Induced pluripotent stem cells (iPSCs) have great memories. They can remember whether they started out as a skin fibroblast, a blood cell or a pancreatic beta cell. Following reprogramming, iPSCs retain epigenetic (DNA packaging) signatures typical of their somatic cell type of origin (reviewed in a previous blog post). This phenomenon, known as ‘epigenetic memory,’ results in a differentiation bias along lineages related to an iPSCs cell type of origin, while limiting the potential of an iPSC to differentiate into alternative cell fates. In other words, an iPSC remembers where it came from and will tend towards that state again.
A number of strategies have been shown to reduce the bias resulting from epigenetic memory, but recently, scientists have begun to question whether this bias in iPSC differentiation potential could be beneficial. The answer is yes, and the benefits are two-fold. First, this technology could be used to expand a starting population of cells, which I’ll explain shortly. Secondly, an iPSC can differentiate more efficiency back down its lineage of origin. In fact, recently, a study published in the journal Cell Stem Cell reported an enhancement of pancreatic differentiation by using iPSCs derived from human pancreatic beta cells.
In the study, beta cells obtained from pancreatic islet cultures were reprogrammed and the chromatin structure (DNA packaging) of pancreatic beta cell-derived iPSCs was compared to those of iPSCs derived from other cell sources. The researchers found that iPSCs derived from pancreatic beta cells had a more similar chromatin structure to primary pancreatic beta cells than their non-pancreatic cousins. This epigenetic alteration resulted in more efficient pancreatic differentiation of beta cell-derived iPSCs.
Diabetes is a devastating condition in which pancreatic beta cells are destroyed, resulting in the inability of patients to regulate their own blood sugar levels. Exploiting epigenetic memory of iPSCs could provide a robust source of pancreatic beta cells for transplantation therapy. A number of studies have reported the successful generation of insulin-producing cells from multipotent and pluripotent stem cells in the past, albeit at a low efficiency. Reprogramming pancreatic islet cultures and re-differentiating these cells back into pancreatic cells provides a robust alternative for generating pancreatic cells for transplantation.
Replacing pancreatic beta cells via transplantation is not a new concept. Pancreatic islets were first successfully transplanted into rats in 1972. In 2000, human patients received islet cell transplantation. One of the major obstacles to islet cell transplantation is the availability of donor pancreata. Donor pancreatic beta cells could be reprogrammed into iPSCs, expanded to generate a large amount of starting ‘material’ and then differentiated into pancreatic cells for transplantation, thus decreasing the number of islet donors required for transplantation.
Will transplantation of stem cell-derived pancreatic cells be enough to treat diabetes? Probably not. Diabetes is an autoimmune condition. Although scientists don’t understand the exact mechanism of disease, we do know that a patient’s immune system attacks and destroys their own beta cells. One major drawback to beta cell transplantation is that transplanted cells are exposed to the patient’s autoimmune environment, which destroyed their own beta cells in the first place. A longitudinal study reported that less than 10% of patients who received islet cell transplantation remained insulin independent after five years. However, more recent studies have reported that insulin independence can be improved when islet cell transplantation is combined with the appropriate immunosuppressive drugs.
Regardless of source, transplanted cells need to be protected from the autoimmune environment of diabetic patients. Bioartifical pancreas technology offers a number of protective options for transplanted cells from an autoimmune response. Additionally, porcine islet cell transplantation has shown some promise; however, insulin production was not as robust as transplanted human islet cells.
Although a cure for diabetes has not yet been identified, perhaps advances in iPSC technology can provide some hope for the 346 million people who suffer from diabetes worldwide.
Angela C. H. McDonald
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