Stem cell therapies have been studied for many years by biologists, as their therapeutic potential for various diseases is great. This is especially the case with diabetes, where the differentiation of stem cells into insulin-secreting pancreatic beta cells could help stabilize or even reverse the disease. Recently, a team of researchers made a new breakthrough in the field: pluripotent stem cells differentiated into pancreatic beta cells made it possible to quickly cure mice suffering from diabetes. Although the results are not yet applicable to humans, they remain extremely promising.
In a study, researchers figured out a new way to coax human pluripotent stem cells (hPSCs) into pancreatic beta cells that make insulin. When these insulin-producing cells were transplanted into mice induced to have an acute form of diabetes, their condition was rapidly cured.
“These mice had very severe diabetes with blood sugar readings of more than 500 milligrams per deciliter of blood — levels that could be fatal for a person — and when we gave the mice the insulin-secreting cells, within two weeks their blood glucose levels had returned to normal and stayed that way for many months,” said principal investigator Jeffrey R. Millman, PhD, an assistant professor of medicine and of biomedical engineering at Washington University.
Transform pluripotent stem cells into pancreatic beta cells
Pluripotent stem cells are essentially blank, undifferentiated cells with the ability to grow into other kinds of cells that exist all throughout the body. Harnessing that potential, in the diabetic context, means researchers could devise ways of tweaking stem cells to become the insulin-producing cells that diabetics lack, helping them to control high blood sugar and stay healthy. |
| Protocol for differentiating pluripotent stem cells into pancreatic beta cells used by researchers. Credits: Nathaniel J. Hogrebe et al. 2020 |
Scientists have been investigating how to do this for years, reporting a number of incremental successes in animal models as our understanding of the processes behind stem cell manipulation increases.
Millman's lab has been busy too. In 2016, they devised a way to produce insulin-secreting cells – derived from patients with type 1 diabetes – that functioned in response to glucose. A few years later, they learned how to augment the level of insulin secretion in stem-cell-derived pancreatic beta cells.
Better master the differentiation of pluripotent stem cells
Now, the researchers have shown a new technique they developed can more efficiently convert human stem cells into insulin-producing cells that more effectively control blood sugar.“A common problem when you’re trying to transform a human stem cell into an insulin-producing beta cell — or a neuron or a heart cell —is that you also produce other cells that you don’t want,” Millman said. “In the case of beta cells, we might get other types of pancreas cells or liver cells.”
Off-target pancreas and liver cells don’t hurt anything when implanted into a mouse, but they don’t fight diabetes either.
However, a new technique now looks like it can keep cell differentiation on target. In the new study, the team found that transcription factors that drive stem cells towards becoming pancreatic cells are linked to the state of the cell's cytoskeleton, a support structure inside cells that acts as a kind of skeleton, made up of microfilaments of various protein fibres.
Actin: it plays a key role in cell differentiation
One of these proteins is called actin, which plays an important role in cellular function, and, it turns out, cell differentiation as well."We found that manipulating cell–biomaterial interactions and the state of the actin cytoskeleton altered the timing of endocrine transcription factor expression and the ability of pancreatic progenitors to differentiate into stem-cell-derived beta cells," the authors explain in their paper.
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| Actin, a cytoskeleton protein, plays a key role in cell differentiation. It is present in two forms: as an actin monomer (actin G, high) and as an actin filament (actin F, low). Credit: Thomas Splettstoesser |
"We were able to make more beta cells, and those cells functioned better in the mice, some of which remained cured for more than a year," Millman explains; control animals, who were not given the cell transplants, ended up dying, such was the severity of their induced diabetes.
That's not all. The same cytoskeletal manipulations also showed potential to better control the differentiation of other kinds of cells, including liver, oesophagus, stomach, and intestine cells, the researchers say. If so, the technique might enhance stem cell treatments for other kinds of pathologies, not just diabetes.
He explained that there still is much to do before this strategy can be used to treat people with diabetes. They will need to test the cells over longer periods of time in larger animal models and work to automate the process to have any hope of producing beta cells that can help the millions of people who currently require insulin injections to control their diabetes. But the research is continuing.
| Bibliography: Targeting the cytoskeleton to direct pancreatic differentiation of human pluripotent stem cells. Hogrebe NJ, Augsornworawat P, Maxwell KG, Velazco-Cruz L, Millman JR Nature Biotechnology https://doi.org/10.1038/s41587-020-0430-6 |
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