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A genetically modified stem cell colony with a dual safety mechanism to control tumor formation and differentiation into undesirable cell types. The cells are stained for the SOX2 (green) and TRA-1-60-R (red) stem cell markers. A nuclear marker is indicated in blue. Image Credit: The Diabetes Research Institute
Researchers have developed methods for generating insulin-producing beta cells from pluripotent stem cells (PSCs) for the clinical treatment of type 1 diabetes (T1D). However, transplantation of these immature cells into patients presents substantial risks, namely the development of tumors (teratomas) and the growth of these stem cells into unwanted cell types. Pluripotent stem cells are known to develop in all cells and tissues of the body.
Today, for the first time, scientists at the Diabetes Research Institute (DRI) of the Miller School of Medicine at the University of Miami have developed a human pluripotent stem cell line containing two "suicide genes" Inducing cell death in all hormones except the desired insulin. producing cells. This dual integrated safety approach, published online in Stem Cell Reports on March 5th, addresses the limitations of beta-derived CPS cells and opens the door to creating safe cell replacement therapies for people with T1D.
Guarantees of pending clinical trial warrants
With clinical trials already using BSC-derived beta cell progenitors and new approaches using beta-type functional cells on the horizon, the need to ensure patient safety is of paramount importance. Research has shown that only 30 to 40% of beta cells are obtained by current CSP differentiation (development) protocols, leaving a significant percentage of undefined cells in the balance. More importantly, undifferentiated cells – cells that have not yet developed into a specific type – can produce tumors during transplantation, despite recent improvements in the protocol.
To address these concerns, the DRI team has decided to design pluripotent stem cell lines that selectively destroy cancer cells and non-insulin-producing cells, such as the liver, brain, brain cells, and other cells. muscle cells and others. The team has tested their approach in vitro and in vivo in a mouse model of diabetes mimicking the state of the disease in humans. Their results demonstrated the elimination of all unwanted cells.
"Not only did our strategy prevent the formation of tumors, but we also eliminated them completely when we activated the suicide genes only after the complete growth of the tumors," said Juan Dominguez-Bendala, lead author of the tumor. Study, Director of Research on Cell Development Strains for Translational Research and Associate Professor of Research in Surgery at the Institute of Diabetes Research at the Miller School of Medicine, University of Miami .
No other research method reported to date offers the same degree of security and specificity, as conventional strategies based on suicide genes result in the destruction of the entire graft (transplant) or fail to selectively expand the population. necessary cells.
Stem cells harboring a set of suicide genes have several pathways in front of them: first, they can stop dividing and become any non-beta cell of the body. For example, muscle, blood or bone. A second alternative is to continue to divide and form a tumor (teratoma). The third option is to become insulin-producing beta cells. Thanks to the genetic modification introduced, the first two ways lead to the destruction of any cell that takes them. Only those who "choose" the right path (ie beta cells of the pancreas) survive. Credit: The Institute for Diabetes Research
Although the team has focused on obtaining insulin-producing cells, this strategy, if it is clinically successful, has applications of far-reaching reach beyond of diabetes.
"By modifying a single module of our suicide tapes, we can customize the strategy of each fabric of your choice. Our main interest is in beta cells, but it could also be adapted to select neurons, cardiac or hepatic cells, for example, "explained Dr. Dominguez-Bendala.
In type 1 diabetes, insulin-producing pancreatic cells have been mistakenly destroyed by the immune system, forcing patients to manage their blood glucose levels through daily treatment. DRI scientists have published Islet Transplantation restored natural insulin production in people with type 1 diabetes, but there are not enough cells to treat the millions of patients who can benefit. Addressing the shortage of insulin-producing cells would solve one of the major problems that prevent biological cure of the disease.
Stem cells harboring a set of suicide genes have several pathways in front of them: first, they can stop dividing and become any non-beta cell of the body. For example, muscle, blood or bone. A second alternative is to continue to divide and form a tumor (teratoma). The third option is to become insulin-producing beta cells. Thanks to the genetic modification introduced, the first two ways lead to the destruction of any cell that takes them. Only those who "choose" the right path (ie beta cells of the pancreas) survive.
This article has been republished from documents provided by the Diabetes Research Institute. Note: Content may have changed for length and content. For more information, please contact the cited source.
Reference:
Qadir, M. M., Álvarez-Cubela, S., K. Belle, T., Sapir, F., Messaggio, F., Johnson, K. B.,. . . Domínguez-Bendala, J. (2019). A secure double approach to prevent tumorigenesis and select β-cells from the pancreas from human embryonic stem cells. Stem Cell Reports. doi: 10.1016 / j.stemcr.2019.01.012
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