Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response.

Tumour cells evade immune surveillance by upregulating the surface expression of programmed death-ligand 1 (PD-L1), which interacts with programmed death-1 (PD-1) receptor on T cells to elicit the immune checkpoint response1,2. Anti-PD-1 antibodies have shown remarkable promise in treating tumours, including metastatic melanoma2-4. However, the patient response rate is low4,5. A better understanding of PD-L1-mediated immune evasion is needed to predict patient response and improve treatment efficacy. Here we report that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface. Stimulation with interferon-γ (IFN-γ) increases the amount of PD-L1 on these vesicles, which suppresses the function of CD8 T cells and facilitates tumour growth. In patients with metastatic melanoma, the level of circulating exosomal PD-L1 positively correlates with that of IFN-γ, and varies during the course of anti-PD-1 therapy. The magnitudes of the increase in circulating exosomal PD-L1 during early stages of treatment, as an indicator of the adaptive response of the tumour cells to T cell reinvigoration, stratifies clinical responders from non-responders. Our study unveils a mechanism by which tumour cells systemically suppress the immune system, and provides a rationale for the application of exosomal PD-L1 as a predictor for anti-PD-1 therapy.

Watching Food Videos Leads to Postparotidectomy Salivary Fistula.

Salivary fistula is a common postparotidectomy complication, and eating sour or spicy food ranks among the leading causes. Here we report a rare postparotidectomy salivary fistula case, a 31-year-old female patient who affirmed that she did not eat any irritating foods but admitted that she had been watching food videos for up to 4 hours every day since she left hospital. This case offers a cautionary tale about postparotidectomy precautions.

Increased salivary microvesicles are associated with the prognosis of patients with oral squamous cell carcinoma.

Microvesicles (MVs), which are cell-derived membrane vesicles present in body fluids, are closely associated with the development of malignant tumours. Saliva, one of the most versatile body fluids, is an important source of MVs. However, the association between salivary MVs (SMVs) and oral squamous cell carcinoma (OSCC), which is directly immersed in the salivary milieu, remains unclear. SMVs from 65 patients with OSCC, 21 patients with oral ulcer (OU), and 42 healthy donors were purified, quantified and analysed for their correlations with the clinicopathologic features and prognosis of OSCC patients. The results showed that the level of SMVs was significantly elevated in patients with OSCC compared to healthy donors and OU patients. Meanwhile, the level of SMVs showed close correlations with the lymph node status, and the clinical stage of OSCC patients. Additionally, the ratio of apoptotic to non-apoptotic SMVs was significantly decreased in OSCC patients with higher pathological grade. Consistently, poorer overall survival was observed in patients with lower ratio of apoptotic to non-apoptotic SMVs. In conclusion, the elevated level of SMVs is associated with clinicopathologic features and decreased survival in patients with OSCC, suggesting that SMVs are a potential biomarker and/or regulator of the malignant progression of OSCC.

Osteoradionecrosis of the Zygoma.

Osteoradionecrosis occurs in 4.74% to 37.5% of patients following radiation therapy for head and neck cancer. Osteoradionecrosis mostly happens in the mandible but seldom occurs in other maxillofacial bones. Here, the authors reported a rare case of zygomatic osteoradionecrosis which occurred after maxillectomy and then radiotherapy because of maxillary myoepithelial carcinoma. After resection of zygoma sequestrum, the defect was repaired with forehead flap and healed uneventfully.

A Double-Lobe Flap Design Combined Nasolabial Advancement and Infraorbital Rotation for Reconstruction of Infraorbital Defect.

Various adjacent flaps have been designed to close infraorbital defect, and each of them is trying to get an aesthetic outcome and meanwhile circumvent eyelid retraction, ectropion, and functional disability. Here, the authors report an adjacent double-lobe flap, which took advantage of nasolabial advancement and infraorbital rotation of the 2 lobes, combinatorially closed a pentagon infraorbital defect by removal of 2 small skin paddles as donor sites, and finally yielded an acceptable aesthetic and functional outcome. This flap may be a new option for closure of polygon infraorbital defects.

Down-regulation of connexin43 and connexin32 in keratocystic odontogenic tumours: potential association with clinical features.

AIMS: The objective of this study was to explore the potential involvement of connexin43 (Cx43) and connexin32 (Cx32), two vital members of the connexin families, in the pathogenesis of keratocystic odontogenic tumours (KCOT). METHODS AND RESULTS: The expression levels of Cx43 and Cx32 in human KCOT and normal oral mucosa (OM) tissues were measured using immunohistochemistry and real-time quantitative polymerase chain reaction (qPCR). The relationship between Cx43 and Cx32 expression and markers of proliferation [proliferating cell nuclear antigen (PCNA), cyclin D1], anti-apoptosis [B cell lymphoma 2 (Bcl-2)] and autophagy [light chain 3 (LC3), Sequestosome 1 p62 (p62)] was then investigated in the KCOT samples. The results showed that Cx43 and Cx32 expression was down-regulated significantly in KCOT samples relative to OM samples. Meanwhile, the expression levels of Cx43 and Cx32 were correlated negatively with the expression levels of PCNA, cyclin D1, Bcl-2, LC3 and p62, as confirmed further by double-labelling immunofluorescence analyses. CONCLUSIONS: This study reveals for the first time that Cx43 and Cx32 are down-regulated in KCOT and suggests an association with growth regulation, anti-apoptosis and autophagy in KCOT.

Evaluation of the clinical photographs in the Journal of Oral and Maxillofacial Surgery: from readers' perspectives.

PURPOSE: This study was designed to evaluate clinical photographs published in the Journal of Oral and Maxillofacial Surgery (JOMS) and understand the current status of oral and maxillofacial surgery. MATERIALS AND METHODS: A total of 1,317 photographs from the JOMS Volume 69 were assessed. These photographs were scored from 1 to 10 for the following parameters: sharpness; depth of field; exposure; composition; color or grayscale; background; position; distortion; label consistency; and white balance. Then, the distributions of scores were analyzed. Each score was compared with the average score. The effects of different subjects; emergency or nonemergency situations; and intraoperative, preoperative, or postoperative conditions on the quality of photographs were analyzed by conducting a nonparametric Kruskal-Wallis test. RESULTS: The total score of each photograph showed a left-skewed distribution, varying from 3 to 10, with an average score of 6.82. Four parameters, including sharpness, depth of field, exposure, and white balance, scored less than the average score. Photographs with an intraoral subject yielded the lowest score, with a significant difference (P < .05). The score of photographs taken during a nonemergency situation was significantly higher than that during an emergency situation (6.84 vs 6.03; P < .001). Photographs of an intraoperative condition yielded a score significantly lower than those of pre- and postoperative conditions (6.53 vs 7.11 and 6.75, respectively; P < .001). Approximately 45.5% of photographs (148 of 325) displayed uncovered eyes and 57.1% of specimens (40 of 70) did not appear with a plotting scale. CONCLUSIONS: Sharpness, depth of field, exposure, and white balance should be considered to a greater extent than the other parameters when oral and maxillofacial photographs are taken, particularly for intraoral conditions, emergency situations, and intraoperative conditions. Enhanced parameters and protection of a patient's identity may significantly improve the average level of photographic quality.

Spatiotemporal characteristics of tissue derived small extracellular vesicles is associated with tumor relapse and anti-PD-1 response.

Small extracellular vesicles (sEVs) residing at tumor tissues are valuable specimens for biopsy. Tumor heterogeneity is common across all cancer types, but the heterogeneity of tumor tissue-derived sEVs (Ti-sEVs) is undefined. This study aims to discover the spatial distributions of Ti-sEVs in oral squamous cell carcinoma (OSCC) tissues and explore how these vesicle distributions affect the patients' prognosis. Multi-regional sampling enabled us to uncover that Ti-sEVs' accumulation at peritumoral sites correlates with a higher disease-free survival rate, and conversely, sparse peritumoral Ti-sEVs tend to forecast a higher risk of relapse. Of those relapsed patients, Ti-sEVs strongly bind to extracellular matrix and subsequently degrade it for allowing themselves enter the bloodstream rather than staying in situ. In advanced OSCC patients, the quantity and spatial distribution of Ti-sEVs prior to anti-PD-1 treatment, as well as the temporal variance of Ti-sEVs before and after immunotherapy, strongly map the clinical response and can help to distinguish the patients with shrinking tumors from those with growing tumors. Our work elucidates the correlation of spatiotemporal features of Ti-sEVs with patients' therapeutic outcomes and exhibit the potential for using Ti-sEVs as a predictor to forecast prognosis and screen the responders to anti-PD-1 therapy.

Morphogenesis of rete ridges in human oral mucosa: a pioneering morphological and immunohistochemical study.

OBJECTIVE: One of the major impediments in tissue-engineered oral mucosa (TEOM) is the lack of rete ridge (RR) structures that can weaken the connection between the epidermis and dermis. This study aimed to investigate the native morphology of RRs as well as the expression of extracellular signal-regulated kinase 1/2 (ERK1/2), Ki67, and keratin-19, which are related to cell mechanotransduction, proliferation, and stemness in the oral epidermis, respectively. METHODS: RR characteristics, including type, density, length, and width, were analyzed in the masticatory mucosa (Mm) and lining mucosa (Lm) sites of 52 specimens. The expression of ERK1/2, Ki67, and keratin-19 was assessed by immunohistochemistry. ERK1/2 activation by masticatory stimuli was confirmed in vitro by loading pressure onto cultured keratinocytes isolated from the specimens. RESULTS: Three types of RR were found. The RRs in the Mm and Lm differed. The length and percentage of ERK1/2-positive (%ERK1/2+) basal layer cells had a negative correlation (p = 0.004), whereas the length and %Ki67+ basal layer cells had a positive correlation (p = 0.013). The %ERK1/2+ basal layer cells and %keratin-19+ basal layer cells had a negative relationship (p = 0.011). ERK1/2 activation in the oral epithelium was induced by pressure and propagated in cultured keratinocytes. CONCLUSION: RRs are longer in the Mm, which may result from the topical basal cell proliferation and migration induced by masticatory pressure via ERK1/2 activation. Our findings preliminarily interpret RR histomorphology as influenced by oral masticatory pressure. Results may benefit future studies on RR development and reconstruction in TEOM models to enhance the epidermis-dermis connection.

A retrospective study of the malignant change of odontogenic keratocyst.

The odontogenic keratocyst (OKC) is a common cystic lesion of the maxilla and mandible. Squamous cell carcinoma (SCC) arising from OKC or dysplasia occurring in OKC is rare. This study aimed to explore the incidence and clinical features of the dysplasia and malignant transformation of OKC. In this study, 544 patients diagnosed with OKC were collected. Among them, 3 patients were diagnosed as SCC arising from OKC, and 12 patients were diagnosed as OKC with dysplasia. The incidence was calculated. Clinical features were analyzed by chi-square test. In addition, a representative case reconstructing mandible with vascularized fibula flap under general anesthesia was reported. And cases reported before were reviewed. The incidence of the dysplasia and malignant transformation of OKC, which are highly associated with the clinical features of swelling and chronic inflammation, is about 2.76%. But the relevance between the dysplasia and malignant transformation and age, gender together with pain is not statistically high. All in all, the clinical features of swelling and chronic inflammation can be considered as characteristics of the dysplasia and malignant transformation of OKC. Although the pain isn't statistically relevant, it may be a dangerous clew. Also, combined with earlier literatures, the dysplasia and malignant transformation of OKC shows unique features of radiographs and histopathology.

Myofascial iliac crest flap for reconstruction of combined oral mucosa-mandibular defects: A single-centre experience.

BACKGROUND: Deep circumflex iliac artery (DCIA) myofascial iliac crest flap has been used for combined oral mucosa-mandibular defects reconstruction. The bone component of this composite flap can reconstruct the mandible with superior contour match, and the muscle fascia which used for repairing the oral mucosa defect will transform into an oral mucosa-like appearance. To explore its scope of clinical application and how the fascia transformed into oral mucosa will give surgeons flexibility to reconstruct the combined oral mucosa-mandibular defects. METHODS: A retrospective review of 18 patients who received combined oral mucosa-mandibular defects reconstruction with DCIA myofascial iliac crest flaps from Dec 2016 to Dec 2020 was performed. The characteristics of the mandibular defects and the flaps were recorded. The postoperative dynamic changes of one graft's fascia were observed from serial photographs. RESULTS: All myofascial iliac crest flaps survived successfully. The bone grafts were from 4.0 to 9.5 cm (mean 7.6 ± 1.5 cm) in length and from 2.0 to 3.5 cm (mean 2.7 ± 0.4 cm) in height. The sizes of fascia were from 13.5 to 48.0 cm2 (mean 27.2 ± 9.4 cm2). The grafted fascia firstly changed into a yellow pseudomembrane-like appearance, and then experienced muscle oedema before finally transformed into an oral mucosa-like appearance at about 60 days after operation. CONCLUSION: Myofascial iliac crest flap is a good option for reconstruction of combined oral mucosa-mandibular defects because of its excellent bone and oral mucosa matches.

Mandibular Reconstruction With the Contralateral Vascularized Iliac Flap Using Individual Design: Iliac Crest Used to Reconstruct the Ramus and the Anterior Border of the Iliac Wing Used to Reconstruct the Inferior Border: A Case Report.

Mandible defects resulting from resection of benign or malignant lesions, trauma, or radionecrosis are commonly encountered in the oral and maxillofacial department. Vascularized bone flaps, in general, provide the best functional and aesthetic outcome. The iliac crest provides a large piece of curved cortico-cancellous bone, measuring 6-16 cm in length. It has a natural curvature that complements the curve of the lateral and sometimes anterior mandible and can be placed accordingly to fill defects. In the paper, we report a mandibular reconstruction with a vascularized iliac flap using individual virtual preoperative planning and 3D printing technology. We want to offer a new design idea for mandibular defect reconstruction.

Interferon-γ induces immunosuppression in salivary adenoid cystic carcinoma by regulating programmed death ligand 1 secretion.

Interferon-γ (IFN-γ), a key effector molecule in anti-tumor immune response, has been well documented to correlate with the intratumoral infiltration of immune cells. Of interest, however, a high level of IFN-γ has been reported in salivary adenoid cystic carcinoma (SACC), which is actually a type of immunologically cold cancer with few infiltrated immune cells. Investigating the functional significance of IFN-γ in SACC would help to explain such a paradoxical phenomenon. In the present study, we revealed that, compared to oral squamous cell carcinoma cells (a type of immunologically hot cancer), SACC cells were less sensitive to the growth-inhibition effect of IFN-γ. Moreover, the migration and invasion abilities of SACC cells were obviously enhanced upon IFN-γ treatment. In addition, our results revealed that exposure to IFN-γ significantly up-regulated the level of programmed death ligand 1 (PD-L1) on SACC cell-derived small extracellular vesicles (sEVs), which subsequently induced the apoptosis of CD8+ T cells through antagonizing PD-1. Importantly, it was also found that SACC patients with higher levels of plasma IFN-γ also had higher levels of circulating sEVs that carried PD-L1 on their surface. Our study unveils a mechanism that IFN-γ induces immunosuppression in SACC via sEV PD-L1, which would account for the scarce immune cell infiltration and insensitivity to immunotherapy.

Internal Jugular Vein Fenestration and Duplication: Anatomical Findings, Prevalence, and Literature Review.

Background: Comprehensive knowledge of the internal jugular vein (IJV) regarding its anatomical variations and the pattern of its course is valuable for preventing unexpected injuries during surgical procedures or central venous access. IJV anatomical anomalies such as fenestration and duplication are rare, mainly represented by case reports, and intraoperative findings. Objective: To present two additional cases of IJV anomalies and highlight its clinical presentation, anatomical characteristics, management, and prevalence through an extensive literature review. Methods and Case Reports: From January 2017 to December 2018, we retrospectively collected data of 221 patients undergoing neck dissection (ND) procedures and identified two patients with IJV anomalies (fenestration and duplication) providing a clinical prevalence of ~0.9%. The IJV fenestration referred to an IJV bifurcation that reunites proximal to the subclavian vein, whereas in the IJV duplication both branches remain separated. In both of our cases, the spinal accessory nerve (SAN) crossed the window between the IJV branches. Conclusion: Anatomical variations are more likely to be identified intraoperatively or incidentally, and due to the risk of SAN and vascular injury, special attention should be taken to identify them preoperatively in order to reduce the risk of iatrogenic injury and unexpected complications.

A deep learning algorithm for detection of oral cavity squamous cell carcinoma from photographic images: A retrospective study.

BACKGROUND: The overall prognosis of oral cancer remains poor because over half of patients are diagnosed at advanced-stages. Previously reported screening and earlier detection methods for oral cancer still largely rely on health workers' clinical experience and as yet there is no established method. We aimed to develop a rapid, non-invasive, cost-effective, and easy-to-use deep learning approach for identifying oral cavity squamous cell carcinoma (OCSCC) patients using photographic images. METHODS: We developed an automated deep learning algorithm using cascaded convolutional neural networks to detect OCSCC from photographic images. We included all biopsy-proven OCSCC photographs and normal controls of 44,409 clinical images collected from 11 hospitals around China between April 12, 2006, and Nov 25, 2019. We trained the algorithm on a randomly selected part of this dataset (development dataset) and used the rest for testing (internal validation dataset). Additionally, we curated an external validation dataset comprising clinical photographs from six representative journals in the field of dentistry and oral surgery. We also compared the performance of the algorithm with that of seven oral cancer specialists on a clinical validation dataset. We used the pathological reports as gold standard for OCSCC identification. We evaluated the algorithm performance on the internal, external, and clinical validation datasets by calculating the area under the receiver operating characteristic curves (AUCs), accuracy, sensitivity, and specificity with two-sided 95% CIs. FINDINGS: 1469 intraoral photographic images were used to validate our approach. The deep learning algorithm achieved an AUC of 0·983 (95% CI 0·973-0·991), sensitivity of 94·9% (0·915-0·978), and specificity of 88·7% (0·845-0·926) on the internal validation dataset (n = 401), and an AUC of 0·935 (0·910-0·957), sensitivity of 89·6% (0·847-0·942) and specificity of 80·6% (0·757-0·853) on the external validation dataset (n = 402). For a secondary analysis on the internal validation dataset, the algorithm presented an AUC of 0·995 (0·988-0·999), sensitivity of 97·4% (0·932-1·000) and specificity of 93·5% (0·882-0·979) in detecting early-stage OCSCC. On the clinical validation dataset (n = 666), our algorithm achieved comparable performance to that of the average oral cancer expert in terms of accuracy (92·3% [0·902-0·943] vs 92.4% [0·912-0·936]), sensitivity (91·0% [0·879-0·941] vs 91·7% [0·898-0·934]), and specificity (93·5% [0·909-0·960] vs 93·1% [0·914-0·948]). The algorithm also achieved significantly better performance than that of the average medical student (accuracy of 87·0% [0·855-0·885], sensitivity of 83·1% [0·807-0·854], and specificity of 90·7% [0·889-0·924]) and the average non-medical student (accuracy of 77·2% [0·757-0·787], sensitivity of 76·6% [0·743-0·788], and specificity of 77·9% [0·759-0·797]). INTERPRETATION: Automated detection of OCSCC by deep-learning-powered algorithm is a rapid, non-invasive, low-cost, and convenient method, which yielded comparable performance to that of human specialists and has the potential to be used as a clinical tool for fast screening, earlier detection, and therapeutic efficacy assessment of the cancer.

Keratinocyte growth factor (KGF) induces podosome formation via integrin-Erk1/2 signaling in human immortalized oral epithelial cells.

Recent study established the role of integrins in keratinocyte growth factor (KGF)-induced oral epithelial adhesion and rete peg elongation. However, how extracellular matrix (ECM) remodeling cooperates with the increased epithelial adhesion during rete peg elongation has yet to be determined. Podosomes are cell-matrix contact structures that combine several abilities, including adhesion and matrix degradation. In the present study, we identified podosome formation at the ventral side of human immortalized oral epithelial cells (HIOECs) upon KGF treatment. Moreover, podosomal components including integrin α6，ß4，α3，ß1 and MMP14 colocalized with the F-actin-cortactin complex and matrix degradation assays demonstrated the ability of the F-actin-cortactin complex to degrade matrix. Inhibition both of integrin subunits ß4 and ß1 with specific blocking antibodies and inhibition of Erk1/2 abrogated the KGF-induced podosome formation. Notably, knockdown of integrin subunits ß4 and ß1 with specific small interfering RNA (siRNA) downregulated the phosphorylation levels of Erk1/2. In contrast, inhibition of both Erk1/2 could upregulate the expression of integrin subunits ß4 and ß1. These results demonstrate that KGF induces podosome formation via integrin-Erk1/2 signaling in HIOECs, suggesting a novel mechanism by which integrins enhance oral epithelial adhesion and rete peg elongation.

Expression of fibrosis-related molecules in the oral mucosa of six animal species: A reference for selecting animal models.

Several animal models have been used in studies associated with oral submucous fibrosis (OSF); however, an appropriate model based on the histopathological characteristics of OSF is still needed. This study aimed to provide histological references for selecting a potential model. The expression intensities of collagen type I (Col I), type III (Col III), type IV (Col IV), fibronectin (FN), transforming growth factors ß (TGF-ß), and connective tissue growth factor (CCN2) in the oral mucosa of the human and six non-human animal species were measured by immunohistochemistry. There was little variation in the expression intensity of Col I while the expression of Col III, Col IV, and FN showed differences. The expression intensities of TGF-ß in dog, rat, sheep, and pig oral mucosae, and those of CCN2 in dog, minipig, rat, and buffalo oral mucosae were equivalent to the expression intensities in human mucosa. The expression of fibrosis-related molecules in the dog oral mucosa optimally mimics the human condition, suggesting its suitability with regard to histopathology as an animal model for the study of OSF.

Histological features of oral epithelium in seven animal species: As a reference for selecting animal models.

Several animals have been used as models for basic and clinical research on oral mucosa. Few studies have focused on the selection of an appropriate animal model. This study aimed to provide histological references for selecting a potential model. Histological features were assessed by exploring 6 morphological characteristics and 2 immunohistochemical markers. The morphological characteristics included keratinization, basal membrane appearance, epithelial thickness, rete ridge length, adjacent rete ridge distance, and regional variation; the immunohistochemical markers included Ki67 (a proliferative marker) and Cytokeratin 19 (CK19; a stemness marker). The histological similarity of each species compared to humans was calculated according to the designated scoring criteria. The results showed that the buccal mucosae from dog and pig were non-keratinized, with similar rete ridge length and distance, compared to that of humans. The dog, rat, and cavy mucosae had analogous gross appearances in the basal membrane. The dog oral mucosae shared similar epithelial thickness with human oral mucosae. Compared to the human mucosa, the dog, pig, rat, and rabbit mucosae exhibited corresponding regional variations. The Ki67-positive cells in human and canine mucosae were predominantly localized in the suprabasal layers, whereas most of the proliferative cells were in the basal layer in other species. CK19 immunoreactivities were detected only in human and canine mucosae. The canine mucosae gained the highest point value (14), whereas the scores for the pig, rat, rabbit, cavy, sheep, and buffalo mucosae were 8, 6, 5, 5, 5, and 2, respectively. The histological variations in the oral epithelium of diverse animal species are considerable; the mucosae from dogs are most similar to human mucosae, implicating its histological basis as an animal model.

M2-polarized macrophages in keratocystic odontogenic tumor: relation to tumor angiogenesis.

The purpose of this study was to evaluate the presence of M2-polarized macrophages and their relationships to angiogenesis in keratocystic odontogenic tumor (KCOT). M2-polarized macrophages were detected in KCOT samples by immunohistochemistry and immunofluorescence. Meanwhile, microvessel density measured with antibody against CD31 was closely correlated with the presence of M2-polarized macrophages. In addition, macrophage colony-stimulating factor (M-CSF) significantly contributed to the activation of M2-polarized macrophages. Moreover, the results of in vitro wound healing, cell migration and tube formation assays further revealed the pro-angiogenic function of M2-polarized macrophage-like cells. This function might be associated with secretion of angiogenic cytokines, such as vascular endothelial growth factor (VEGF), transforming growth factor-ß (TGF-ß) and matrix metalloprotein-9 (MMP-9). This study demonstrates for the first time that M2-polarized macrophages are prevalent in KCOT, and their presence is dependent on M-CSF expression. More importantly, these tumor-supportive cells can also promote tumor angiogenesis by secreting angiogenic cytokines.

Physical forces make rete ridges in oral mucosa.

Rete ridge has important functions in the epidermis, but the current tissue engineered oral mucosa or skin equivalents are generally lack of this structure. To regenerate a rete ridge structure in the oral mucosa equivalents, we firstly attempted to make clear how rete ridge is formed in the oral mucosa and the preliminary study disclosed the mechanical stress evoked the morphogenesis of rete ridge. In this paper, we make a hypothesis that the morphogenesis of rete ridge is elicited by the physical forces and proceed with the internal pushing forces derived from the keratinocyte division, among these process, the activated ERK and PC cascades, accompanied with the MMPs liberated growth factors are working together to induce the keratinocyte proliferation, these cell divisions produced internal forces, which not only push the keratinocyte stem cells and progenitor cells to migrate in the contrary directions but also in turn to activate the ERK and PC cascades, meanwhile, the activated MMPs degrade the ECM of lamina propria, under these internal pushing forces and the remodeling of lamina propria, rete ridge is gradually formed. This hypothesis gives us the possibility to regenerate the rete ridge structure in the tissue engineered oral mucosa or skin equivalents through simulating the morphogenesis of rete ridge.