Mitomycin C treatment improves pancreatic islet graft longevity in intraportal islet transplantation by suppressing proinflammatory response

Yamane, Keisaku; Anazawa, Takayuki; Tada, Seiichiro; Fujimoto, Nozomu; Inoguchi, Kenta; Emoto, Norio; Nagai, Kazuyuki; Masui, Toshihiko; Okajima, Hideaki; Takaori, Kyoichi; Sumi, Shoichiro; Üemoto, Shinji

doi:10.1038/s41598-020-69009-8

Cited by 5 publications

(3 citation statements)

References 44 publications

(55 reference statements)

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“…For example, sirolimus, affects the MAPK10 gene product, has been shown to normalize glucose metabolism in diabetic mice 63 , 64 , decrease IR in diabetic rats 65 , and prevent IR in humans 66 (Supplementary Table S16 ). Similarly, mitomycin (another compound that affects the MAPK10 gene product) has been hypothesized to suppress pro-inflammatory events and cause the induction of regulatory T cells differentiation following islet allograft transplantation 67 .…”

Section: Resultsmentioning

confidence: 99%

Untangling the genetic link between type 1 and type 2 diabetes using functional genomics

Nyaga

Vickers

Jefferies

et al. 2021

Sci Rep

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There is evidence pointing towards shared etiological features between type 1 diabetes (T1D) and type 2 diabetes (T2D) despite both phenotypes being considered genetically distinct. However, the existence of shared genetic features for T1D and T2D remains complex and poorly defined. To better understand the link between T1D and T2D, we employed an integrated functional genomics approach involving extensive chromatin interaction data (Hi-C) and expression quantitative trait loci (eQTL) data to characterize the tissue-specific impacts of single nucleotide polymorphisms associated with T1D and T2D. We identified 195 pleiotropic genes that are modulated by tissue-specific spatial eQTLs associated with both T1D and T2D. The pleiotropic genes are enriched in inflammatory and metabolic pathways that include mitogen-activated protein kinase activity, pertussis toxin signaling, and the Parkinson’s disease pathway. We identified 8 regulatory elements within the TCF7L2 locus that modulate transcript levels of genes involved in immune regulation as well as genes important in the etiology of T2D. Despite the observed gene and pathway overlaps, there was no significant genetic correlation between variant effects on T1D and T2D risk using European ancestral summary data. Collectively, our findings support the hypothesis that T1D and T2D specific genetic variants act through genetic regulatory mechanisms to alter the regulation of common genes, and genes that co-locate in biological pathways, to mediate pleiotropic effects on disease development. Crucially, a high risk genetic profile for T1D alters biological pathways that increase the risk of developing both T1D and T2D. The same is not true for genetic profiles that increase the risk of developing T2D. The conversion of information on genetic susceptibility to the protein pathways that are altered provides an important resource for repurposing or designing novel therapies for the management of diabetes.

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Section: Resultsmentioning

confidence: 99%

Untangling the genetic link between type 1 and type 2 diabetes using functional genomics

Nyaga

Vickers

Jefferies

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Rat and human pancreatic islets preconditioned with diazoxide, a potassium channel activator, and subsequently exposed to hypoxic conditions are protected from hypoxia-induced necrosis by an unknown mechanism and ameliorate hyperglycemia in STZ-induced diabetic rats and immune deficient mice, respectively ( 149 ). Transplanted mouse pancreatic islet allografts preconditioned with mitomycin c, an antitumor antibiotic, experience a median survival duration of 28 days without immunosuppression compared to 13 days in the control group ( 150 ). In an in vitro model, mitomycin c treatment suppressed allograft proinflammatory cytokine expression, decreased inflammatory cell infiltration, and upregulation of CD4+-suppressing regulatory T cells ( 150 ).…”

Section: Transplant Preconditioningmentioning

confidence: 99%

“…Transplanted mouse pancreatic islet allografts preconditioned with mitomycin c, an antitumor antibiotic, experience a median survival duration of 28 days without immunosuppression compared to 13 days in the control group ( 150 ). In an in vitro model, mitomycin c treatment suppressed allograft proinflammatory cytokine expression, decreased inflammatory cell infiltration, and upregulation of CD4+-suppressing regulatory T cells ( 150 ). A green tea polyphenol and anti-inflammatory agent, epigallocatechin 3-gallate (EGCG), also improves pancreatic islet transplant viability ( 151 ).…”

Section: Transplant Preconditioningmentioning

confidence: 99%

Immune Protection of Stem Cell-Derived Islet Cell Therapy for Treating Diabetes

Tahbaz

Yoshihara

2021

Front. Endocrinol.

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Insulin injection is currently the main therapy for type 1 diabetes (T1D) or late stage of severe type 2 diabetes (T2D). Human pancreatic islet transplantation confers a significant improvement in glycemic control and prevents life-threatening severe hypoglycemia in T1D patients. However, the shortage of cadaveric human islets limits their therapeutic potential. In addition, chronic immunosuppression, which is required to avoid rejection of transplanted islets, is associated with severe complications, such as an increased risk of malignancies and infections. Thus, there is a significant need for novel approaches to the large-scale generation of functional human islets protected from autoimmune rejection in order to ensure durable graft acceptance without immunosuppression. An important step in addressing this need is to strengthen our understanding of transplant immune tolerance mechanisms for both graft rejection and autoimmune rejection. Engineering of functional human pancreatic islets that can avoid attacks from host immune cells would provide an alternative safe resource for transplantation therapy. Human pluripotent stem cells (hPSCs) offer a potentially limitless supply of cells because of their self-renewal ability and pluripotency. Therefore, studying immune tolerance induction in hPSC-derived human pancreatic islets will directly contribute toward the goal of generating a functional cure for insulin-dependent diabetes. In this review, we will discuss the current progress in the immune protection of stem cell-derived islet cell therapy for treating diabetes.

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Considerations Pertaining to Implant Sites for Cell-Based Insulin Replacement Therapies

Marfil-Garza,

Cuesta-Gomez,

Shapiro

2023

Pluripotent Stem Cell Therapy for Diabetes

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Mitomycin C treatment improves pancreatic islet graft longevity in intraportal islet transplantation by suppressing proinflammatory response

Abstract: the transplanted livers of the control and MMC groups by ELISA. INF-γ levels were significantly lower in the livers of the MMC group than in those of the control group (Fig. 5B, n = 4; p < 0.01).

Cited by 5 publications

References 44 publications

Untangling the genetic link between type 1 and type 2 diabetes using functional genomics

Untangling the genetic link between type 1 and type 2 diabetes using functional genomics

Immune Protection of Stem Cell-Derived Islet Cell Therapy for Treating Diabetes

Considerations Pertaining to Implant Sites for Cell-Based Insulin Replacement Therapies

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