Strategy for Clinical Setting of Co-transplantation of Mesenchymal Stem Cells and Pancreatic Islets.

Islet transplantation may be the most efficient therapeutic technique for patients with type 1 diabetes mellitus (T1DM). However, the clinical application of this method is faced with numerous limitations, including isolated islet apoptosis, recipient rejection, and graft vascular reconstruction. Mesenchymal stem cells (MSCs) possess anti-apoptotic, immunomodulatory, and angiogenic properties. Here, we review recent studies on co-culture and co-transplantation of islets with MSCs. We have summarized the methods of preparation of co-transplantation, especially the merits of co-culture, and the effects of co-transplantation. Accumulating experimental evidence shows that co-culture of islets with MSCs promotes islet survival, enhances islet secretory function, and prevascularizes islets through various pretransplant preparations. This review is expected to provide a reference for exploring the use of MSCs for clinical islet co-transplantation.

Exosomal microRNA-Based therapies for skin diseases.

Based on engineered cell/exosome technology and various skin-related animal models, exosomal microRNA (miRNA)-based therapies derived from natural exosomes have shown good therapeutic effects on nine skin diseases, including full-thickness skin defects, diabetic ulcers, skin burns, hypertrophic scars, psoriasis, systemic sclerosis, atopic dermatitis, skin aging, and hair loss. Comparative experimental research showed that the therapeutic effect of miRNA-overexpressing exosomes was better than that of their natural exosomes. Using a dual-luciferase reporter assay, the targets of all therapeutic miRNAs in skin cells have been screened and confirmed. For these nine types of skin diseases, a total of 11 animal models and 21 exosomal miRNA-based therapies have been developed. This review provides a detailed description of the animal models, miRNA therapies, disease evaluation indicators, and treatment results of exosomal miRNA therapies, with the aim of providing a reference and guidance for future clinical trials. There is currently no literature on the merits or drawbacks of miRNA therapies compared with standard treatments.

Exosomal-microRNAs Improve Islet Cell Survival and Function In Islet Transplantation.

Exosomal-microRNAs (Exo-miRNAs) are key regulators of islet cell function, including insulin expression, processing, and secretion. Exo-miRNAs have a significant impact on the outcomes of islet transplantation as biomarkers for evaluating islet cell function and survival. Furthermore, they have been linked to vascular remodeling and immune regulation following islet transplantation. Mesenchymal stem cell-derived exosomes have been shown in preliminary studies to improve islet cell viability and function when injected or transplanted into mice. Overall, Exo-miRNAs have emerged as novel agents for improving islet transplantation success rates. The role of islet-derived Exo-miRNAs and mesenchymal stem cells-derived Exo-miRNAs as biomarkers and immunomodulators in islet regeneration, as well as their role in improving islet cell viability and function in islet transplantation, are discussed in this review.

Transplantation of insulin-producing cells derived from human MSCs to treat diabetes in a non-human primate model.

BACKGROUND: Islet cell transplantation is an emerging therapy in the treatment of diabetes mellitus. Differentiation of islet cells from mesenchymal stem cells (MSCs) is a potential solution to the challenge of insufficient donor sources. This study investigated whether human umbilical cord-derived MSCs could effectively differentiate into insulin-producing cells (IPCs) and evaluated the therapeutic efficacy of IPCs in treating diabetes. METHODS: IPCs were induced from MSCs by a two-step protocol. IPC expression products were evaluated by western blot and real-time PCR. IPC insulin secretion was evaluated by ELISA. The viability of IPCs was measured by FDA/PI and dithizone staining. The non-human primate tree shrew was used as a diabetes model. After a single STZ induction into a diabetes model, a single intraportal transplantation of IPCs, MSCs, or normal saline was performed (n = 6 per group). Blood glucose was monitored for 3 weeks, then the animals were euthanized and the distribution of IPCs in the liver was examined pathologically. RESULTS: After about 3 weeks of in vitro induction, IPCs formed microspheres of 100-200 µm, with >95% viable cells that were dithizone stain positive. IPCs expressed islet-related genes and proteins and secreted high levels of insulin whether stimulated by low or high levels of glucose. After transplantation of IPCs into diabetic tree shrews, blood glucose levels decreased rapidly to near normal and were significantly lower than the MSC or saline groups for 3 weeks thereafter. CONCLUSION: We present the novel discovery that IPCs derived from human umbilical cord MSCs exert a therapeutic effect in a non-human primate model of diabetes. This study provides a preliminary experimental basis for the use of autologous MSC-derived IPCs in the treatment of human diabetes.

Exosomal microRNAs as diagnostic biomarkers and therapeutic applications in neurodegenerative diseases.

Originating from slow irreversible and progressive loss and dysfunction of neurons and synapses in the nervous system, neurodegenerative diseases (NDDs) affect millions of people worldwide. Common NDDs include Parkinson's disease, Alzheimer's disease multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. Currently, no sensitive biomarkers are available to monitor the progression and treatment response of NDDs or to predict their prognosis. Exosomes (EXOs) are small bilipid layer-enclosed extracellular vesicles containing numerous biomolecules, including proteins, nucleic acids, and lipids. Recent evidence indicates that EXOs are pathogenic participants in the spread of neurodegenerative diseases, contributing to disease progression and spread. EXOs are also important tools for diagnosis and treatment. Recently, studies have proposed exosomal microRNAs (miRNAs) as the targets for therapies or biomarkers of NDDs. In this review, we outline the latest research on the roles of exosomal miRNAs in NDDs and their applications as potential diagnostic and therapeutic biomarkers, targets, and drugs for NDDs.

In vitro research of mesenchymal stem cell-coated human islets to alleviate instant blood-mediated inflammatory reaction / 器官移植

Objective To evaluate the effect of mesenchymal stem cell (MSC) coated-islets on instant blood-mediated inflammatory reaction (IBMIR) after islet transplantation. Methods MSC labeled with tracer and human islets were placed into an ultra-low adsorption cell culture dish, shaken and mixed twice at an interval of 0.5 h, and then incubated at 37 ℃ and 5% CO2 for 24 h to obtain MSC-coated islets. The coating effect of MSC and in vitro function of the islets were assessed. A blood circulation tube-shaped model was established in vitro. In the blank control group, 0.2 mL of islet culture solution was added. In the islet group, 800 islet equivalent quantity (IEQ) of uncoated islets were supplemented. In the MSC-coated islets group, 800 IEQ of MSC-coated islets were added, and circulated for 60 min at 37 ℃. A portion of 0.5 mL blood sample was taken for routine blood test at 0, 30 and 60 min, respectively. After 60 min circulation, the blood sample was filtered with a 70 μm filter to collect plasma, blood clots and islets. Blood clots and islets were subject to hematoxylin-eosin (HE) staining and immunohistochemical staining. Morphological changes and the aggregation of CD11b-positive cells surrounding the islets were observed. The contents of plasma thrombin-antithrombin complex (TAT), tissue factor (TF), C3a, C5b-9, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1 and IL-8 were determined by enzyme-linked immune absorbent assay. Results After 24 h co-incubation, the islets were coated by MSC, with a coating degree of approximately 80%. In the islet and MSC-coated islet group, a large quantity of neutrophils and monocytes were observed surrounding the blood clots and islets, and the quantity of CD11b-positive cells in the MSC-coated islet group was less compared with that in the islet group. After co-incubation with the whole blood for 0, 30 and 60 min, the quantity of platelets, neutrophils and monocytes was declined in the MSC-coated and islet groups, and gradually decreased over time. Compared with the blank control group, the quantity of platelets, monocytes and neutrophils was lower, whereas the TF content was higher in the MSC-coated islet group. Compared with the islet group, the quantity of platelets, monocytes and neutrophils was higher, whereas the TAT and TF contents were less in the MSC-coated islet group, the differences were statistically significant (all P < 0.05). Compared with the blank control group, the expression levels of C3a, C5b-9, IL-6, TNF-α and IL-8 were up-regulated in the MSC-coated islet group. Compared with the islet group, the expression levels of C3a, C5b-9, IL-1β, IL-6, TNF-α, IL-8 and MCP-1 were down-regulated in the MSC-coated islet group, and the differences were statistically significant (all P < 0.05). Conclusions MSC-coated islets may reduce the exposure of islet TF in the blood and prevent the incidence of IBMIR during the coagulation response stage, thereby mitigating the injury and loss of islet allograft in the early stage of islet transplantation.