Effects and mechanism of stem cells from human exfoliated deciduous teeth combined with hyperbaric oxygen therapy in type 2 diabetic rats

Abstract

OBJECTIVES: Mesenchymal stem cells (MSCs) are potentially ideal for type 2 diabetes treatment, owing to their multidirectional differentiation ability and immunomodulatory properties. Here we investigated whether the stem cells from human exfoliated deciduous teeth (SHED) in combination with hyperbaric oxygen (HBO) could treat type 2 diabetic rats, and explored the underlying mechanism. METHODS: SD rats were used to generate a type 2 diabetes model, which received stem cell therapy, HBO therapy, or both together. Before and after treatment, body weight, blood glucose, and serum insulin, blood lipid, pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), and urinary proteins were measured and compared. After 6 weeks, rats were sacrificed and their organs were subjected to hematoxylin and eosin staining and immunofluorescence staining for insulin and glucagon; apoptosis and proliferation were analyzed in islet cells. Structural changes in islets were observed under an electron microscope. Expression levels of Pdx1, Ngn3, and Pax4 mRNAs in the pancreas were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: In comparison with diabetic mice, those treated with the combination or SHE therapy showed decreased blood glucose, insulin resistance, serum lipids, and pro-inflammatory cytokines and increased body weight and serum insulin. The morphology and structure of pancreatic islets improved, as evident from an increase in insulin-positive cells and a decrease in glucagon-positive cells. Terminal deoxynucleotidyl transferasemediated dUTP nick end labeling (TUNEL) staining of islet cells revealed the decreased apoptosis index, while Ki67 and proliferating cell nuclear antigen staining showed increased proliferation index. Pancreatic expression of Pdx1, Ngn3, and Pax4 was upregulated. CONCLUSION: SHED combined with HBO therapy was effective for treating type 2 diabetic rats. The underlying mechanism may involve SHED-mediated increase in the proliferation and trans-differentiation of islet b-cells and decrease in pro-inflammatory cytokines and apoptosis of islets.

Therapeutic Potential of Stem Cells from Human Exfoliated Deciduous Teeth Infusion into Patients with Type 2 Diabetes Depends on Basal Lipid Levels and Islet Function

“…55,56 SHEDmediated immunomodulation and islet function restoration have been documented in our previous reports, which potentially contribute to treatment of T2DM. 31,56 In this study, we also observed the…”

“…The mechanisms underlying MSC-mediated therapy for diabetes have not been elucidated. It has been suggested that MSCs may directly differentiate into IPCs, [23][24][25] promote islet β-cell regeneration, 26,27,31 and improve insulin resistance, 31,[47][48][49] thus playing an important role in improving the glucose metabolism. In addition, regulation of the interplay between immune response and the microenvironment of islet cells may contribute to MSC-mediated therapy for diabetes.…”

“…In addition, regulation of the interplay between immune response and the microenvironment of islet cells may contribute to MSC-mediated therapy for diabetes. 31,[50][51][52] For the potential mechanisms underlying SHED treatment of T2DM, differentiation of MSCs into pancreas islet after the infusion might be restricted because of limited pancreas homing and rapid apoptosis of the infused cells. 20,53,54 Nevertheless, infused MSCs are still capable of inducing recovery of β cells based on microenvironmental modulation.…”

“…37,38,61 Our previous animal experiment also showed that the HOMA-IR of T2DM rats decreased significantly after intravenous infusion of SHED. 31 The differences in the results of clinical trials and animal experiments with respect to the effects of stem cell therapy on islet function and insulin sensitivity may be due to species-specific differences in response and differences in the source, dosage, and treatment course of MSCs used. Especially for those who have a long course of disease and have used insulin, it cannot reflect the real insulin resistance.…”

“…30 In addition, previous studies showed that SHED are effective for treating type 2 diabetic rats with mechanisms related to improvement of islet β cells and the liver metabolism. 31,32 Although SHED and DPSCs have many advantages in clinical use, such as their abundant, easy access, low rate of side effects, and lack of ethical disputes, there is no research establishing clinical efficacy of SHED or DPSCs to treat diabetes. In this study, we assess the safety and effectiveness of allogenic SHED transplantation in patients with T2DM and evaluate potential factors regulating therapeutic efficacy of SHED.…”