Human induced pluripotent stem cells hold promise for diabetes treatment
Diabetes is gradually becoming one of the biggest health challenges in modern times. Since 2017, the World Health Organization has classified diabetes along with cancer, respiratory and cardiovascular diseases as the top four non-communicable diseases to be addressed by global health authorities. A war against diabetes thus started.
Over the past decades, peptide-based diabetes mellitus treatment has led to a revolution in the treatment of diabetes due to their multi-functional properties. The most studied diabetes-related peptides include Amylins peptide, Chromogranin A, Exendins Fragments, Insulin C-Peptides, Insulin-Like Growth Factors (IGF) and more.
Stop the “sugar tide”
Despite manifesting as a simple disease, diabetes actually takes many forms. Type I diabetes occurs because the autoimmune response destroys beta cells - the insulin-producing cells in the pancreas. On the other hand, type 2 diabetes (T2D) occurs because cells no longer respond to insulin. Little known is monogenic diabetes, which is a rare form of diabetes caused by mutations in a single gene. However, over time, islet β-cell failure and β-cell death are a common feature of all types of diabetes.
Diabetic drugs can help patients control blood glucose levels for a long time, but they can't cure or improve the health of pancreatic beta cells. Obesity is the main cause of diabetes in the US, while pancreatic β-cell failure is the main cause of diabetes in Asia. Therefore, some research teams believe that stem cells could be used to fight diabetes. Unlike most cells in the body, stem cells have the ability to self-renew and can differentiate into a variety of cell types, including pancreatic beta cells. Therefore, stem cells may be used to replace dead pancreatic beta cells in patients with diabetes, thereby restoring insulin production and glucose regulation in these patients.
hiPSCs and diabetes
Stem cells can be obtained by first reprogramming blood cells and fibroblasts (a type of cell in the skin) of people with diabetes into human induced pluripotent stem cells (hiPSCs), and then, before these hiPSCs can be differentiated into pancreatic beta cells and transplanted back to the patient, gene editing is performed to correct diabetes-related mutations or gene mutations. This approach potentially allows for an almost unlimited supply of islet beta cells for cell replacement therapy. Since what was transplanted is the patient’s own cells, the possibility of transplant rejection is less likely to occur.
In addition to cell replacement therapy, hiPSCs can help elucidate the underlying molecular mechanisms of diabetes. For example, hiPSCs from patients diagnosed with MODY (maturity-onset diabetes of the young, a subtype of monogenic diabetes) is helpful in understanding how genetic networks control pancreatic and liver development. These two organs are essential for normal glucose metabolism.
In addition, by using hiPSCs as a platform for genetic screening, scientists may be able to better divide patients into different treatment groups. At the same time, it is possible to identify new drug targets based on such screening methods. This will make the ideal of precision medicine for diabetes closer to reality as a one-size-fits-all solution is not suitable for all patients, and should be prescribed based on the inherent genetic defects unique to each patient with diabetes.
Research in the future
The use of hiPSCs in genetic screening and drug discovery for diabetes has been performed in many laboratories around the world. On the other hand, therapies involving the replacement of dysfunctional pancreatic beta cells with hiPSCs still have a long way to go before they are approved for clinical use.
It should be reminded that the protocol to differentiate hiPSCs into pancreatic beta cells is not 100% effective, and some residual pluripotent cells may still be latent in differentiated pancreatic beta cells. Hence, if these pluripotent cells were also transplanted with pancreatic beta cells, they could cause teratoma, a tumor that could lead to life-threatening complications.
The exact function of pancreatic beta cells produced by hiPSCs has not been fully verified. Most importantly, they need to function like real human pancreatic beta cells or islets. Otherwise, individuals' glucose levels will not be properly regulated, leading to health risks. Another concern is the safety of gene editing technologies, such as the popular CRISPR / Cas9 system, in correcting genetic mutations associated with diabetes. Unless bad or unexpected off-target consequences of CRISPR-mediated genome editing can be ruled out, the possibility of using gene-edited hiPSCs for cell replacement therapy may still be limited.
In short, there is a need for close cooperation between laboratories and clinics in the fight against diabetes, so that scientific research can eventually be translated into therapeutic value for patients and society.
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