Dataset Information

Syngeneic bone marrow transplantation in combination with PI3K inhibitor reversed hyperglycemia in later-stage streptozotocin-induced diabetes.

ABSTRACT:

Background

Type 1 diabetes (T1D) is a multiple factor autoimmune disease characterized by T cell-mediated immune destruction of islet β cells. Autologous hematopoietic stem cell transplantation (AHSCT) has been a novel strategy for patients with new-onset T1D, but not for those with a later diagnosis. Disturbance of regulatory T cells (Tregs) likely contributes to poor response after transplantation in later-stage T1D. Inhibition of phosphoinositide 3-kinases (PI3K)/Akt signaling maintains Tregs' homeostasis.

Methods

We built a later-stage streptozotocin (STZ)-induced T1D mouse model. Syngeneic bone marrow transplantation (syn-BMT) was performed 20 days after the onset of diabetes in combination with BKM120 (a PI3K inhibitor). Meanwhile, another group of STZ-diabetic mice were transplanted with bone marrow cells cocultured with BKM120 in vitro for 24 h. Fasting glucose and glucose tolerance were recorded during the entire experimental observation after syn-BMT. Samples were collected 126 days after syn-BMT. Hematoxylin and eosin (H&E) staining was used to detect the effect of PI3K inhibitor combined with syn-BMT on morphology of the T1D pancreas. CD4⁺CD25^- T cells and CD4⁺CD25⁺ T cells were sorted by magnetic cell sorting (MACS), then fluorescence activated cell sorting (FACS) and quantitative real-time PCR (qPCR) were used to detect the effect of PI3K inhibitor on modulating immune disorder and restoring the function of Treg cells.

Results

Our investigation showed syn-BMT in combination with BKM120 effectively maintained normoglycemia in later-stage T1D. The disease remission effects may be induced by the rebalance of Th17/Tregs dysregulation and restoration of Tregs' immunosuppressive function by BKM120 after syn-BMT.

Conclusions

These results may reveal important connections for PI3K/Akt inhibition and Tregs' homeostasis in T1D after transplantation. AHSCT combining immunoregulatory strategies such as PI3K inhibition may be a promising therapeutic approach in later-stage T1D.

SUBMITTER: Zhang S

PROVIDER: S-EPMC8667114 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Syngeneic bone marrow transplantation in combination with PI3K inhibitor reversed hyperglycemia in later-stage streptozotocin-induced diabetes.

Zhang Shiyun S Dai Qianqian Q Zhang Bin B Liu Siyang S Wang Ying Y Zhang Yixue Y Chen Dongyue D Zong Ningning N Wang Hongwei H Ding Jingjing J Gao Qian Q Wen Yanting Y

Annals of translational medicine 20211101 22

<h4>Background</h4>Type 1 diabetes (T1D) is a multiple factor autoimmune disease characterized by T cell-mediated immune destruction of islet β cells. Autologous hematopoietic stem cell transplantation (AHSCT) has been a novel strategy for patients with new-onset T1D, but not for those with a later diagnosis. Disturbance of regulatory T cells (Tregs) likely contributes to poor response after transplantation in later-stage T1D. Inhibition of phosphoinositide 3-kinases (PI3K)/Akt signaling maintai ...[more]

PMID: 34988151

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Project description:Introduction: Chemicals, such as MNU (N-methyl-N-nitrosourea) and NaIO3 (sodium iodate), are widely used to induce retinal degeneration in rodents. Streptozotocin (STZ) is an analog of N-acetyl glucosamine in which an MNU moiety is linked to a hexose and has a special toxic effect on insulin-producing pancreatic β-cells. It is commonly used to induce hyperglycemia to model diabetes. While intracerebroventricular injection of STZ can produce Alzheimer's disease independent of hyperglycemia, most retinal studies using STZ focus on the effects of hyperglycemia on the retina, but whether STZ has any impact on retinal cells independent of hyperglycemia is unknown. We aimed to investigate the role of cytotoxicity of STZ in rat retina. Methods: Intravitreal or subcutaneous injection of STZ was performed on newborn rats. Electroretinogram (ERG) and H&E staining investigated retinal function and morphological changes. Retinal cell types, cell death, proliferation, inflammation, and angiogenesis were studied by immunostaining. RNA sequencing was performed to examine the transcriptome changes of retinal cells after intravitreal injection of STZ. Results: Intravitreal (5 μg or 10 μg) or subcutaneous (30 mg/kg) injection of STZ at the early stage of newborn rats couldn't induce hyperglycemia but caused NSIR (Neonatal STZ-induced retinopathy), including reduced ERG amplitudes, retinal rosettes and apoptosis, cell cycle arrest, microglial activation, and delayed retinal angiogenesis. STZ did not affect the early-born retinal cell types but significantly reduced the late-born ones. Short-term and long-term hyperglycemia had no significant effects on the NSIR phenotypes. RNA sequencing revealed that STZ induces oxidative stress and activates the p53 pathway of retinal cells. Locally or systemically, STZ injection after P8 couldn't induce SINR when all retinal progenitors exit the cell cycle. Conclusion: NSIR in rats is independent of hyperglycemia but due to STZ's direct cytotoxic effects on retinal progenitor cells. NSIR is a typical reaction to STZ-induced retinal oxidative stress and DNA damage. This significant finding suggests that NSIR may be a valuable model for studying retinal progenitor DNA damage-related diseases, potentially leading to new insights and treatments.

Project description:Type 1 diabetes mellitus is a progressive disease caused by the destruction of pancreatic β-cells, resulting in insulin dependency and hyperglycemia. While transplanted bone marrow-derived mesenchymal stem/stromal cells (BMMSCs) have been explored as an alternative therapeutic approach for diseases, the choice of delivery route may be a critical factor determining their sustainability. This study evaluated the effects of intrapancreatic and intravenous injection of human BMMSCs (hBMMSCs) in streptozotocin (STZ)-induced type 1 diabetic mouse model. C57/BL6 mice were intraperitoneally injected with 115 mg/kg STZ on day 0. hBMMSCs (1 × 106 cells) or vehicle were injected into the pancreas or jugular vein on day 7. Intrapancreatic, but not intravenous, hBMMSC injection significantly reduced blood glucose levels on day 28 compared with vehicle injection by the same route. This glucose-lowering effect was not induced by intrapancreatic injection of human fibroblasts as the xenograft control. Intrapancreatically injected fluorescence-labeled hBMMSCs were observed in the intra- and extra-lobular spaces of the pancreas, and intravenously injected cells were in the lung region, although the number of cells mostly decreased within 2 weeks of injection. For hBMMSCs injected twice into the pancreatic region on days 7 and 28, the injected mice had further reduced blood glucose to borderline diabetic levels on day 56. Animals injected with hBMMSCs twice exhibited increases in the plasma insulin level, number and size of islets, insulin-positive proportion of the total pancreas area, and intensity of insulin staining compared with vehicle-injected animals. We found a decrease of Iba1-positive cells in islets and an increase of CD206-positive cells in both the endocrine and exocrine pancreas. The hBMMSC injection also reduced the number of CD40-positive cells merged with glucagon immunoreactions in the islets. These results suggest that intrapancreatic injection may be a better delivery route of hBMMSCs for the treatment of type 1 diabetes mellitus.

Dataset Information

Syngeneic bone marrow transplantation in combination with PI3K inhibitor reversed hyperglycemia in later-stage streptozotocin-induced diabetes.

Background

Methods

Results

Conclusions

Publications

Syngeneic bone marrow transplantation in combination with PI3K inhibitor reversed hyperglycemia in later-stage streptozotocin-induced diabetes.

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