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Successful Preclinical Islet Transplantation in the Subcutaneous Space for Type 1 Diabetes

ABSTRACT: Successful Preclinical Islet Transplantation in the Subcutaneous Space for Type 1 Diabetes

PROVIDER: PRJNA607700 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11119400.fastq.gz	Fastqsanger.gz
	SRR11119401.fastq.gz	Fastqsanger.gz
	SRR11119402.fastq.gz	Fastqsanger.gz
	SRR11119403.fastq.gz	Fastqsanger.gz
	SRR11119404.fastq.gz	Fastqsanger.gz

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Successful Preclinical Islet Transplantation in the Subcutaneous Space for Type 1 Diabetes

Project description:The intrahepatic milieu is inhospitable to intraportal islet allografts, limiting their applicability to ameliorate Type 1 Diabetes (T1D). Islet viability in the subcutaneous space represents an unfulfilled paradigm that is crucial to ensure widespread adoption and safety of clinical islet transplantation. Herein we report that human islets transplanted subcutaneously uniformly promote long-term euglycemia when admixed with a device-free Islet Viability Matrix (IVM), through a previously unknown anti-apoptotic mechanism.

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Project description:Islet transplantation is an attractive treatment for patients with insulin-dependent diabetes mellitus, and currently the liver is the favored transplantation site. However, an alternative site is desirable because of the low efficiency of hepatic transplantation, requiring 2-3 donors for a single recipient, and because the transplanted islets cannot be accessed or retrieved. Here we describe a novel site for islet transplantation, the inguinal subcutaneous white adipose tissue. In this site, transplanted islets are engrafted as clusters and function to reverse diabetes in mice. Importantly, transplanted islets can be visualized by CT and are easily retrievable, and allograft rejection is preventable by blockade of co-stimulatory signals. Of much interest, the efficiency of islet transplantation is superior to the liver, with increased mass of transplanted β cells. Furthermore, transplanted human islets function to reverse diabetes in immunodeficient mice. Thus, this adipose tissue site may be ideal for clinical islet transplantation.

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Differential gene expression on islet transplantation with or without the presence of autologous fibroblasts

Project description:Pancreatic islet transplantation was performed in the subcutaneous space of diabetic nude mice. In order to promote long survival and function of transplanted islets a plasma-based scaffold was developed in combination with fibroblasts as graft-supporting accesory cells. Gene expression analysis was carried out to evaluate expression differences due to the presence of fibroblast which could explain the long-term glycemic control observed under these circumstances.

2017-08-30 | GSE84900 | GEO

Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes.

Project description:The intrahepatic milieu is inhospitable to intraportal islet allografts1-3, limiting their applicability for the treatment of type?1 diabetes. Although the subcutaneous space represents an alternate, safe and easily accessible site for pancreatic islet transplantation, lack of neovascularization and the resulting hypoxic cell death have largely limited the longevity of graft survival and function and pose a barrier to the widespread adoption of islet transplantation in the clinic. Here we report the successful subcutaneous transplantation of pancreatic islets admixed with a device-free islet viability matrix, resulting in long-term euglycaemia in diverse immune-competent and immuno-incompetent animal models. We validate sustained normoglycaemia afforded by our transplantation methodology using murine, porcine and human pancreatic islets, and also demonstrate its efficacy in a non-human primate model of syngeneic islet transplantation. Transplantation of the islet-islet viability matrix mixture in the subcutaneous space represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type?1 diabetes.

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Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

Project description:Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

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Subcutaneous adipose tissue: comparison of weight maintainence and weight regain following an 8-week low calorie diet

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Chromatin accessibility changes underlying progression from islet autoantibody positivity to type 1 diabetes

Project description:Type 1 diabetes (T1D) usually has a preclinical phase identified by the presence of circulating autoantibodies to pancreatic islet antigens, and most young children who have multiple autoantibodies progress to diabetes within 10 years. While autoantibodies denote underlying islet autoimmunity, how this process is initiated and then progresses to clinical diabetes on a background of genetic susceptibility is not clearly understood. Only one study has thus far reported changes in gene expression in isolated immune cells associated with progression to islet autoimmunity. We analysed chromatin accessibility by ATAC-seq in CD4+ T cells in four genetically at-risk children with islet autoantibodies who progressed to diabetes in ≤ 3 years (‘progressors’), compared to five at-risk children matched for sex, age and HLA who had not progressed (‘non-progressors). From ATAC-seq data, we generated the first map of chromatin accessibility in T cells of islet autoantibody-positive children. Progression was associated with a subtle reconfiguration of regulatory chromatin regions, and some of the chromatin conformation changes could be linked to progression associated expression changes at cytotoxic genes.

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