Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels
Yifeng LinShunni DongXiaohang YeJuan LiuJiaqun LiYanye ZhangMixue TuSiwen WangY. YingRuixue ChenFeixia WangFei-Da NiJianpeng ChenBinyang DuDan Zhang
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Abstract Background Thin endometrium is a primary cause of defective endometrial receptivity, resulting in infertility or recurrent miscarriage. Much effort has been devoted toward regenerating thin endometrium by stem cell-based therapies. The human placenta-derived mesenchymal stem cells (HP-MSCs) are emerging alternative sources of MSCs with various advantages. To maximize their retention inside the uterus, we loaded HP-MSCs with cross-linked hyaluronic acid hydrogel (HA hydrogel) to investigate their therapeutic efficacy and possible underlying mechanisms. Methods Ethanol was injected into the mice uterus to establish the endometrium-injured model. The retention time of HP-MSCs and HA hydrogel was detected by in vivo imaging, while the distribution of HP-MSCs was detected by immunofluorescence staining. Functional restoration of the uterus was assessed by testing embryo implantation rates. The endometrial morphological alteration was observed by H&E staining, Masson staining, and immunohistochemistry. In vitro studies were further conducted using EdU, transwell, tube formation, and western blot assays. Results Instilled HP-MSCs with HA hydrogel (HP-MSCs-HA) exhibited a prolonged retention time in mouse uteri than normal HP-MSCs. In vivo studies showed that the HP-MSCs-HA could significantly increase the gland number and endometrial thickness ( P < 0.001, P < 0.05), decrease fibrous area ( P < 0.0001), and promote the proliferation and angiogenesis of endometrial cells (as indicated by Ki67 and VEGF, P < 0.05, P < 0.05, respectively) in mice injured endometrium. HP-MSCs-HA could also significantly improve the embryo implantation rate ( P < 0.01) compared with the ethanol group. Further mechanistic study showed the paracrine effects of HP-MSCs. They could not only promote the proliferation and migration of human endometrial stromal cells via the JNK/Erk1/2-Stat3-VEGF pathway but also facilitate the proliferation of glandular cells via Jak2-Stat5 and c-Fos-VEGF pathway. In turn, the increased VEGF in the endometrium promoted the angiogenesis of endothelial cells. Conclusion Our study suggested the potential therapeutic effects and the underlying mechanisms of HP-MSCs-HA on treating thin endometrium. HA hydrogel could be a preferable delivery method for HP-MSCs, and the strategy represents a promising therapeutic approach against endometrial injury in clinical settings. Graphical abstractCite
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The low molecular weight hyaluronic acid(LMWHA) and hyaluronic acid oligosaccharides(o-HA) have the activities of antioxidation,immunomodulation,wound healing,angiogenesis and antitumor.Hyaluronic acid(HA) can be degraded by oxidants to LMWHA and o-HA.This paper introduces the oxidation degradation of HA.
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The methods for isolation and purification of hyaluronic acid are summarized. The structural properties of this mucopolysaccharide are discussed, and hyaluronic acid-hydrolyzing enzymes are characterized. Data on the biological role, properties, and content of hyaluronic acid in tissues are reviewed. The possibilities of the application of hyaluronic acid in medicine, cosmetology, veterinary science, and hygiene are discussed.
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Hyaluronic acid, is extract by different procedures from various sources like pig, rabbit, oxes and human are available, but these processes have certain imitations like low yield, and also it requires the killing of these animals which is against the experimental ethics. In the present study, we have carried out the extraction of hyaluronic acid from cock’s comb which was further analyzed with qualitative test, viscosity, UV absorption, endotoxin detection assay. Also, the protein contamination of extracted hyaluronic acid was determined by using SDS-PAGE of hyaluronic acid was studied for checking the protein contaminants and it was noted that there were no bands observed in the well loaded with extracted hyaluronic acid sample indicating that the final extract of hyaluronic acid is not contaminated with the protein. The extraction and purification of hyaluronic acid by using the method reported here give pure hyaluronic acid. The viscosity of extracted hyaluronic acid was found to be 2.55 poise which is economical and can be used for industrial production of hyaluronic acid having clinical applications
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Sir: We would like to thank Dr. Andrea Sisti and colleagues for their interest and thoughtful comments regarding our article. As they highlighted, hyaluronic acid fillers have multiple effects. Hyaluronic acid acts not only as a tissue augmenter but also as a biostimulatory inducer (i.e., it enhances the formation of extracellular matrix and the production of new tissue). Physicians dealing with hyaluronic acid fillers should sufficiently understand these pleiotropic properties. We performed this study because we occasionally observed a sustained tissue-volumizing effect in the clinical setting more than 1 year after hyaluronic acid filler treatment when hyaluronic acid was subcutaneously injected using the bolus injection technique. We examined the histologic changes inside and outside the injected hyaluronic acid filler using an in vivo rodent model. This experiment revealed that hyaluronic acid stimulated the surrounding tissues and acted as a scaffold for autologous tissue proliferation, thereby resulting in the development of lattice structures by fibroblasts and induction of collagen fibers. The hyaluronic acid filler–injected space was gradually replaced by autologous tissues composed of fibroblasts, connective tissue, blood vessels, and adipocytes. Therefore, the partial replacement by autologous tissues caused a long-lasting effect despite the hyaluronic acid filler being gradually metabolized and absorbed. In several clinical cases of treatment with hyaluronic acid filler, hyaluronic acid–injected sites could not be recovered to their original condition even when hyaluronidase was injected into the treatment site. Thus, newly generated autologous tissues within the hyaluronic acid filler–injected space may be associated with these irreversible mechanisms. Although there are some differences between an animal model and a human, the results of our experiment can be applied to clinical hyaluronic acid treatments. It may be beneficial to not only inject the hyaluronic acid filler into the intradermal layer but also add a bolus injection into the subcutaneous layer to obtain a long-lasting effect. Furthermore, physicians should consider hydrophilicity (the volume of the hyaluronic acid filler increases by approximately 1.8-fold 4 weeks after injection), shape deformation (the height of the hyaluronic acid filler reduces by two-thirds 4 weeks after injection), and autologous tissue production characteristics over time for controlling the amount of hyaluronic acid filler during the initial treatment. Two concerns are considered as future perspectives. Currently, there are various types of commercially available hyaluronic acid fillers that differ in viscosity, elasticity, and concentration. However, in the present experiment, we elucidated the in vivo kinetics of only one hyaluronic acid filler (Juvéderm Vista ULTRA PLUS; Allergan plc, Dublin, Ireland). Therefore, it is necessary to examine which hyaluronic acid fillers act as a scaffold and which cause calcification or granulation, resulting in a risk of developing a lump in the future. Second, hyaluronic acid fillers may be developed into regenerative medicine in the near future if specific cells (adipocytes or chondrocytes) can be grown in hyaluronic acid–injected spaces by incorporating them into the filler before injection. DISCLOSURE None of the authors has a financial interest in any of the products, devices, or companies mentioned in this communication. No funding was obtained. Noriyuki Aoi, M.D.Masato Mochizuki, M.D.Department of Plastic, Oral, and Maxillofacial SurgeryTeikyo University School of MedicineTokyo, Japan Koichi Gonda, M.D.Department of Plastic SurgeryTohoku Medical and Pharmaceutical University HospitalSendai, Japan Shinichi Hirabayashi, M.D.Yuzo Komuro, M.D.Department of Plastic, Oral and Maxillofacial SurgeryTeikyo University School of MedicineTokyo, Japan
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Hyaluronic acid is an acidic polysaccharide that is widely distributed in various parts of the body. Hyaluronic acid has anti-inflammation,anti-infection,anti-edema effect and accelerates the tissue remodeling and healing in the wound. The article mainly reviewed the physiological function of hyaluronic acid and its application in the field of oral medicine.
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The most important studies on hyaluronic acid carried out within the recent 5-7 years are reviewed. Chemical structure, physical parameters and properties of hyaluronic acid are considered. Various functions of hyaluronic acid are discussed on the basis of current information.
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Hyaluronic acid is a naturally derived, non - immunogenic, non - adhesive glycosaminoglycan that plays a prominent role in various wound - healing processes, as it as it is naturally angiogenic when degraded to small fragments. Hyaluronic acid promotes early inflammation which is critical for initiating wound healing, but then moderates later stages of the process, allowing matrix stabilization and reduction of long term inflammation. Hyaluronic acid is widely distributed in mammalian cells and tissue but is primarily found in synovial fluid, vitreous humor of the eye and loose connective tissue such as rooster comb, umbilical cord, dermis and arterial wall. It is also found in the capsular component of certain bacterial such as Streptococcus sp. and Staphylococcus sp. These have been biotechnologically developed and are now a main source of commercial Hyaluronic acid for pharmaceutical, medical and cosmetic application. The present review was based on Hyaluronic acid production and application. This review assesses the following topics: Structural features and properties of Hyaluronic acid, Rheological properties of Hyaluronic acid, Lubricity of Hyaluronic acid, Hydrophilicity of Hyaluronic acid, Hyaluronic acid production by bacterial fermentation, Biosynthesis of Hyaluronic acid in Streptococcus, Enzymes involved in Hyaluronic acid biosynthesis, Optimization and extraction of Hyaluronic acid, Analysis of Hyaluronic acid and Applications of Hyaluronic acid.
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