Induced pluripotent stem cells (iPSCs), since its discovery in 20061, have been widely recognized as the next revolutionary milestone for stem cell therapies and a compelling substitute for the controversial embryonic stem cells (ESCs) technology. After a decade of effort and diligence, this Nobel Prize winning breakthrough2 might just be the answer to a variety of diseases for which novel solutions are in great demand.
The very first generation of iPSCs, as the name suggested, were produced through a screening of 24 reprogramming factors that were shown to be relevant in inducing and maintaining embryonic stem cell pluripotency. Yamanaka and colleagues employed a retroviral delivery system to transduce these genes into mouse embryonic fibroblasts (MEFs). The designed construct to demonstrate the re-programming effect is composed of an ESC-specific Fbox15 promoter that does not express in normal somatic cells and a β-galactosidase reporter to evaluate the Fbox15 locus expression and activity. Without the candidate factors, the MEFs would be susceptible to the selection pressure of genecitin. However, a modulated combination of the re-programming factors are able to alter the fibroblasts into pluripotent ES-like cells that can survive in genecitin environment.
Figure 1. A schematic representation of the iPSC principle
After multiple rounds of selection, a cocktail of re-programming factors comprising of Oct3/4, Sox2, Klf4, and c-Myc were identified and was hence named OSKM cocktail with their initial letters3. These factors, which have already been shown to take various important roles in embryonic development, are additionally accredited as the magicians that rejuvenate somatic cells into pluripotent cells. Subsequently, this technology has been successfully translated to other somatic cells including lymphocytes, melanocytes, pancreatic β cells, stomach cells and many more.
Comparing to its precedent ESCs, iPSCs has successfully avoided the long-debated ethical issue as ESC generation involves embryo destructions. The very fact the ESCs are from the embryo also significantly limits the application in clinical usages due to the scarce amount of its supply. Additionally, the reproducibility and simplicity of this technique has made the research on this topic easier than ever before.
Possessing the essence of pluripotency, iPSCs could differentiate into multiple cells types such as neurons, heart muscle cells, blood cells and cartilage cells for potential therapeutic applications including regenerative medicine and drug development. Taking into consideration of the clinical trial that was just announced in July 2018 using iPSC to treat Parkinson’s disease, there are in total 3 approved human clinical trials ongoing with this technology and they all take place in Japan. The very first clinical trial was launched in 2014 at the RIKEN Center for Developmental Biology in Kobe, Japan and the study utilized iPSC-derived retinal cells to treat Macular Degeneration5. The trial has been reported to be relatively safe with only one adverse effect in 4 years. The second project approved was earlier this year at the Osaka University and iPSCs were used to generate heart muscle cells for ischemic heart disease. With the natural advantage of indefinite proliferation, iPSCs has always been a hot field in therapeutics development for neural degenerative diseases such as Parkinson’s disease. In the recent launched clinical trial design, dopaminergic progenitors were to be injected into the putamen area of the patients. As shown in the animal study, the injection of the dopaminergic progenitors would differentiate into neurons and produce the neuron transmitter dopamine accordingly that stimulate this specific area known to associate with Parkinson’s disease.
Although iPSC technology is still at cradle stage, there are more than enough reasons to believe that it will led stem cell therapy into a new era.
