Novel ways to increase SC-beta cell’s survivability and functioning via genetic manipulation

New advancements in the transplantation of stem cell-derived insulin-producing beta cells (SC-beta cells) to cure type 1 diabetes (T1D) have created substantial curiosity and anticipation. A key obstacle to the functioning and long-term survival of SC-beta cells is their susceptibility to pressure or attacks from the immune system, finally resulting in malfunction or death of the cells.

Novel ways to increase SC-beta cell’s survivability and functioning via genetic manipulation
The image shows stem cell-derived islets clusters (SC-islets), and the research team used these cell clusters in the study. The green is the transcription factor NKX6.1, red is C-peptide, and blue is the nucleus (DAPI). Image Credit: Courtesy of The Foundry.

A recent study published in the journal Stem Cell Reports has found novel methods to likely increase the survivability of SC-beta cells via genetic manipulation of the cells.

In response to food consumption, glucose (sugar) levels increase in the blood. They are controlled by the hormone insulin—secreted by a certain type of cell present in the pancreas—the beta-cell. Beta-cells secrete insulin in response to glucose, which thereby reduces blood glucose levels.

The blood glucose levels increase beyond normal levels, thereby resulting in diabetes when beta-cells are damaged or dysfunctional. In patients having type 1 diabetes (T1D), beta cells are targeted and damaged by the immune system of a patient.

T1D patients rely on insulin injections every day, yet it is challenging to control glucose levels. Diabetic patients can go through high fluctuations of low or high blood glucose levels, resulting in possible organ failure, shorter lifespan, and, in certain cases, severely life-threatening conditions.

A substitute to frequent insulin injections is a form of transplantation of beta cells, acquired from organ donors who are no more, or, nowadays, retrieved from stem cells. After transplantation, SC-beta cell life and functioning mainly rely on their resistance to the immune response of the body and/or a noxious milieu present at the transplantation site.

On top of it, beta cells under stress are considered to be more vulnerable to immune cell attack, so eliminating SC-beta cell stress might be essential in the T1D context.

Nayara Leite, Douglas Melton, and co-workers from the Harvard Stem Cell Institute have searched for means to increase SC-beta cell stress resistance and survival. With genetic tools, the researchers particularly reduced the amounts of four mediators of stress vulnerability and immune cell detection in SC-beta cells.

Consequently, the programmed cells were more resistant towards stress from inflammatory molecules or high glucose, and less vulnerable to get attacked by immune cells, with an overall enhanced life expectancy in laboratory-based experiments.

Future work is required to address if genetic modification of SC-beta cells can safeguard transplanted cells against immune cell attack or other stressors permanently, resulting in greater survival and functioning, without negatively impacting their job or safety profile.

Source:
Journal reference:

Leite, N. C., et al. (2022) Genetic manipulation of stress pathways can protect stem-cell-derived islets from apoptosis in vitro. Stem Cell Reports. doi.org/10.1016/j.stemcr.2022.01.018

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