Abstract
Islet transplantation has become an important treatment modality for Type 1 Diabetes Mellitus (T1DM); nonetheless, the procedure may be limited by donor availability. An alternative has been the increasing use of cellular therapies derived from human Embryonic Stem Cells (hESC), showing very promising results in maturation, yield and ultimately, in insulin secretion in response to adequate stimuli. We recently developed a new technique for cellular transplantation under the skin. This manuscript evaluates the capabilities of the pre-vascularized Device-Less (DL) site to allow transplantation of Pancreatic Endoderm (PE) cells differentiated from hESC to treat diabetes mellitus. Fifty immunodeficient mice, n = 25 diabetic and n = 25 non-diabetic, were transplanted with PE cells. Animals were followed for 22 weeks and grafts were retrieved to evaluate engraftment and subsequent maturation. Diabetic mice showed slightly better engraftment (48% vs. 36%, p = 0.19) and secreted higher concentration of human C-peptide upon glucose stimulation (0.32 ± 0.15 ng/mL vs. 0.13 ± 0.09 ng/mL, p = 0.30), although differences were not significant. This maturation was not sufficient to successfully reverse diabetes. Monomorphic cystic changes were detected in 12% and 8%, respectively (diabetics vs. non-diabetics, p = 0.32) and all grafts seemed to be adequately contained by the surrounding collagen wall within the DL space. Our findings support the capabilities of the DL site to host PE cells and allow safe maturation as a new strategy to treat diabetes.
Highlights
The recent advances in immunotherapy have allowed Islet Transplantation (IT) to become a mainstay treatment for Type 1 Diabetes Mellitus (T1DM)
Significant variability is associated with this treatment modality and many factors may affect the successful utilization of a donated pancreas
We describe the use of the DL technique to safely allow engraftment and maturation of Pancreatic Endoderm (PE) cells derived from a human Embryonic Stem Cells (hESC) line in an experimental xeno-transplant model of diabetes
Summary
The recent advances in immunotherapy have allowed Islet Transplantation (IT) to become a mainstay treatment for Type 1 Diabetes Mellitus (T1DM). Finding the most efficient transplant site remains a dilemma given the infusion volume needed at the time of transplant and the potential need for graft retrieval in the event of tumor formation [7,8]. These reasons are a deterrent to use the conventional intra portal route for this transplantation modality. Our group recently described a novel pre-vascularized Device-Less (DL) technique for cell transplantation in the subcutaneous space [9] This approach was successful in reversing diabetes with mouse and human islets and is currently being used for other cell therapies. We describe the use of the DL technique to safely allow engraftment and maturation of Pancreatic Endoderm (PE) cells derived from a hESC line in an experimental xeno-transplant model of diabetes
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