yet the precise mechanisms involving kinetic mineral-interface bonding and mineral growth remain elusive. Herein, we systematically optimized the parameters for alkaline phosphatase (ALP)-mediated mineralization on TiO₂ nanotubes (TNT) surfaces. To bridge the gap between macroscopic observations and microscopic origins, we employed an integrated approach combining molecular dynamics simulations (MDS) and first-principles calculations to elucidate the underlying atomistic and electronic-level mechanisms. Experimental results demonstrated that ALP regulates mineralization by catalyzing the hydrolysis of organic phosphate, thereby maintaining a sustained and controllable local supply of PO₄³⁻ ions. Molecular dynamics simulations revealed that ALP acts as a molecular regulator by forming stable ALP-CaP clusters. These clusters temporarily delay the direct aggregation of Ca²⁺ and PO₄³⁻ ions, therefore preventing premature precipitation and promoting homogeneous mineral deposition within the TNT scaffolds. Subsequently, first-principles calculations provided deep insights into the electronic structure, identifying specific coordination sites and quantifying the interfacial binding energies between these mineral precursors and the TNT internal surfaces. The analysis confirms that ALP residues bridge CaP clusters to the TNT interface via Ca²⁺–O–COO– (coordination bond) and OPO₄³⁻–H–NH₂ (hydrogen bond), while Ca²⁺ ions from the clusters anchor simultaneously to the TNT. These multi-point interactions and charge redistribution collectively enhance the interfacial binding energy. The resulting composites exhibit a potent inductive effect on osteogenesis. This synergy of experiment and theory provides a comprehensive understanding of the interfacial physics driving mineral deposition during enzyme-mediated mineralization, laying the foundation for the development of functional biomimetic interfaces.
Despite the therapeutic promise of stem cell aggregates in bone regeneration, clinical outcomes remain unstable due to the complex and incompletely understood fate of transplanted cells. Here, we investigated the role of programmed cell death in this process, moving beyond the established paradigm of apoptosis. Our study demonstrates that stem cell aggregates (CAs) from human exfoliated deciduous teeth (SHEDs) implanted into a murine femoral defect model undergo necroptosis in a time-dependent manner. Pre-induction of necroptosis in CAs prior to transplantation profoundly impaired bone repair, significantly reducing new bone formation, osteogenic differentiation, and vascularization at the defect site. Conversely, pharmacological inhibition of necroptosis using Necrostatin-1 rescued the regenerative capacity. Crucially, we identified that this inhibitory effect is primarily mediated by extracellular vesicles released during necroptosis (Nec-EVs). Inhibition of Nec-EV biogenesis with GW4869 restored bone healing. Characterization confirmed the successful isolation of phosphorylated mixed lineage kinase domain-like protein (pMLKL)-enriched Nec-EVs. Proteomic analysis revealed a distinct cargo profile in Nec-EVs, notably enriched in proteins involved in translation regulation and RNA metabolism. Functionally, Nec-EVs directly suppressed the proliferation and osteogenic potential of bone marrow stem cells (BMSCs) in vitro, and their local application in vivo was sufficient to recapitulate the impaired bone regeneration phenotype. Collectively, this work establishes necroptosis and its associated vesicular signaling as novel detrimental axes in cell-based bone regeneration, providing mechanistic insights and potential therapeutic targets for enhancing the reliability of regenerative therapies.
Oral ulcers are among the most common inflammatory lesions of the oral mucosa and often cause severe pain. However, current treatments are limited by short mucosal retention, suboptimal therapeutic efficacy, and steroid-associated side effects, underscoring the need for more effective and durable therapeutic strategies. Here, we developed exosome-loaded microneedle patches (Exo-MNPs) by incorporating mesenchymal stem cell-derived exosomes (MSC-exo) into gelatin methacryloyl (GelMA)/polyvinylpyrrolidone (PVP) microneedles and evaluated their potential to accelerate oral ulcer healing. Exo-MNPs were systematically characterized in terms of morphology, mechanical strength, and in vitro bioactivity. In rat ulcer models, Exo-MNPs markedly accelerated wound closure, promoted epithelial regeneration, reduced inflammation, and increased collagen deposition. Multi-omics profiling using single-cell RNA sequencing (scRNA-seq) and proteomics revealed that Exo-MNPs act through the TSP-1/CD47/NF-κB axis to reprogram macrophage phenotypes and promote regenerative epithelial subpopulations via intercellular crosstalk. These findings demonstrate that Exo-MNPs represent a promising localized bioactive therapy for oral ulcers and illuminate key immune–epithelial mechanisms underlying their therapeutic effects.