Hearing loss has become increasingly prevalent and causes considerable disability, thus gravely burdening the global economy. Irreversible loss of hair cells is a main cause of sensorineural hearing loss, and currently, the only relatively effective clinical treatments are limited to digital hearing equipment like cochlear implants and hearing aids, but these are of limited benefit in patients. It is therefore urgent to understand the mechanisms of damage repair in order to develop new neuroprotective strategies. At present, how to promote the regeneration of functional hair cells is a key scientific question in the field of hearing research. Multiple signaling pathways and transcriptional factors trigger the activation of hair cell progenitors and ensure the maturation of newborn hair cells, and in this article, we first review the principal mechanisms underlying hair cell reproduction. We then further discuss therapeutic strategies involving the co-regulation of multiple signaling pathways in order to induce effective functional hair cell regeneration after degeneration, and we summarize current achievements in hair cell regeneration. Lastly, we discuss potential future approaches, such as small molecule drugs and gene therapy, which might be applied for regenerating functional hair cells in the clinic.
Infant, Newborn ; Humans ; Hair Cells, Auditory, Inner/physiology* ; Ear, Inner/physiology* ; Hair Cells, Auditory/physiology* ; Regeneration/genetics* ; Stem Cells

OBJECTIVE: To provide useful information for selecting the most appropriate peripheral nerve injury model for different research purposes in nerve injury and repair studies, and to compare nerve regeneration capacity and characteristics between them. METHODS: Sixty adult SD rats were randomly divided into two groups and underwent crush injury alone (group A, n = 30) or transection injury followed by surgical repair (group B, n = 30) of the right hind paw. Each group was subjected to the CatWalk test, gastrocnemius muscle evaluation, pain threshold measurement, electrophysiological examination, retrograde neuronal labeling, and quantification of nerve regeneration before and 7, 14, 21, and 28 days after injury. RESULTS: Gait analysis showed that the recovery speed in group A was significantly faster than that in group B at 14 days. At 21 days, the compound muscle action potential of the gastrocnemius muscle in group A was significantly higher than that in group B, and the number of labeled motor neurons in group B was lower than that in group A. The number of new myelin sheaths and the g-ratio were higher in group A than in group B. There was a 7-day time difference in the regeneration rate between the two injury groups. CONCLUSION The regeneration of nerve fibers was rapid after crush nerve injury, whereas the transection injury was relatively slow, which provides some ideas for the selection of clinical research models.
Animals ; Rats ; Nerve Fibers ; Nerve Regeneration ; Rats, Sprague-Dawley ; Sciatic Nerve/injuries*

Severe muscle injury is hard to heal and always results in a poor prognosis. Recent studies found that extracellular vesicle-based therapy has promising prospects for regeneration medicine, however, whether extracellular vesicles have therapeutic effects on severe muscle injury is still unknown. Herein, we extracted apoptotic extracellular vesicles derived from mesenchymal stem cells (MSCs-ApoEVs) to treat cardiotoxin induced tibialis anterior (TA) injury and found that MSCs-ApoEVs promoted muscles regeneration and increased the proportion of multinucleated cells. Besides that, we also found that apoptosis was synchronized during myoblasts fusion and MSCs-ApoEVs promoted the apoptosis ratio as well as the fusion index of myoblasts. Furthermore, we revealed that MSCs-ApoEVs increased the relative level of creatine during myoblasts fusion, which was released via activated Pannexin 1 channel. Moreover, we also found that activated Pannexin 1 channel was highly expressed on the membrane of myoblasts-derived ApoEVs (Myo-ApoEVs) instead of apoptotic myoblasts, and creatine was the pivotal metabolite involved in myoblasts fusion. Collectively, our findings firstly revealed that MSCs-ApoEVs can promote muscle regeneration and elucidated that the new function of ApoEVs as passing inter-cell messages through releasing metabolites from activated Pannexin 1 channel, which will provide new evidence for extracellular vesicles-based therapy as well as improving the understanding of new functions of extracellular vesicles.
Creatine/metabolism* ; Extracellular Vesicles ; Muscle, Skeletal/metabolism* ; Myoblasts/metabolism* ; Regeneration ; Connexins/metabolism*

OBJECTIVE: To investigate whether the placement of absorbable collagen membrane increase the stability of alveolar ridge contour after guided bone regeneration (GBR) using buccal punch flap. METHODS: From June 2019 to June 2023, patients who underwent GBR using buccal punch flap simultaneously with a single implant placement in posterior region (from first premolar to second molar) were divided into coverage group, in which particular bone graft was covered by collagen membrane and non-coverage group. Cone beam CT (CBCT) was taken before surgery (T0), immediately after surgery (T1), and 3-7 months after surgery (T2), and the thickness of the buccal bone plate at different levels (0, 2, 4, and 6 mm) below the smooth-rough interface of the implant (BBT-0, -2, -4, -6) was mea-sured after superimposition of CBCT models using Mimics software. RESULTS: A total of 29 patients, including 15 patients in coverage group and 14 patients in non-coverage group, were investigated in this study. At T0, T1, and T2, there was no significant difference in BBT between the two groups (P>0.05). At T1, BBT-0 was (2.50±0.90) mm in the coverage group and (2.97±1.28) mm in the non-coverage group, with corresponding BBT-2 of (3.65±1.08) mm and (3.58±1.26) mm, respectively. At T2, BBT-0 was (1.22±0.55) mm in the coverage group and (1.70±0.97) mm in the non-coverage group, with corresponding BBT-2 of (2.32±0.94) mm and (2.57±1.26) mm, respectively. From T1 to T2, there were no statistically significant differences in the absolute values [(0.47±0.54)-(1.33±0.75) mm] and percentages [(10.04%±24.81%)-(48.43%±18.32%)] of BBT change between the two groups. The thickness of new bone formation in the buccal bone plate from T0 to T2 ranged from (1.27±1.09) mm to (2.75±2.15) mm with no statistical difference between the two groups at all levels. CONCLUSION In the short term, the GBR using buccal punch flap with or without collagen membrane coverage can effectively repair the buccal implant bone defect. But collagen membrane coverage showed no additional benefit on alveolar ridge contour stability compared with non-membrane coverage.
Humans ; Cohort Studies ; Retrospective Studies ; Alveolar Ridge Augmentation ; Collagen ; Cone-Beam Computed Tomography ; Bone Regeneration ; Dental Implantation, Endosseous

Salivary gland (SG) dysfunction, due to radiotherapy, disease, or aging, is a clinical manifestation that has the potential to cause severe oral and/or systemic diseases and compromise quality of life. Currently, the standard-of-care for this condition remains palliative. A variety of approaches have been employed to restore saliva production, but they have largely failed due to damage to both secretory cells and the extracellular matrix (niche). Transplantation of allogeneic cells from healthy donors has been suggested as a potential solution, but no definitive population of SG stem cells, capable of regenerating the gland, has been identified. Alternatively, mesenchymal stem cells (MSCs) are abundant, well characterized, and during SG development/homeostasis engage in signaling crosstalk with the SG epithelium. Further, the trans-differentiation potential of these cells and their ability to regenerate SG tissues have been demonstrated. However, recent findings suggest that the "immuno-privileged" status of allogeneic adult MSCs may not reflect their status post-transplantation. In contrast, autologous MSCs can be recovered from healthy tissues and do not present a challenge to the recipient's immune system. With recent advances in our ability to expand MSCs in vitro on tissue-specific matrices, autologous MSCs may offer a new therapeutic paradigm for restoration of SG function.
Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells ; Quality of Life ; Regeneration ; Salivary Glands ; Stem Cells

Periodontal bone regeneration is a major challenge in the treatment of periodontitis. Currently the main obstacle is the difficulty of restoring the regenerative vitality of periodontal osteoblast lineages suppressed by inflammation, via conventional treatment. CD301b⁺ macrophages were recently identified as a subpopulation that is characteristic of a regenerative environment, but their role in periodontal bone repair has not been reported. The current study indicates that CD301b⁺ macrophages may be a constituent component of periodontal bone repair, and that they are devoted to bone formation in the resolving phase of periodontitis. Transcriptome sequencing suggested that CD301b⁺ macrophages could positively regulate osteogenesis-related processes. In vitro, CD301b⁺ macrophages could be induced by interleukin 4 (IL-4) unless proinflammatory cytokines such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) were present. Mechanistically, CD301b⁺ macrophages promoted osteoblast differentiation via insulin-like growth factor 1 (IGF-1)/thymoma viral proto-oncogene 1 (Akt)/mammalian target of rapamycin (mTOR) signaling. An osteogenic inducible nano-capsule (OINC) consisting of a gold nanocage loaded with IL-4 as the "core" and mouse neutrophil membrane as the "shell" was designed. When injected into periodontal tissue, OINCs first absorbed proinflammatory cytokines in inflamed periodontal tissue, then released IL-4 controlled by far-red irradiation. These events collectively promoted CD301b⁺ macrophage enrichment, which further boosted periodontal bone regeneration. The current study highlights the osteoinductive role of CD301b⁺ macrophages, and suggests a CD301b⁺ macrophage-targeted induction strategy based on biomimetic nano-capsules for improved therapeutic efficacy, which may also provide a potential therapeutic target and strategy for other inflammatory bone diseases.
Animals ; Mice ; Bone Regeneration ; Cytokines/metabolism* ; Interleukin-4/therapeutic use* ; Macrophages/physiology* ; Mammals ; Osteogenesis ; Periodontitis/drug therapy*

In growing children, growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest. Interestingly, one type of fracture injuries within the growth plate achieve amazing self-healing, however, the mechanism is unclear. Using this type of fracture mouse model, we discovered the activation of Hedgehog (Hh) signaling in the injured growth plate, which could activate chondrocytes in growth plate and promote cartilage repair. Primary cilia are the central transduction mediator of Hh signaling. Notably, ciliary Hh-Smo-Gli signaling pathways were enriched in the growth plate during development. Moreover, chondrocytes in resting and proliferating zone were dynamically ciliated during growth plate repair. Furthermore, conditional deletion of the ciliary core gene Ift140 in cartilage disrupted cilia-mediated Hh signaling in growth plate. More importantly, activating ciliary Hh signaling by Smoothened agonist (SAG) significantly accelerated growth plate repair after injury. In sum, primary cilia mediate Hh signaling induced the activation of stem/progenitor chondrocytes and growth plate repair after fracture injury.
Mice ; Animals ; Hedgehog Proteins/genetics* ; Receptors, G-Protein-Coupled/metabolism* ; Cilia/metabolism* ; Cartilage/metabolism* ; Regeneration

Oligonucleotide drugs have the characteristics of targeting, modifiability and high biosafety. Recent studies have shown that oligonucleotide can be used to make biosensors, vaccine adjuvants, and has the functions of inhibiting alveolar bone resorption, promoting jaw and alveolar bone regeneration, anti-tumor, destroying plaque biofilm, and precise control of drug release. Therefore, it has a broad application prospect in the field of stomatology. This article reviews the classification, action mechanism and research status of oligonucleotide in stomatology. The aim is to provide ideas for further research and application of oligonucleotide.
Humans ; Alveolar Bone Loss ; Biofilms ; Bone Regeneration ; Oligonucleotides ; Oral Medicine

Hepatic parenchymal cells are a type of liver cells that performs important functions such as metabolism and detoxification. The contribution of hepatic parenchymal cells, bile duct cells, and hepatic stem/progenitor cells to new hepatic parenchymal cells in the process of liver injury repair has become a controversial issue due to their strong proliferation ability. Lineage tracing technology, which has emerged in the past decade as a new method for exploring the origin of cells, can trace specific type of cells and their daughter cells by labeling cells that express the specific gene and their progeny. The article reviews the current literature on the origin and contribution of hepatic parenchymal cells by this technique. About 98% of new hepatic parenchymal cells originate from the existing hepatic parenchymal cells during liver homeostasis and after acute injury. However, under conditions of severe liver injury, such as inhibition of hepatic parenchymal cell proliferation, bile duct cells (mainly liver stem/progenitor cells) become the predominant source of hepatic parenchymal cells, contributing a steady increased hepatocyte regeneration with the extension of time.
Hepatocytes/metabolism* ; Liver/metabolism* ; Bile Ducts ; Stem Cells ; Liver Regeneration/physiology* ; Cell Differentiation

The gold-standard for bone substitution of large bone defects continues to be autogenous bone graft. Artificial bone substitutes are difficult to replace the autogenous bone grafting due to excessive immune response, fast biodegradation characteristics and inappropriate biocompatibility. Given these drawbacks, osteoimmunology and its advanced functional biomaterials have gained growing attention in recent years. Immune system plays an essential role during bone healing via regulating the shift from inflammatory to anti-inflammation phenotype, and inflammatory cytokines response. The inflammatory reaction mainly include infiltration of immune cells (such as macrophages, neutrophils, T cells, B cells, etc) and release of inflammatory factors (such as IL-1β, IL-6, TNF-α, etc.) at the bone defects, which subsequently affect the step-wised process of bone healing rejuvenation. Hence, advanced bone biomaterials with immunomodulatory properties is of great significance for the treatment of patients with recalcitrant bone defects, especially for delayed healing or non-union. The reciprocal mechanism of immuno-modulated bone healing, however, is not fully understood and more research is required in the future.
Osteogenesis ; Cytokines ; Biocompatible Materials ; Macrophages ; T-Lymphocytes ; Bone Regeneration