Induced Pluripotent Stem Cell Therapy for Human Diseases: Are We There Yet?

Recently, Yamanaka and others have developed methods to retrodifferentiate adult somatic cells into induced pluripotent stem (iPS) cells using a combination of transcription factors. These iPS cells, which exhibit embryonic cell‐like characteristics, can be reprogrammed to become differentiated cells that can bear a variety of cellular functions. The generation of iPS cells has revolutionized the field of regeneration of medicine. There is a variety of technologies that have been used to produce iPS cells. Clinical applications of these cells in patients are still infancy and many hurdles related to safety must be overcome. Here we focus on our studies of efficacy of iPS –based therapy for hemophilia A and diabetes on animal models. We showed that iPS cells could be produced from C57BL6 mice without hemophilia or diabetes using the factors Oct 4, Sox2 and KLF4 to retro‐differentiate skin fibroblasts. The resulting iPS cells, when cultured under selective growth conditions, formed 1) endothelial cells and endothelial cell precursors; 2) islet cell clusters that were able to release insulin in response to glucose stimulations. Endothelial precursors produced from iPS cells were injected into the liver of sublethally irradiated male mice with an exon 16 deletion within the FVIII gene. After a week, the hemophilia mice were subjected to a tail clip bleeding challenge. All of the non‐engrafted hemophilia mice died within 2–8 hours after the challenge. All five of the engrafted mice survived. The surviving engrafted hemophilia mice had significant FVIII activity. We followed three transplanted mice and their level of FVIII activity was maintained at high levels for one year post engraftment, at levels equal to or exceeding FVIII levels in wild type mice. It is interesting to note that cell engraftment can ameliorate symptoms of Hemophilia A in mice for 1 year, approximately 40% of the average mouse lifespan. Importantly, these mice have not exhibited any evidence of serious illness or evidence of tumor formation during this period although the sample size is very small. For diabetes, we transplanted islet clusters into either type 1 or 2 diabetes mouse models via intra‐portal vein with one dose containing as few as 200,000 iPS derived islet‐like cells, which were sufficient to restore insulin secretion and normalization of glucose levels for at least 20–30% of the life expectancy of mice. While the potential value of transplanting stem cells or tissues derived from iPS cells is high, the potential risks should not be ignored. iPS cell‐based therapies need to be systemically evaluated in pre‐ clinical large animal models or non‐human primates before they can be applied to human subjects.