Telehealth Utilization in Oral Medicine and Oral and Maxillofacial Surgery.

Objectives: The objectives of this retrospective study were to analyze telehealth utilization for two specialty care practices: oral medicine (OM) and oral and maxillofacial surgery (OMFS) during the first 2 years of the pandemic, its impact as a new treatment modality and on participating providers, as well as identify the type of patient visit that most readily adopted telehealth. Methods: Retrospective study of patients who sought specialty services, OM and OMFS, at an outpatient clinic in a university health system setting between March 1, 2019, and February 28, 2022. Source data were obtained from Epic, an electronic medical record application. Data were graphed using Tableau and Microsoft Excel software. Statistical analysis was performed utilizing chi-squared test and analysis of variance (ANOVA). Results: OMFS utilized telehealth 12% of the time, and OM 8% of the time. The majority (87%) of telehealth visits were for return patients (RPs). Compared with the first year of the pandemic, there was a decrease in the number of telehealth visits in the second year (p = 0.0001). As of August 2022, new patient (NP) telehealth encounters have largely returned to prepandemic levels (0-1.5%), whereas RP telehealth visits remained at an average level of 11.4% (9.4-12.4%). Surveyed providers consider telehealth as an effective complement to in-person care and will continue its use (4.2/5 Likert scale). Conclusions: Telehealth has become a viable pathway of care for OM and OMFS who previously did not utilize the remote platform to deliver healthcare. As a new treatment modality, telehealth is perceived as impactful in increasing access to specialty care by participating providers. NP visits are now almost completely in person, but telehealth continues for RPs. Ongoing demand for telehealth highlights urgency to develop appropriate standards and effective remote diagnostic/monitoring tools to maximize telehealth's capability to leverage finite health care resources and increase access to specialty care.

Targeted inhibition of eIF5Ahpu suppresses tumor growth and polarization of M2-like tumor-associated macrophages in oral cancer.

Eukaryotic initiation factor 5A2 (eIF5A2) is overexpressed in many types of cancer, and spermidine-mediated eIF5A hypusination (eIF5Ahpu) appears to be essential to most of eIF5A's biological functions, including its important role in regulating cancer cell proliferation, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) properties as well as immune cell functions. Here we investigated the role of eIF5Ahpu in the growth of oral squamous cell carcinoma cells (OSCCs) and OSCC-induced polarization of M2-like tumor-associated macrophages (TAMs). TCGA dataset analysis revealed an overall upregulation in the mRNA expression of eIF5A2 and several key enzymes involved in polyamine (PA) metabolism in HNSCC, which was confirmed by Western blot and IHC studies. Blocking eIF5Ahpu by GC-7 but not the upstream key enzyme activities of PA metabolism, remarkably inhibited cell proliferation and the expression of EMT- and CSC-related genes in OSCC cells. In addition, blocking eIF5Ahpu robustly inhibited OSCC-induced M2-like TAM polarization in vitro. More Importantly, blocking eIF5Ahpu dramatically retarded tumor growth and infiltration/polarization of M2-like TAM in a syngeneic orthotopic murine tongue SCC model. Thus, eIF5Ahpu plays dual functions in regulating tumor cell growth and polarization of M2-TAMs in OSCC.

Potential Application of Orofacial MSCs in Tissue Engineering Nerve Guidance for Peripheral Nerve Injury Repair.

Injury to the peripheral nerve causes potential loss of sensory and motor functions, and peripheral nerve repair (PNR) remains a challenging endeavor. The current clinical methods of nerve repair, such as direct suture, autografts, and acellular nerve grafts (ANGs), exhibit their respective disadvantages like nerve tension, donor site morbidity, size mismatch, and immunogenicity. Even though commercially available nerve guidance conduits (NGCs) have demonstrated some clinical successes, the overall clinical outcome is still suboptimal, especially for nerve injuries with a large gap (≥ 3 cm) due to the lack of biologics. In the last two decades, the combination of advanced tissue engineering technologies, stem cell biology, and biomaterial science has significantly advanced the generation of a new generation of NGCs incorporated with biological factors or supportive cells, including mesenchymal stem cells (MSCs), which hold great promise to enhance peripheral nerve repair/regeneration (PNR). Orofacial MSCs are emerging as a unique source of MSCs for PNR due to their neural crest-origin and easy accessibility. In this narrative review, we have provided an update on the pathophysiology of peripheral nerve injury and the properties and biological functions of orofacial MSCs. Then we have highlighted the application of orofacial MSCs in tissue engineering nerve guidance for PNR in various preclinical models and the potential challenges and future directions in this field.

Quality of life in patients with oral potentially malignant disorders: oral lichen planus and oral epithelial dysplasia.

OBJECTIVE: The aim of this study was to evaluate and compare quality of life (QoL) parameters in patients with oral potential malignant disorders (OPMDs), namely, oral lichen planus (OLP) and oral epithelial dysplasia (OED). STUDY DESIGN: A cross-sectional study was completed at the oral maxillofacial surgery/oral medicine practices at University of Pennsylvania. Patients with clinical and histopathologic confirmation of OLP or OED from January to June 2021 were included in the study. The primary predictor variable was the OPMD type. The primary outcome variable was the score of 3 separate surveys: the Chronic Oral Mucosal Disease Questionnaire-26 (COMDQ-26), Oral Potential Malignant Disorder QoL Questionnaire (OPMDQoL), and Hospital Anxiety and Depression Scale. Multiple linear regression was used to determine independent predictors of increased/decreased questionnaire scores. RESULTS: The final study sample consisted of 100 patients:53 patients had OLP (53.0%), 39 patients had OED (39.0%), and 8 patients had OLP with OED (8.0%). Relative to OED, OLP added 15.7 points to the COMDQ-26 survey score (P < .001). Relative to OED, OLP added 8.9 points to the OPMDQoL survey score (P = .003). CONCLUSIONS: Oral lichen planus shows significantly poorer QoL specifically within the COMD-26 and OPMDQoL questionnaires, compared with OED. Additionally, patients with OPMDs aged 40 to 64 years were independently associated with higher COMD-26 scores compared with older patients (>65 years).

Asymmetric Maxillary Expansion Introduced by Surgically Assisted Rapid Palatal Expansion: A Systematic Review.

PURPOSE: A commonly reported complication of surgically assisted rapid palatal expansion (SARPE) that has not been explored extensively is uneven expansion between left and right sides, which requires secondary surgery for correction. This systematic review aims to analyze the prevalence and potential causes of asymmetric expansion in the transverse dimension after SARPE to guide the clinical practice. METHODS: Electronic databases and manual search were used to search for original articles published on SARPE on March 11, 2022. Original human studies that recorded the number and percentage of asymmetric expansion after two-piece SARPE were included. The 2020 Preferred Reporting Items for Systemic Reviews and Meta-Analyses guideline was implemented for the quality assessment and data analysis of the included articles. The study was registered at the International Prospective Register of Systematic Reviews under the number CRD42022300782. RESULTS: After applying inclusion and exclusion criteria, 13 articles were included in the final review. The risk of bias was high in 8 studies and medium in the other 5 studies. Overall, the prevalence of asymmetric expansion in the transverse dimension (different amount of expansion between left and right sides) was 7.52%, with 12.90% of patients involved receiving a second surgery for correction. Expander design did not significantly affect the rate of asymmetry expansion. Pterygomaxillary fissure release significantly increased the rate of asymmetry expansion (11.02% vs 5.08%, P < .001). In comparison, lateral nasal wall osteotomy (4.26% vs 14.77%, P < .001) and release of the nasal septum (5.22% vs 17.15%, P < .001) significantly lowered the rate of asymmetry expansion, respectively. CONCLUSIONS: Asymmetric dentoskeletal expansion between left and right sides is a common complication of SARPE procedures, mostly caused by variations in surgical cuts. However, the risk of bias in currently available publications is high. Further studies are warranted to fully understand the causes of asymmetric expansion.

Potential application of dental stem cells in regenerative reconstruction of oral and maxillofacial tissues: a narrative review.

Background and Objective: Oral and maxillofacial (OMF) defects caused by congenital conditions, injuries, ablative surgery for benign and malignant head & neck tumor, can often lead to OMF deformities and malfunctions in speech, mastication/chewing, and swallowing as well as have deleterious psychological effects and socioeconomic burdens to patients. Due to the unique complex 3D geometry of the head and neck region, reconstruction and rehabilitation of OMF defects remain a major challenge for OMF surgeons.The purpose of this narrative review is to update the information on the biological properties and functions of mesenchymal stem cells derived from various dental tissues (dental-MSCs) and their potential application in tissue engineering (TE) and regenerative reconstruction of OMF tissues. Methods: A data-based search was performed by using PubMed database whereby articles published between 2000 and 2021 in English were included in the search with the following key words: dental stem cells, OMF reconstruction, OMF TE and regeneration. Key Content and Findings: Currently, the advancement in stem cell biology, biomaterial science, and TE technology has demonstrated the significant potential application of stem cell-based therapy in regenerative reconstruction and rehabilitation of OMF defects. However, no stem cell-based product or device has been translated into clinical application to replace microsurgical free tissue transfer, the current mainstay of care in the reconstruction of OMF defects. Conclusions: Currently, microsurgical free tissue transfer remains the gold standard mainstay of care for the reconstruction of OMF defects due to their abundant blood supply and flexibility for transplantation. However, several major challenges, such as the limited availability, the requirement of a second surgery, donor site morbidity, and the risk of free flap failure, have promoted the development of novel approaches. Due to the advancement in stem cell biology, biomaterial science, and TE technology, stem cell-based regenerative therapy is emerging as a promising therapeutic approach for a variety of diseases, including regenerative reconstruction and rehabilitation of OMF defects. In this narrative review, we update on the characteristics and biological functions of mesenchymal stem cells derived from various dental tissues (dental-MSCs) and their released cell-free products, extracellular vesicles (EVs). We also highlighted their potential application in TE and regenerative reconstruction of OMF defects in animal models and clinical studies and the potential challenges in this field.

Implantation of a nerve protector embedded with human GMSC-derived Schwann-like cells accelerates regeneration of crush-injured rat sciatic nerves.

BACKGROUND: Peripheral nerve injuries (PNIs) remain one of the great clinical challenges because of their considerable long-term disability potential. Postnatal neural crest-derived multipotent stem cells, including gingiva-derived mesenchymal stem cells (GMSCs), represent a promising source of seed cells for tissue engineering and regenerative therapy of various disorders, including PNIs. Here, we generated GMSC-repopulated nerve protectors and evaluated their therapeutic effects in a crush injury model of rat sciatic nerves. METHODS: GMSCs were mixed in methacrylated collagen and cultured for 48 h, allowing the conversion of GMSCs into Schwann-like cells (GiSCs). The phenotype of GiSCs was verified by fluorescence studies on the expression of Schwann cell markers. GMSCs encapsulated in the methacrylated 3D-collagen hydrogel were co-cultured with THP-1-derived macrophages, and the secretion of anti-inflammatory cytokine IL-10 or inflammatory cytokines TNF-α and IL-1ß in the supernatant was determined by ELISA. In addition, GMSCs mixed in the methacrylated collagen were filled into a nerve protector made from the decellularized small intestine submucosal extracellular matrix (SIS-ECM) and cultured for 24 h, allowing the generation of functionalized nerve protectors repopulated with GiSCs. We implanted the nerve protector to wrap the injury site of rat sciatic nerves and performed functional and histological assessments 4 weeks post-surgery. RESULTS: GMSCs encapsulated in the methacrylated 3D-collagen hydrogel were directly converted into Schwann-like cells (GiSCs) characterized by the expression of S-100ß, p75NTR, BDNF, and GDNF. In vitro, co-culture of GMSCs encapsulated in the 3D-collagen hydrogel with macrophages remarkably increased the secretion of IL-10, an anti-inflammatory cytokine characteristic of pro-regenerative (M2) macrophages, but robustly reduced LPS-stimulated secretion of TNF-1α and IL-1ß, two cytokines characteristic of pro-inflammatory (M1) macrophages. In addition, our results indicate that implantation of functionalized nerve protectors repopulated with GiSCs significantly accelerated functional recovery and axonal regeneration of crush-injured rat sciatic nerves accompanied by increased infiltration of pro-regenerative (M2) macrophages while a decreased infiltration of pro-inflammatory (M1) macrophages. CONCLUSIONS: Collectively, these findings suggest that Schwann-like cells converted from GMSCs represent a promising source of supportive cells for regenerative therapy of PNI through their dual functions, neurotrophic effects, and immunomodulation of pro-inflammatory (M1)/pro-regenerative (M2) macrophages.

Are Bacteria Just Bystanders in the Pathogenesis of Inflammatory Jaw Conditions?

PURPOSE: It is unclear whether certain bacteria initiate the development of inflammatory jaw conditions, or whether these diseases create a milieu for dysbiosis and secondary colonization of indigenous flora. At present, there are no comparative studies on the types of bacteria that colonize different inflammatory jaw conditions. Accordingly, this study aims to identify and compare the types of bacteria isolated in osteomyelitis, osteoradionecrosis, and MRONJ. METHODS: This is a retrospective cohort study of patients diagnosed with inflammatory jaw conditions. The predictor variables were classification of bacteria as oral flora, categorized herein as resident bacteria, non-resident bacteria, or opportunistic organisms. The outcome variables were a diagnosis of osteomyelitis, osteoradionecrosis, and MRONJ. Covariates were age, sex, penicillin allergy, a diagnosis of diabetes and a history of smoking. Data analysis was performed using ANOVA and chi-squared tests. RESULTS: A total of 105 patients with inflammatory jaw conditions were enrolled. The final sample size was 69 subjects of which 16 were diagnosed with osteomyelitis, 20 with osteoradionecrosis, and 33 with MRONJ. There was no difference in the frequency that resident bacteria were isolated. Non-resident bacteria, which included Staphylococcus and Enterococcus among others, were isolated more frequently at 75% in osteomyelitis compared to 60% in osteoradionecrosis and 48% in MRONJ cases. There is weak evidence of significant difference when comparing osteomyelitis and MRONJ cases (P = .08). Opportunistic organisms, which included Mycobacterium and Candida, were isolated more frequently in osteoradionecrosis at 30% compared to 12.5% in osteomyelitis and 12.12% in MRONJ cases. There is weak evidence of significant difference when comparing osteoradionecrosis and MRONJ cases (P = .1). CONCLUSION: Non-resident bacteria including Staphylococcus and Enterococcus may be more frequently isolated in patients with osteomyelitis, while opportunistic organisms like Mycobacterium and Candida may be more frequently found in patients diagnosed with osteoradionecrosis.

Gingiva-Derived Mesenchymal Stem Cells: Potential Application in Tissue Engineering and Regenerative Medicine - A Comprehensive Review.

A unique subpopulation of mesenchymal stem cells (MSCs) has been isolated and characterized from human gingival tissues (GMSCs). Similar to MSCs derived from other sources of tissues, e.g. bone marrow, adipose or umbilical cord, GMSCs also possess multipotent differentiation capacities and potent immunomodulatory effects on both innate and adaptive immune cells through the secretion of various types of bioactive factors with immunosuppressive and anti-inflammatory functions. Uniquely, GMSCs are highly proliferative and have the propensity to differentiate into neural cell lineages due to the neural crest-origin. These properties have endowed GMSCs with potent regenerative and therapeutic potentials in various preclinical models of human disorders, particularly, some inflammatory and autoimmune diseases, skin diseases, oral and maxillofacial disorders, and peripheral nerve injuries. All types of cells release extracellular vesicles (EVs), including exosomes, that play critical roles in cell-cell communication through their cargos containing a variety of bioactive molecules, such as proteins, nucleic acids, and lipids. Like EVs released by other sources of MSCs, GMSC-derived EVs have been shown to possess similar biological functions and therapeutic effects on several preclinical diseases models as GMSCs, thus representing a promising cell-free platform for regenerative therapy. Taken together, due to the easily accessibility and less morbidity of harvesting gingival tissues as well as the potent immunomodulatory and anti-inflammatory functions, GMSCs represent a unique source of MSCs of a neural crest-origin for potential application in tissue engineering and regenerative therapy.

Exosomes from TNF-α-treated human gingiva-derived MSCs enhance M2 macrophage polarization and inhibit periodontal bone loss.

Mesenchymal stem cell (MSC)-derived exosome plays a central role in the cell-free therapeutics involving MSCs and the contents can be customized under disease-associated microenvironments. However, optimal MSC-preconditioning to enhance its therapeutic potential is largely unknown. Here, we show that preconditioning of gingival tissue-derived MSCs (GMSCs) with tumor necrosis factor-alpha (TNF-α) is ideal for the treatment of periodontitis. TNF-α stimulation not only increased the amount of exosome secreted from GMSCs, but also enhanced the exosomal expression of CD73, thereby inducing anti-inflammatory M2 macrophage polarization. The effect of GMSC-derived exosomes on inflammatory bone loss were examined by ligature-induced periodontitis model in mice. Local injection of GMSC-derived exosomes significantly reduced periodontal bone resorption and the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and these effects were further enhanced by preconditioning of GMSCs with TNF-α. Thus, GMSC-derived exosomes also exhibited anti-osteoclastogenic activity. Receptor activator of NF-κB ligand (RANKL) expression was regulated by Wnt5a in periodontal ligament cells (PDLCs), and exosomal miR-1260b was found to target Wnt5a-mediated RANKL pathway and inhibit its osteoclastogenic activity. These results indicate that significant ability of the TNF-α-preconditioned GMSC-derived exosomes to regulate inflammation and osteoclastogenesis paves the way for establishment of a therapeutic approach for periodontitis.

LGR5+ epithelial tumor stem-like cells generate a 3D-organoid model for ameloblastoma.

Ameloblastoma (AM) is a benign but locally aggressive tumor with high recurrences. Currently, underlying pathophysiology remains elusive, and radical surgery remains the most definitive treatment with severe morbidities. We have recently reported that AM harbors a subpopulation of tumor epithelial stem-like cells (AM-EpiSCs). Herein, we explored whether LGR5+ epithelial cells in AM possess stem-like cell properties and their potential contribution to pathogenesis and recurrence of AM. We found that LGR5 and stem cell-related genes were co-expressed in a subpopulation of AM epithelial cells both in vivo and in vitro, which were enriched under 3D-spheroid culture. As compared to LGR5- counterparts, LGR5+ AM epithelial cells showed increased expression of various EMT- and stemness-related genes, and functionally, exhibited increased capacity to form 3D-spheroids and generate human tumor 3D organoids, which recapitulated the histopathologic features of distinct subtypes of solid AM, thus, contributing a useful human tumor platform for targeted therapeutic screening. Treatment with a selective BRAFV600E inhibitor, vemurafenib, unexpectedly enriched the subpopulation of LGR5+ AM-EpiSCs in tumor 3D organoids, which may have explained therapeutic resistances and recurrences. These findings suggest that LGR5+ AM-EpiSCs play a pivotal role in pathogenesis and progression of AM and targeted inhibition of both BRAF and LGR5 potentially serves a novel nonsurgical adjuvant therapeutic approach for this aggressively benign jaw tumor.

Considerations in the evaluation and management of oral potentially malignant disorders during the COVID-19 pandemic.

AIM: The COVID-19 pandemic has resulted in society experiencing unprecedented challenges for health care practitioners and facilities serving at the frontlines of this pandemic. With regard to oral cancer, there is a complete absence of literature regarding the long-term impact of pandemics on patients with oral potentially malignant disorders (OPMDs). The objective of this article is to put forth an institutional multidisciplinary approach for the evaluation and management of OPMDs. METHODS: A multidisciplinary approach was put formalized within our institution to risk stratify patients based on need for in-person assessment vs telehealth assessment during the COVID-19 pandemic. RESULTS: With judicious risk stratification of patients based on clinical features of their OPMD and with consideration of ongoing mitigation efforts and regional pandemic impact, providers are able to safely care for their patients. CONCLUSIONS: The COVID-19 pandemic has required health care practitioners to make novel decisions that are new to us with development of creative pathways of care that focused on patient safety, mitigation efforts, and clinical management of disease processes. The care of patients with OPMDs requires special considerations especially as patients at high risk for severe COVID-19 illness are also higher risk for the development of OPMDs.

Trainee Contribution Is Not Associated With Citation Frequency: A Retrospective Study.

PURPOSE: Publication citation frequency is a measure of scientific influence. The purpose of this study was to measure the association between trainee involvement in publications and citation frequency. MATERIALS AND METHODS: A retrospective cohort study of the Journal of Oral and Maxillofacial Surgery from January to December 2010 was conducted. For each included publication, the study topic and design were recorded. The primary predictor variable was trainee involvement (yes or no). For the purpose of our study, the term "trainee" encompassed dental students, graduate (non-dental) students, oral and maxillofacial surgery residents, and non-oral and maxillofacial surgery residents, as indicated by author affiliations listed in each article. The outcome variable was the number of citations accumulated between 2010 and 2017. Descriptive statistics were computed. Analyses of variance were performed to compare citation distribution among study types and designs. Student t tests and χ2 tests were performed. RESULTS: The sample consisted of 111 publications, of which 85 (76.6%) had at least 1 trainee author. Among all publications, the mean number of citations was significantly different across study designs (P = .03), with case reports earning the lowest number of citations on average (mean, 14.9 citations). Trainee publications had significantly different distributions of study topics (P = .02) and designs (P < .01). Among publications with a trainee author, the most common topic was pathology (37%) and the most common study design was a case report (45%). Despite the higher proportion of case reports, the mean number of citations between trainee (mean, 30.4 citations) and non-trainee (mean, 30.5 citations) publications was not significantly different (P = .99). CONCLUSIONS: Including trainees does not alter the citation frequency of the articles published in the Journal of Oral and Maxillofacial Surgery. This finding is encouraging to both academic surgeons and their trainees, as a higher volume of students and residents can be engaged in research while preserving the influence of the published works.

A 15-Year Review of Trainee Contributions to the Journal of Oral and Maxillofacial Surgery.

PURPOSE: The purpose of this study was to quantify trainee contributions to the Journal of Oral and Maxillofacial Surgery (JOMS). MATERIALS AND METHODS: This was retrospective cohort study of research articles published in the JOMS from 2002 to 2016. Predictor variables were the presence and type of trainee author. Outcomes were study topic and design. Comparisons were performed using χ2 tests. To quantify trainee contributions, the 1) number and 2) proportion of articles with a trainee author and 3) the proportion of trainee authors per publication were calculated. The association between time and the number and proportion of trainee articles was determined using simple correlations. The association between time and percentage of trainee authors per publication was determined using analysis of variance. RESULTS: Of the 1,455 articles included in this study, 72.0% had at least 1 trainee author and trainees composed 27.6% of all authorships. The number and proportion of trainee articles slowly increased with time, and there was a strong correlation between percentage of trainee articles and publication year (r = 0.86; P < .01). Compared with articles without a trainee, a larger proportion of trainee articles were on orthognathic procedures (P < .01). Trainee articles also had a larger proportion of case reports and series (P = .03) and retrospective cohort studies (P < .01) and a smaller proportion of prospective cohort studies (P = .02), literature reviews and meta-analysis (P < .01), and randomized controlled trials (P = .02). CONCLUSIONS: Trainee authors contributed to most JOMS articles, and an increasing percentage of articles included trainee authors. Efforts should be made to include trainees in studies with higher levels of evidence.

Clozapine reduces nicotine self-administration, blunts reinstatement of nicotine-seeking but increases responding for food.

People with schizophrenia display significantly higher rates of smoking than the general population, which may be due to an interaction between nicotine and antipsychotic medication. While the conventional antipsychotic drug haloperidol sometimes increases cigarette smoking in patients with schizophrenia, there is some evidence suggesting that clozapine, an atypical antipsychotic drug, may reduce nicotine use in these patients. However, the effects of antipsychotic drugs like clozapine on aspects of nicotine self-administration and reinstatement have not been systematically examined. In the current study, we assessed the effect of clozapine on nicotine self-administration under fixed ratio and progressive ratio schedules of reinforcement, as well as reinstatement of nicotine-seeking following a period of abstinence. To determine the specificity of its effect on nicotine reward, we also tested the effect of clozapine on responding for food reinforcement under fixed ratio and progressive ratio schedules. For comparison, we also examined the effects of haloperidol, a first-generation antipsychotic drug, under some of the same behavioral conditions as clozapine. We show that clozapine inhibits nicotine self-administration and reinstatement of nicotine-seeking but also increases the amount of effort that rats will exert for food reward. In contrast, haloperidol at a wide range of doses attenuated responding for nicotine and food reward, suggestive of a non-specific reduction in reinforcer efficacy. These results show the potential utility of clozapine as a smoking cessation treatment for patients with schizophrenia, in addition to its antipsychotic properties.

Gingiva-Derived Mesenchymal Stem Cell-Extracellular Vesicles Activate Schwann Cell Repair Phenotype and Promote Nerve Regeneration.

IMPACT STATEMENT: Peripheral nerve injuries (PNIs) are common and debilitating, usually resulting in considerable long-term disability and remaining an unmet clinical need. Even though the combination of mesenchymal stem cells (MSCs) and the state-of-the-art tissue engineering technologies has shown promising therapeutic potentials for PNI, there is still not a single licensed stem cell-based product for peripheral nerve repair/regeneration. Emerging evidence indicates that MSC-derived extracellular vesicles (EVs) are comparably effective as MSCs in the therapy of a variety of disease models or pathological conditions. This report shows that local delivery of gingiva-derived mesenchymal stem cell (GMSC)-derived EVs could obviously promote axonal regeneration and functional recovery of injured mice sciatic nerves. Importantly, the findings suggest that GMSC-derived EVs promoted the expression of Schwann cell dedifferentiation/repair phenotype-related genes in vitro, particularly c-JUN, a key transcription factor that drives the activation of repair phenotype of Schwann cells during PNI and regeneration.

3D bio-printed scaffold-free nerve constructs with human gingiva-derived mesenchymal stem cells promote rat facial nerve regeneration.

Despite the promising neuro-regenerative capacities of stem cells, there is currently no licensed stem cell-based product in the repair and regeneration of peripheral nerve injuries. Here, we explored the potential use of human gingiva-derived mesenchymal stem cells (GMSCs) as the only cellular component in 3D bio-printed scaffold-free neural constructs that were transplantable to bridge facial nerve defects in rats. We showed that GMSCs have the propensity to aggregate into compact 3D-spheroids that could produce their own matrix. When cultured under either 2D- or 3D-collagen scaffolds, GMSC spheroids were found to be more capable of differentiating into both neuronal and Schwann-like cells than their adherent counterparts. Using a scaffold-free 3D bio-printer system, nerve constructs were printed from GMSC spheroids in the absence of exogenous scaffolds and allowed to mature in a bioreactor. In vivo transplantation of the GMSC-laden nerve constructs promoted regeneration and functional recovery when used to bridge segmental defects in rat facial nerves. Our findings suggest that GMSCs represent an easily accessible source of MSCs for 3D bio-printing of scaffold-free nervous tissue constructs with promising potential application for repair and regeneration of peripheral nerve defects.

Neural Crest Stem-Like Cells Non-genetically Induced from Human Gingiva-Derived Mesenchymal Stem Cells Promote Facial Nerve Regeneration in Rats.

Non-genetic induction of somatic cells into neural crest stem-like cells (NCSCs) is promising for potential cell-based therapies for post-traumatic peripheral nerve regeneration. Here, we report that human gingiva-derived mesenchymal stem cells (GMSCs) could be reproducibly and readily induced into NCSCs via non-genetic approaches. Compared to parental GMSCs, induced NCSC population had increased expression in NCSC-related genes and displayed robust differentiation into neuronal and Schwann-like cells. Knockdown of the expression of Yes-associated protein 1 (YAP1), a critical mechanosensor and mechanotransducer, attenuated the expression of NCSC-related genes; specific blocking of RhoA/ROCK activity and non-muscle myosin II (NM II)-dependent contraction suppressed YAP1 and NCSC-related genes and concurrently abolished neural spheroid formation in NCSCs. Using a rat model of facial nerve defect, implantation of NCSC-laden nerve conduits promoted functional regeneration of the injured nerve. These promising findings demonstrate that induced NCSCs derived from GMSCs represent an easily accessible and promising source of neural stem-like cells for peripheral nerve regeneration.

Acquisition of nicotine self-administration in amphetamine and phencyclidine models of schizophrenia: A role for stress?

Nicotine use and dependence is very high in patients with schizophrenia. One possible reason is that altered dopamine or glutamate activity in schizophrenia enhances the reinforcing effectiveness of nicotine. We used animal models to test the hypothesis that a hyperdopaminergic state (induced by repeated intermittent injections of amphetamine) or altered glutamate function (subchronic injection of phencyclidine, PCP) facilitates spontaneous acquisition of nicotine self-administration in rats. In Experiment 1 animals in an amphetamine-induced sensitized state (AISS) did not differ from saline-injected controls in their acquisition and maintenance of nicotine self-administration. This effect was replicated in experiment 2, but it was also found that AISS rats and saline-injected controls showed higher rates of nicotine self-administration compared to uninjected controls. This difference was maintained across several fixed ratio and progressive ratio schedules of reinforcement. In Experiment 3 PCP treated rats and their saline-injected controls did not differ in nicotine self-administration. However, both groups showed consistently increased responding for nicotine on FR and PR schedules compared to an uninjected control group. Injection-stress appeared to influence the outcomes of these experiments in two ways. Firstly, injection stress potentially masked the impact of the AISS and PCP treatment on nicotine self-administration. Secondly, injection stress itself may have been sufficient to induce plastic changes in dopamine and glutamate systems, and these changes enhanced the acquisition and maintenance of nicotine self-administration. Further investigation is needed into the role of stress in the development of nicotine use and dependence, in the aetiology of schizophrenia and in their co-morbidity.