Towards Diabetes Treatment with Stem Cell-Generated Beta Cells

In the highly respected journal Nature Biotechnology, a recently published article describes recent advances towards cell therapy treatment for type 1 diabetes.  A Swedish-Finnish collaboration between Uppsala and Helsinki University has produced the most well-developed insulin-producing beta cells from stem cells so far. Anders Tengholm is a Professor at the Department of Medical Cell Biology who, together with Professor Sebastian Barg, has overseen the Swedish contribution to the study.

“This article is the result of a long and extensive collaboration with many participants. During five or six years, we have gone from producing rather poorly functioning cells to ones that work astonishingly well – they have just as good insulin secretion as cells from human organ donors. We have seen a fantastic development,” says Anders Tengholm.

Beta cells are located together with other cell types in micro-organs known as islets of Langerhans. Today, transplantations of islets are performed on a few patients with particularly severe diabetes. However, a limiting factor is the shortage of organ donors. Furthermore, islets of Langerhans foreign to the body are often rejected by the patient’s immune system, causing the treatment to fail. This is where stem cell-generated beta cells may come to play an important role; scaling up the laboratory production would provide an unlimited source of cells for transplantation and, by using the patients’ own cells as starting material, the problems with rejection of foreign tissue can be avoided.

“In the future, one can imagine being able to take a skin cell from the diabetes patient, convert it to a stem cell, and make the stem cell into beta cells and islets that may be transplanted back into the patient. The maturation of beta cells from stem cells is a complex procedure that takes a couple of months. At defined time points, the content of the cell culture medium is changed. It can for example be the addition or removal of factors stimulating or inhibiting cell growth. As the concept has existed for quite some time, the new advancements stem from minor but significant modifications of the protocol. We have mainly altered the last steps of the procedure and prolonged the cultivation process in presence of new factors,” says Anders Tengholm.

More knowledge about the function of cells

Production of cells have taken place in Helsinki. The Finnish colleagues have also studied, for example, the gene expression and metabolism of the cells. In the meantime, a similar cell production has been established in Uppsala by Professor Per-Ola Carlsson and Docent Joey Lau Börjesson, who are both co-authors of the article. Anders Tengholm and Sebastian Barg have focused on characterizing the function of the new cells.

(Image removed) Anders Tengholm is a Medical Doctor, Professor of Medical cell Biology and part of the Uppsala Diabetes Centre researcher network.

“Uppsala University is strong in physiology, which deals with the function of cells and organs. The functional characterization performed in this study is the most complete and extensive investigation of stem cell-derived beta cells performed so far. We have primarily studied how the cells react to stimulation with glucose and the most important steps that make them release insulin. My group has used advanced microscopy methods to investigate changes of the levels of certain messenger substances needed for insulin to be released and compared to human cells. Sebastian Barg has examined ion channels and electrical currents – just like nerve cells, beta cells signal through electrical impulses. Furthermore, he has studied the actual insulin release process by imaging the small membrane vesicles in the cells that contain insulin,” says Anders Tengholm.

In the future, the experimental environment itself may have use for stem cell-generated beta cells, as these cells are easier to modify genetically than donated cells. While researchers hope that the new cells will be useful as tools for other studies, they deviate somewhat from their bodily counterparts.

“In many aspects, they are much alike, but we also observe differences in some central steps. The new cells generate energy from glucose in a way that differs from native beta cells. In fact, it is difficult to understand how the cells can release insulin so effectively when some steps in the process appear underdeveloped. While the cells are not yet truly ideal as experimental tools, we can still learn from the differences and potentially discover mechanisms that previously have been overlooked,” says Anders Tengholm.

A Step in the Right Direction

So far, the cells have worked well after transplantation to experimental animals. However, for transplant treatments with stem cell-generated beta cells to be a viable alternative for humans, several questions and challenges remain. First and foremost, the cells must be safe for use. For example, if immature cells remain in the islets, they could give rise to tumours or produce too much insulin. Researchers also do not know whether the disease will reoccur post treatment – type 1 diabetes is considered to be the result of an auto-immune process, so the immune system could potentially also attack the new cells.

“Accordingly, many years of work remains before it will be possible to treat patients. The collaboration continues both with the Finnish researchers and the Uppsala colleagues. It seems as if the stem cell-derived beta cells develop further after transplantation into mice, and this is important to investigate. We are also eager to study the neighbours of the beta cells within the islets. There is an intricate interplay between the different cell types, which is important for the normal function of islets. We know very little about these interactions in islets that are stem cell-derived. Even if we still have a long road ahead of us, the recently published study inspires hope for a possible future treatment of diabetes with cell therapy.”

Anton Nyström

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