Silencing ALDH3B2 shifts pancreatic duct cells toward insulin production
A Harvard team screened more than 19,000 genes and identified ALDH3B2 as a brake on the identity of human pancreatic duct cells. Silencing it shifted some cells toward an insulin-producing beta-like state, and transplanted cells lowered blood glucose in diabetic mice for six weeks. Insulin output remained below that of natural beta cells, however, and the study did not test a treatment in people.
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The gene screen found a brake on cell identity
Researchers at Harvard Medical School and Joslin Diabetes Center searched for genes that keep pancreatic duct cells from becoming beta cells. A CRISPR screen that disabled more than 19,000 genes one by one in an immortalised human duct-cell line identified ALDH3B2 as the strongest candidate. When the gene was silenced, activity in genes defining duct cells fell, while beta-cell genes involved in producing and processing insulin switched on. Medical Xpress and GEN report the same peer-reviewed Science Translational Medicine study and the change in cell identity initiated by loss of ALDH3B2.[1], [2]
Converted cells secreted insulin in diabetic mice
The researchers also silenced ALDH3B2 in primary human pancreatic duct cells. The cells developed insulin-containing granules and released human insulin when glucose rose. After transplantation into diabetic, immune-deficient mice, they lowered blood glucose to near-normal levels for six weeks. The conversion was not direct: cells first moved through a temporary state resembling immature pancreatic progenitor cells and then toward a beta-like state. The result showed that duct cells could be redirected under laboratory conditions and perform a measurable function after transplantation.[1], [2]
Beta-like cells remained short of natural beta cells
Glucose-stimulated insulin output from the converted cells remained far below the level made by natural human beta cells. The cell population was also heterogeneous, with some cells retaining features of both duct and beta cells. The mouse blood-glucose finding does not mean that a safe or effective treatment has been found for people. The researchers say they still need to determine how ALDH3B2 restricts cell plasticity before conversion efficiency and maturation can improve. The enzyme may be a target that drugs can inhibit, but that approach has not been tested in patients.[1], [2]
