Enhanced Differentiation Capacity and Transplantation Efficacy of Insulin-Producing Cell Clusters from Human iPSCs Using Permeable Nanofibrous Microwell-Arrayed Membrane for Diabetes Treatment.

In Kyong Shim,Dong Sung Kim,Jinah Jang,Song Cheol Kim,Hanse Goh,Yu Na Lee,Dohui Kim,Seong Jin Lee,Jaeseung Youn

doi:10.3390/pharmaceutics14020400

Abstract

Although pancreatic islet transplantation is a potentially curative treatment for insulin-dependent diabetes, a shortage of donor sources, low differentiation capacity, and transplantation efficacy are major hurdles to overcome before becoming a standard therapy. Stem cell-derived insulin-producing cells (IPCs) are a potential approach to overcoming these limitations. To improve the differentiation capacity of the IPCs, cell cluster formation is crucial to mimic the 3D structure of the islet. This study developed a biodegradable polycaprolactone (PCL) electrospun nanofibrous (NF) microwell-arrayed membrane permeable to soluble factors. Based on the numerical analysis and experimental diffusion test, the NF microwell could provide sufficient nutrients, unlike an impermeable PDMS (polydimethylsiloxane) microwell. The IPC clusters in the NF microwells showed higher gene expression of insulin and PDX1 and insulin secretion than the PDMS microwells. The IPC clusters in the NF microwell-arrayed membrane could be directly transplanted. Transplanted IPC clusters in the microwells survived well and expressed PDX1 and insulin. Additionally, human c-peptide was identified in the blood plasma at two months after transplantation of the membranes. The NF microwell-arrayed membrane can be a new platform promoting IPC differentiation capacity and realizing an in situ transplantation technique for diabetic patients.

Highlights

Diabetes is a cause of various systemic complications, such as heart disease, kidney failure, stroke, and diabetic neuropathy, along with a shortened life expectancy, leading to substantial medical costs worldwide [1]
General insulin injections can cause severe hypoglycemia and cannot prevent long-term complications because they do not allow for precise blood glucose control such as that provided by a healthy pancreas [2,3,4]
We successfully developed a differentiation and transplantation technology of insulin-secreting cells for the fundamental treatment of diabetes

Summary

Introduction

Diabetes is a cause of various systemic complications, such as heart disease, kidney failure, stroke, and diabetic neuropathy, along with a shortened life expectancy, leading to substantial medical costs worldwide [1]. In insulin-dependent diabetes, exogenous insulin injections are the standard treatment to reduce hyperglycemia. General insulin injections can cause severe hypoglycemia and cannot prevent long-term complications because they do not allow for precise blood glucose control such as that provided by a healthy pancreas [2,3,4]. Precise real-time diabetes control tailored to the blood glucose level is important to prevent complications of diabetes [5,6]. Transplantation of the pancreas and pancreatic islets is a potentially curative treatment for diabetes. Only 20% of these patients remained insulin-independent by five years, and the remaining 80% needed insulin injections again [8]. Pancreatic islet transplantation is an ideal treatment, there are still many hurdles it must overcome before becoming a standard therapy. Its significant issues include a shortage of donor sources and a low engraftment efficacy of the islets after transplantation [9]

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