Cellular Alchemy
Insulin-producing cells can be obtained from intestinal cells
LifeSciencesToday based on Penn Medicine –
Cellular Alchemy: Penn Study Shows How to Make Insulin-Producing Cells from Gut CellsThe death of insulin-producing beta cells of the pancreas is the basis of type 1 and type 2 diabetes.
"We are looking for ways to get new beta cells for these patients to one day replace their daily insulin injections," says study leader Ben Stanger, MD, PhD, associate professor of medicine at the Department of Gastroenterology at the Perelman School of Medicine at the University of Pennsylvania.).
One of the approaches to the treatment of this disease is the transplantation of islet cells to patients with severe type 1 diabetes to restore normal blood sugar levels. Another area of research is the use of stem cells to produce beta cells from them. However, both of these strategies have limitations: islet cells are in short supply, and stem cell-based approaches still have a long way to go before they can be used in the clinic.
"Using the right combination of transcription factors to transform any cell into any other type of cell is a powerful idea. This is cellular alchemy," Dr. Stanger comments.
A new study by Dr. Stanger and postdoctoral fellow Yi-Ju Chen, PhD, published in the journal Cell Reports (De Novo Formation of Insulin-Producing "Neo-beta Cell Islets" from Intestinal Crypts), proves that the introduction of three proteins regulating the activity of genes - the so–called transcription factors – in immune-deficient mice, it transforms a specific group of cells of the intestinal mucosa into cells close to insulin-producing beta cells. This work opens up prospects for the use of differentiated pancreatic cells as a source of new beta cells.
In 2008, the laboratory of Dr. Stanger's supervisor introduced three factors responsible for reprogramming into beta cells - Pdx1(P), MafA(M), and Ngn3(N) – together called PMN – into the acinar cells of the pancreas. This manipulation led to the appearance of some structural and physiological features of beta cells in acinar cells.
Insulin-expressing cells (red) appearing among mouse intestinal crypt cells (green),
received three reprogramming factors into beta cells.
(Photo: Ben Stanger, MD, PhD, Perelman School of Medicine)
Based on the results of this study, Stanger's group set out to determine which other cell types, if any, could be reprogrammed into beta cells.
"We expressed PMN in a number of tissues in one- to two–month-old mice," says Dr. Stanger. "After three days, the mice died of hypoglycemia."
The researchers realized that some of the mouse cells (non-acinar) produced too much additional insulin, in fact, a lethal amount of it.
After tracking down what type of cell it was, "we saw the temporary expression of these three factors in the cells of the intestinal crypts near the pancreas," explains Dr. Stanger.
Scientists have called these beta-like transformed cells "neo-ostrovkovye". The neostructured cells expressed insulin and demonstrated the structural features of beta cells. In addition, they reacted to glucose: under its influence, they secreted insulin, and also eliminated hyperglycemia in diabetic mice.
The researchers figured out how to turn on these factors only in the cells of the intestinal crypts in order to prevent the side effect of the deadly hypoglycemia that killed mice.
Moreover, PMN expression in human intestinal "organoids" – miniature intestinal structural units that can be grown in culture – also transforms intestinal epithelial cells into beta-like cells.
The interconversion of terminally differentiated cells can serve as a powerful tool for the treatment of degenerative diseases, including diabetes, based on cell therapy. To determine which, if any, adult tissues are capable of activating the islet beta cell program, scientists conducted in vivo screening of a wide range of tissues by expressing three factors of reprogramming into beta cells in them. They found that the temporary expression of these factors – Pdx1, MafA and Ngn3 (PMN) – in the intestine contributes to the rapid conversion of intestinal crypt cells into endocrine cells, which merge into "neostructures" below the base of the crypts. Neoostrovkov cells express insulin and demonstrate ultrastructural features of beta cells. It is important to note that intestinal neostrovki respond to glucose and are able to reduce hyperglycemia in diabetic mice. In addition, PMN expression in human intestinal "organoids" stimulates the transformation of intestinal epithelial cells into beta-like cells. Thus, these results demonstrate that the intestine is an accessible and abundant source of functional insulin-producing cells. (Fig. Cell Reports)"Our results show that the intestine can be an affordable and rich source of functional insulin-producing cells," says Dr. Stanger.
"Our ultimate goal is to obtain epithelial cells of diabetic patients who underwent endoscopy, multiply these cells, inject PMN into them to transform them into beta–like cells, and then return them to the patient as replacement therapy. To make this possible, there is a long way to go: it is necessary, among other things, to improve the functional properties of these cells so that they resemble beta cells more, and to find alternative ways to transform intestinal cells into beta-like cells without gene therapy."
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