Converted Human Pancreatic Duct Cells Show Diabetes Therapy Potential

A research study from Harvard Medical School has revealed that a malfunction in the aldehyde dehydrogenase family 3 member B2 (ALDH3B2) gene can transform human pancreatic duct cells into functional β-like cells. These β-like cells are capable of secreting insulin in response to glucose and can help lower blood glucose levels when transplanted into diabetic mice.

Led by Peng Yi, PhD, an investigator at Joslin Diabetes Center and assistant professor of medicine at Harvard Medical School, the research team suggests that targeting ALDH3B2 in human pancreatic duct cells could potentially replenish β-cell mass for effective diabetes therapy. The findings were published in Science Translational Medicine in a paper titled “Loss of function of ALDH3B2 transdifferentiates human pancreatic duct cells into β-like cells.”

Diabetes is characterized by a deficiency in pancreatic β cells, regardless of the underlying cause. Restoring a functional β cell population is essential for controlling and potentially curing diabetes. Although pancreatic duct cells have been shown to transdifferentiate into β-like cells, the exact process and its mechanisms remain unclear.

To investigate this, Li and colleagues employed a genome-wide CRISPR screening approach to identify genes involved in the transdifferentiation of human pancreatic duct cells into β cells. The study discovered that the loss of function in the ALDH3B2 gene was sufficient to convert both cell line-based and human pancreatic duct cells into functional β-like cells. This loss of function promoted insulin promoter activation and shifted gene expression toward a more β-cell-like profile.

Furthermore, the transdifferentiated cells exhibited substantially increased expression of β-cell marker genes, insulin secretion in response to glucose, and lowered blood glucose levels to near normal for six weeks post-transplantation into diabetic mice. However, the glucose-stimulated insulin production was lower compared to natural human β cells, indicating that loss of function in other genes beyond ALDH3B2 might be necessary for complete transdifferentiation.

Further research is required to identify the exact mechanism by which ALDH3B2 limits duct cell plasticity and to improve conversion efficiency, promote maturation, and advance this therapeutic strategy. Despite the limitations, the study identifies a gene that holds potential for targeting human pancreatic duct cells to replenish β-cell mass, thereby offering a promising avenue for diabetes therapy.