Gene-edited human stem cell–derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice

Differentiation of insulin-producing pancreatic β cells from induced pluripotent stem cells (iPSCs) derived from patients with diabetes promises to provide autologous cells for diabetes cell replacement therapy. However, current approaches produce patient iPSC-derived β (SC-β) cells with poor function in vitro and in vivo. Here, we used CRISPR-Cas9 to correct a diabetes-causing pathogenic variant in Wolfram syndrome 1 (WFS1) in iPSCs derived from a patient with Wolfram syndrome (WS). After differentiation to β cells with our recent six-stage differentiation strategy, corrected WS SC-β cells performed robust dynamic insulin secretion in vitro in response to glucose and reversed preexisting streptozocin-induced diabetes after transplantation into mice. Single-cell transcriptomics showed that corrected SC-β cells displayed increased insulin and decreased expression of genes associated with endoplasmic reticulum stress. CRISPR-Cas9 correction of a diabetes-inducing gene variant thus allows for robust differentiation of autologous SC-β cells that can reverse severe diabetes in an animal model.

Lung Based Engineered Micro-Pancreas Sustains Human Beta Cell Survival and Functionality

The whole world has been affected by a dramatically increasing prevalence of diabetes. Today, the etiology of both type 1 and type 2 diabetes is thought to revolve around the dysfunction of β-cells, the insulin producing cells of the body. Within the pharmaceutical industry, the evaluation of new drugs for diabetes treatment is mostly done using cell lines or rodent islets and depends solely on the assessment of static insulin secretion. However, the use of cell lines or rodent islets is limiting lack of similarity of the human islet cells, leading to a constrain of the predictive value regarding the clinical potential of newly developed drugs. To overcome this issue, we developed an Engineered Micro-Pancreas as a unique platform for drug discovery. The Engineered Micro Pancreas is composed of (i) an organ-derived micro-scaffold, specifically a decellularized porcine lung-derived micro-scaffold and (ii) cadaveric islets seeded thereon. The Engineered Micro Pancreas remained viable and maintained insulin secretion in vitro for up to three months. The quantities of insulin were comparable to those secreted by freshly isolated human islets and therefore hold the potential for real-time and metabolic physiology mimicking drug screening.

The insulinotrophic effect of insulin-like peptide 5 in vitro and in vivo

We report that INSL5 increases glucose-dependent insulin secretion in vitro and in vivo, and the intestinal L-cell line GLUTag expresses RXFP4 and responds to INSL5 stimulation by secreting GLP-1.