Pilot 27 – Cirulli

P30 CFRTC – Pilot 27

Derivation of Functional Islet Tissue from CF Patient-derived iPSC

PI: Vincenzo Cirulli, PhD
Associate Professor, Medicine, Metabolism, Endocrinology & Nutrition

Funding Period: 2024 – 2025

Abstract: Cystic fibrosis (CF) arises from mutations in the CFTR gene, causing abnormal fluid secretion in organsli ke the lungs and pancreas. Over 2,000 mutations in CFTR have been identified since 1989, affecting various organs such as the salivary glands, liver, intestine, and reproductive tracts. Cystic fibrosis-related diabetes mellitus (CFRD) is the most common non-pulmonary co-morbidity occurring in CF patients. For a long time, the primary hypothesis proposed to explain CFRD has implicated damage to the insulin-producing b-cells by exocrine enzymes accumulating in the pancreas, and the chronic pancreatitis that results from the impaired anion transport into the proximal ducts that leads to decreased secretion of acidic fluid, precipitation of secreted proteins, and inevitable intraluminal obstruction of the ducts causing progressive pancreatitis, inflammation and damage to the islets. More recently, mounting evidence has been provided in support of the notion that CFTR is expressed in islet cells, and it regulates the secretion of both glucagon and insulin by a-cells and b-cells, respectively.

In this context, although the severity of the β-cells insulin secretory defect may depend on the type of FTR mutation, and the duration of the chronic pancreatitis, in patients requiring total pancreatectomy, the isolation of pancreatic islets and their intraportal auto-transplantation has led to the successful cure of the CF-related diabetes. Yet, total pancreatectomy, required for islet isolation and their auto-transplantation is only performed in the most severe cases of pancreatitis to relieve recurrent abdominal pain severe enough to require opioid treatment, and lower the risk of both pancreatic and gastrointestinal cancer, reported to be higher in CF patients. Hence, identifying alternative source for the production of autologous islet tissue would greatly enhance the population-wide applicability of islet replacement therapies for CFRD patients.

In recent years, significant progress in stem cell (SC) biology has paved the way for new cell therapies applicable to a number of degenerative diseases, including diabetes. Accordingly, a SC-based replacement therapy is emerging as a promising cure for diabetes. Our laboratory at the UW Institute for Stem Cell and Regenerative Medicine (ISCRM) has developed new protocols for the derivation of SC lines and their differentiation into functional islet tissue, from both embryonic SCs and induced pluripotent SC (iPSCs).