Follistatin expressed in mechanically-damaged salivary glands of male mice induces proliferation of CD49f(+) cells

Salivary glands (SGs) are very important for maintaining the physiological functions of the mouth. When SGs regenerate and repair from various damages, including mechanical, radiological, and immune diseases, acinar and granular duct cells originate from intercalated duct cells. However, the recovery is often insufficient because of SGs' limited self-repair function. Furthermore, the precise repair mechanism has been unclear. Here, we focused on CD49f, one of the putative stem cell markers, and characterized CD49f positive cells (CD49f(+) cells) isolated from male murine SGs. CD49f(+) cells possess self-renewal ability and express epithelial and pluripotent markers. Compared to CD49f negative cells, freshly isolated CD49f(+) cells highly expressed inhibin beta A and beta B, which are components of activin that has anti-proliferative effects. Notably, an inhibitor of activin, follistatin was expressed in mechanically-damaged SGs, meanwhile no follistatin was expressed in normal SGs in vivo. Moreover, sub-cultured CD49f(+) cells highly expressed both Follistatin and a series of proliferative genes, expressions of which were decreased by Follistatin siRNA. These findings indicated that the molecular interaction between activin and follistatin may induce CD49f(+) cells proliferation in the regeneration and repair of mouse SGs

Salivary Secretory Disorders, Inducing Drugs, and Clinical Management

Background: Salivary secretory disorders can be the result of a wide range of factors. Their prevalence and negative effects on the patient's quality of life oblige the clinician to confront the issue. Aim: To review the salivary secretory disorders, inducing drugs and their clinical management. Methods: In this article, a literature search of these dysfunctions was conducted with the assistance of a research librarian in the MEDLINE/PubMed Database. Results: Xerostomia, or dry mouth syndrome, can be caused by medication, systemic diseases such as Sjögren's Syndrome, glandular pathologies, and radiotherapy of the head and neck. Treatment of dry mouth is aimed at both minimizing its symptoms and preventing oral complications with the employment of sialogogues and topical acting substances. Sialorrhea and drooling, are mainly due to medication or neurological systemic disease. There are various therapeutic, pharmacologic, and surgical alternatives for its management. The pharmacology of most of the substances employed for the treatment of salivary disorders is well-known. Nevertheless, in some cases a significant improvement in salivary function has not been observed after their administration. Conclusion: At present, there are numerous frequently prescribed drugs whose unwanted effects include some kind of salivary disorder. In addition, the differing pathologic mechanisms, and the great variety of existing treatments hinder the clinical management of these patients. The authors have designed an algorithm to facilitate the decision making process when physicians, oral surgeons, or dentists face these salivary dysfunctions

Lacrimal gland development: From signaling interactions to regenerative medicine

The lacrimal gland plays a pivotal role in keeping the ocular surface lubricated, and protecting it from environmental exposure and insult. Dysfunction of the lacrimal gland results in deficiency of the aqueous component of the tear film, which can cause dryness of the ocular surface, also known as the aqueous-deficient dry eye disease. Left untreated, this disease can lead to significant morbidity, including frequent eye infections, corneal ulcerations, and vision loss. Current therapies do not treat the underlying deficiency of the lacrimal gland, but merely provide symptomatic relief. To develop more sustainable and physiological therapies, such as in vivo lacrimal gland regeneration or bioengineered lacrimal gland implants, a thorough understanding of lacrimal gland development at the molecular level is of paramount importance. Based on the structural and functional similarities between rodent and human eye development, extensive studies have been undertaken to investigate the signaling and transcriptional mechanisms of lacrimal gland development using mouse as a model system. In this review, we describe the current understanding of the extrinsic signaling interactions and the intrinsic transcriptional network governing lacrimal gland morphogenesis, as well as recent advances in the field of regenerative medicine aimed at treating dry eye disease

The effect of basic fibroblast growth factor on regeneration in a surgical wound model of rat submandibular glands

This study developed an animal model of surgically wounded submandibular glands (SMGs) and investigated the effects of collagen gel with basic fibroblast growth factor (bFGF) on tissue regeneration of surgically wounded SMGs in vivo. The animal model was produced by creating a surgical wound using a 3-mm diameter biopsy punch in SMGs. The wound was filled with collagen gel with bFGF (bFGF group) or without bFGF (control group). In the animal model of surgically wounded SMGs, salivary glands without scar tissue around the wound area were observed with smaller areas of collagen gel. Small round and spindle-shape cells invaded the collagen gel in both groups after operation day (AOD) 5, and this invasion dramatically increased at AOD 7. Host tissue completely replaced the collagen gel at AOD 21. The invading immune cells in the group treated with collagen gel with bFGF were positive for vimentin, α-smooth muscle actin (αSMA), CD49f, c-kit and AQP5 at AOD 7. Similarly, the mRNA expression of vimentin, αSMA, CD49f, keratin19 and AQP5 was also increased. This study suggests that the use of collagen gels with bFGF improves salivary gland regeneration

The effect of fibroblast growth factor 7 on human dental pulp stem cells for differentiation to AQP5-positive and αSMA-positive cells in vitro and in vivo

OBJECTIVES: Transplantation of stem cells into wounds has become popular in regeneration therapies. As stem cells for transplantation, human dental pulp stem cells (hDPSCs) are known to be pluripotent cells that are relatively easy to collect from the pulp of deciduous or wisdom teeth. The purpose of this study was to investigate whether hDPSCs treated with fibroblast growth factor 7 (FGF7) would contribute to the regeneration of wounded rat submandibular glands (SMGs). MATERIALS AND METHODS: In in vitro studies, hDPSCs were treated with or without FGF7 and mRNA expression levels were examined at days 3, 7 and 14 using qRT‐PCR. The target genes analyzed were BMI1 as an undifferentiated marker, AQP5 as an acinar cell marker, CK19 as a ductal epithelial cell marker, αSMA as a myoepithelial cell marker and VIMENTIN as a fibroblast marker. In in vivo studies, hDPSCs treated with or without FGF7 for 14 days were mixed with type I collagen gels and were transplanted into wounded rat SMGs. Hematoxylin–Eosin and immunohistochemical staining were performed at days 3 and 7, and the numbers of positive cells were counted. The primary antibodies used were against BMI1, AQP5, αSMA, PanCK and VIMENTIN. RESULTS: In the in vitro studies, mRNA levels of BMI1 were decreased and αSMA were increased at days 3, 7 and 14, while AQP5 was increased at day 14 in the FGF7 group. In the in vivo studies, the proliferation of hDPSCs and cell islands was observed at day 7 in the FGF7 group. Few BMI1‐positive cells were observed, while numbers of AQP5‐positive and αSMA‐positive cells were increased at days 3 and 7 in the FGF7 group. Moreover, cell islands were AQP5‐positive. CONCLUSION: These results suggest that FGF7‐treated hDPSCs differentiate into AQP5‐positive and αSMA‐positive cells. Moreover, AQP5‐positive cell aggregations were formed

Salivary secretory disorders, inducing drugs, and clinical management

Background: Salivary secretory disorders can be the result of a wide range of factors. Their prevalence and negative effects on the patient's quality of life oblige the clinician to confront the issue. Aim: To review the salivary secretory disorders, inducing drugs and their clinical management. Methods: In this article, a literature search of these dysfunctions was conducted with the assistance of a research librarian in the MEDLINE/PubMed Database. Results: Xerostomia, or dry mouth syndrome, can be caused by medication, systemic diseases such as Sjögren's Syndrome, glandular pathologies, and radiotherapy of the head and neck. Treatment of dry mouth is aimed at both minimizing its symptoms and preventing oral complications with the employment of sialogogues and topical acting substances. Sialorrhea and drooling, are mainly due to medication or neurological systemic disease. There are various therapeutic, pharmacologic, and surgical alternatives for its management. The pharmacology of most of the substances employed for the treatment of salivary disorders is well-known. Nevertheless, in some cases a significant improvement in salivary function has not been observed after their administration. Conclusion: At present, there are numerous frequently prescribed drugs whose unwanted effects include some kind of salivary disorder. In addition, the differing pathologic mechanisms, and the great variety of existing treatments hinder the clinical management of these patients. The authors have designed an algorithm to facilitate the decision making process when physicians, oral surgeons, or dentists face these salivary dysfunctions

The role of the P2X7 nucleotide receptor in salivary gland inflammation

Salivary gland inflammation is a hallmark of Sjogren's syndrome (SS), a common autoimmune disease characterized by lymphocytic infiltration and the consequent impairment of the salivary gland and loss of saliva secretion, predominantly in women. The current therapeutic management of SS is relatively ineffective and does not address the underlying inflammatory processes contributing to the pathology of SS. In this study, two novel therapeutic approaches were evaluated to limit salivary gland inflammation and improve secretory function, i.e., antagonism of the P2X7 nucleotide receptor (P2X7R), which prevents salivary gland inflammation and activation of the P2Y[subscript2] nucleotide receptor (P2Y[subscript2]R) which stimulates the regeneration of damaged salivary glands. The P2X7R is an ATP-gated non-selective cation channel that regulates inflammatory responses in cells and tissues, including salivary gland epithelium. The P2X7R contributes to the pathology of a variety of inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. In immune cells, P2X7R activation induces the production of pro-inflammatory cytokines, including IL-1[beta] and IL-18, by inducing the oligomerization of the multiprotein complex NLRP3-type inflammasome. This study (Chapter II) sheds light on the role of the P2X7R in salivary gland inflammation and hyposalivation. Our results show that in primary mouse submandibular gland (SMG) epithelial cells, P2X7R activation induces the assembly of the NLRP3 inflammasome and the maturation and release of IL-1[beta], responses that are absent in SMG cells isolated from mice devoid of P2X7Rs (P2X7R[superscript-/-]). P2X7R-mediated IL-1[beta] release in SMG epithelial cells is dependent on downhill transmembrane Na[superscript+] and/or K[superscript+] fluxes, the activation of heat shock protein 90 (HSP90), a protein required for the activation and stabilization of the NLRP3 inflammasome, and the generation of mitochondrial ROS. In vivo administration of the P2X7R antagonist A438079 in the CD28[superscript-/-], IFN[superscript][superscript-/-], NOD.H-2[superscripth4] mouse model of salivary gland exocrinopathy ameliorated salivary gland inflammation and enhanced carbachol-induced saliva secretion. These findings demonstrate that P2X7R antagonism in vivo represents a promising therapeutic strategy to limit salivary gland inflammation and improve secretory function. The P2Y[subscript2]R, a G protein-coupled receptor equipotently activated by ATP and UTP, is upregulated in a variety of tissues, including salivary gland epithelium, in response to injury or stress and is proposed to play a role in tissue regeneration. The results indicated that P2Y2R activation with UTP enhances the migration, aggregation and self-organization of dispersed salivary epithelial cells forming spheres that display characteristics similar to differentiated acini in salivary glands. One of the consequences of the chronic inflammatory disease SS is the fibrosis of the salivary gland. The role of transforming growth factor- [beta] (TGF-[beta]) is well established in the fibrosis and regeneration of various organs, including the liver, lung and kidney. In this study, results with a submandibular gland (SMG) duct ligation-induced mouse model of fibrosis indicated that 7 days of SMG duct ligation resulted in upregulation of TGF-β signaling components which correlated with the upregulation of the fibrosis markers collagen 1 and fibronectin, responses that were inhibited by administration of the TGF-[beta] receptor 1 inhibitors. These results suggest that TGF-[beta] signaling contributes to duct ligation-induced changes in salivary epithelium that correlate with glandular fibrosis.Includes biblographical reference

Ocular Tissue Engineering

Tissue engineering emerged back in the 1990s as a new concept to overcome the problem of tissue and organ failure. Over recent decades, there has been incredible progress towards the regeneration of tissues such as bone, heart valves, cartilage, cornea, and retina. In terms of ocular tissue engineering, despite the scientific and strategic incentive for reconstructing ocular tissues, there is also a tremendous need for novel therapeutic options in treating numerous eye diseases related to tissue failure. The aim of this Special Issue is to discuss tissue engineering applications of ocular tissues including but not limited to cornea, retina, and lenses