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Stem cells and diabetes

Self-renewing stem cells show potential in combating diabetes

Stem cells could potentially be used to replace the defunct pancreatic beta cells of diabetic patients, restoring their insulin production and glucose-regulating capabilities

Stem cells could help turn the tide against diabetes, but more research is needed to better control their differentiation and insulin-producing properties, according to investigators from A*STAR's Institute of Molecular and Cell Biology (IMCB), Singapore. Led by Dr Adrian Teo, a Principal Investigator at A*STAR, the research team have proposed that by harnessing the power of stem cells to self-renew and can be differentiated into a variety of cell types, including pancreatic beta cells.

Therefore, stem cells could potentially be used to replace the defunct pancreatic beta cells of diabetic patients, restoring their insulin production and glucose-regulating capabilities. The study, ‘HNF4A Haploinsufficiency in MODY1 Abrogates Liver and Pancreas Differentiation from Patient-Derived Induced Pluripotent Stem Cells’, was published in iScience.

Dr Adrian Teo

"Over time, however, pancreatic beta cell failure and beta cell death is a common denominator for all types of diabetes," said Teo, adding that while obesity is a major contributing factor to diabetes in the West, the main contributing factor in Asia is generally pancreatic beta cell failure. "Although current diabetes medication can help to control blood glucose levels for extended periods of time, they do not cure or even improve pancreatic beta cell health."

Rather than rely on embryos as a source of stem cells, Teo envisions obtaining blood cells and fibroblasts - a type of cell in the skin - from diabetic patients, then reprogramming them into human induced pluripotent stem cells (hiPSCs). Subsequently, gene editing may be carried out to correct diabetes-associated mutations or gene variants in these hiPSCs before they are differentiated into pancreatic beta cells and transplanted back into the patient.

"This method potentially allows for the creation of a near-unlimited supply of pancreatic beta cells for cell replacement therapy," explained Blaise Su Jun Low, a final year PhD student in Teo's lab. "Because patients will be transplanted with their own cells, graft rejection is less likely to occur."

Beyond cell replacement therapy, hiPSCs can also help shed light on the underlying molecular mechanisms of diabetes. For example, Teo's research group uses hiPSCs from patients diagnosed with maturity-onset diabetes of the young (MODY) - a subtype of monogenic diabetes - to understand how certain gene networks control pancreas and liver development. Both organs are crucial for normal glucose metabolism.

The broad experimental setup is as follows: first, the researchers induce hiPSCs from MODY patients to differentiate into foregut endoderm and human pancreatic precursors - the parts of human embryos that eventually give rise to the pancreas and liver, and then to pancreatic beta-like cells. The team then compared the gene expression pattern of MODY hiPSC-derived foregut endoderm, pancreatic precursors and beta-like cells to that of normal individuals.

With this approach, Teo's team discovered that mutations in a gene called HNF4A result in reduced overall expression of genes specifying pancreas and liver development in MODY 1 patients. Importantly, Teo noted that this discovery would not have been possible using mouse models, since mice with one mutant copy of HNF4A do not develop diabetes, unlike the situation in humans.

"Currently, there are more than 14 forms of MODY, each caused by mutations in a different gene (e.g. HNF4A, HNF1A, PAX4 and INS)," Teo explained. "Interestingly, gene variants found in many of these MODY genes are associated with T2D, the most common form of diabetes that affects approximately 90 percent of the diabetic population."

The findings from MODY patients may therefore be relevant to the pathophysiology of T2D as well, Teo added.

Furthermore, by using hiPSCs as a platform for genetic screens, researchers may be able to better stratify patients into different treatment groups. At the same time, novel drug targets may be identified based on such screening methods. This brings the ideal of precision medicine for diabetes closer to reality, no longer will a one-size-fits-all solution be applied to all patients, but medicines will be prescribed based on underlying genetic defects that are unique to each diabetic person.

The use of hiPSCs in genetic screening and drug discovery for diabetes is already underway in many laboratories around the world. On the other hand, therapy involving hiPSC replacement of dysfunctional pancreatic beta cells still has some way to go before it can be approved for use in the clinics.

Low cautioned that protocols for differentiating hiPSCs into pancreatic beta cells are not yet 100 percent efficient, and some residual pluripotent cells may still lurk among differentiated pancreatic beta cells. If these pluripotent cells are also transplanted along with the pancreatic beta cells, they could result in a teratoma - a tumour that could lead to life-threatening complications, she said.

The precise function of hiPSC-derived pancreatic beta cells has yet to be fully verified, Teo continued. "They need to function just like bona fide human pancreatic beta cells or islets," he warned. "Otherwise the glucose levels of the individual will not be properly regulated, posing health risks."

Yet another concern lies with the safety of gene-editing technologies such as the popular CRISPR/Cas 9 system when correcting diabetes-associated gene mutations. Unless undesirable or unexpected off-target consequences of CRISPR-mediated genome editing can be ruled out, the use of gene-edited hiPSCs for cell replacement therapy will likely remain limited, said Teo. In spite of these challenges, Teo's group remains optimistic and undeterred.

"For hiPSC-based cell therapy without any genome editing, there are currently a few clinical trials ongoing to evaluate the ability of these hiPSCs to mature into pancreatic beta cells and regulate blood glucose levels," he said. "Our lab and many others in the world are now working on optimising the pancreatic differentiation protocol to eliminate residual hiPSCs and improve the functionality of hiPSC-derived pancreatic beta cells such that they behave similarly to bona fide insulin-secreting cells in the islets of the human pancreas."

In fighting the good fight against diabetes, Teo underscored the importance of close collaboration between the lab and clinic. "We believe that partnerships with clinicians and pancreas transplant surgeons are a win-win model that can help us translate our scientific efforts toward eventual therapeutic value for our patients and society," he concluded.

To access this paper, please click here

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