Potential Medical Applications Of Ips Cells Biology Essay


The use of stem cells for medical applications has been major goal and the source of considerable excitement for many years. Pluripotent stem cells offer the greatest potential, due to their ability to differentiate into any cell types; and have therefore been pursued extensively (1). The first pluripotent stem cells discovered were Embryonic stem (ES) cells, in 1999, which was a major breakthrough offering great hope for therapeutic applications of stem cells (2). ES cells have been differentiated into a number of different types of cells and animal models have demonstrated therapeutic benefits (3, 4). However the drive for cell transplantation studies in humans is fraught with political and legal opposition stemming from ethical concerns surrounding the use of human embryos, as well as practical issues such as shortage of available oocytes, and immune rejection of transplanted cells (2, 5).

In 2006, Takahashi and Yamanka genetically reprogrammed somatic cells to become pluripotent cells through exogenous expression of key transcription factors (1, 6, 7); a feat that won Yamanka the Nobel Prize for medicine and physiology in 2012. This major breakthrough heralded the possibility of applying pluripotent stem cells (using iPS) cells to disease profiling and cell replacement therapy without the moral and practical barriers that ES cells present (1). From a practical perspective the supply of somatic cells that can be used to produce iPS cells is almost limitless compared to oocytes necessary for ES cell productions, while patient-specific iPSs used in cell transplantation will be prevent risk of immunorejection (1). Moreover iPS cell do not carry the moral objection against destruction of embryos, associated with ES cells.

Following the initial discovery, research groups rapidly derived iPS cells from a number of different diseases that could be employed for disease profiling and pathogenesis and drug assessment, while others performed cell replacement therapy in animal models (5, 8, 9). Different processes for cell reprogramming were also investigated, with gene transfer being achieved using viral vectors, non viral plasmids and recombinant protein delivery, using six possible transcription factors: Oct4, Sox2 c-Myc, Klf4, Nanog, Lin28 (see fig. 1. (1)). The evolution of methods used is important if the ultimate goal of clinical application of these cells is to be achieved. Importantly, the use of viral vectors for genomic integration, as well as the use of oncogenic transcription factors such as c-Myc, should be avoided to reduce risk of tumorigenesis in vivo (1, 10, 11).

IPS cells are shown to resemble ES cells in terms of morphology (see fig. 2 (7)), expression of pluripotent cell genes such as OCT4 and NANOG, telomerase and mitotic activity, as well as ability to form teratomas; the gold standard for assessing pluripotency (2, 12). However despite functional similarities, on genetic analysis some studies have revealed some subtle differences between the two cell types, for example gene expression profiles, as revealed by Chin et al (2, 13). Nonetheless iPS cell are still regarded as a viable alternative to ES cells as a source of pluripotent cells. Medical application of these stem cells encompasses three main areas disease modelling, predictive drug effects and toxicology, and cell replacement therapy. This review will describe the most significant studies performed in each of these areas in this rapidly moving field, as well as indicating current limitations.

Disease modelling and drug effects

While direct clinical applications of iPSs require a significant amount of work before it may be fully implemented, disease modelling provides an immediate and useful function. This innovative notion involves extracting cells from a patient with a known disease and inducing them into iPS cells and therefore they have the capacity to renew indefinitely in a laboratory and to form any cell of the body. For example to investigate a patient with a suspected genetic heart defect, a patient’s fibroblast could be obtained, induced into iPS cells and differentiated into cardiocytes for investigation of the abnormality present and test drug effects on this (see left side of fig 3.). These cells are not only disease specific but patient specific with the possibility of identifying exact abnormalities and testing drug effects shape individualised treatment. Such individualised treatment would have the greatest impact on complex, sporadic or rare genetic diseases.

Park et al, only two years after the discovery of iPS cellss demonstrated the potential of this technology with the derivation of iPSs from 10 different diseases including Down’s syndrome and Parkinson’s disease (8). Ebert et al (2009), conducted the first study into disease modelling, and used using iPS cells derived from patients with spinal muscular atropy (SMA), an inherited neurological condition. Using the knowledge that this disorder causes loss of lower motor neurones, the derived iPS cells were differentiated in motor neurones in vitro, and exhibited selective deficits after 8 weeks in culture, when compared with unaffected family members (14). This established how disease mechanisms could be observed using this model however it did not evaluate the effect of novel therapies or drugs.

Lee et al (2009) went further and showed the potential of modelling disease and testing therapy by creating iPS cells from patients with familial dysautonomia (FD) (15). FD is a terminal peripheral neuropathy caused by a single point mutation the IKBKAP gene and manifests as dysfunction and extensive deficit in autonomic and sensory nervous systems (7, 15, 16). The derived iPS cells were differentiated in central and peripheral neurone precursors, and three FD specific phenotypes were found including neural crest precursors expressing very low levels of non-mutated IKBKAP (15). While this verified the benefit of iPS cells for modelling pathogenesis the study went on to show that the abnormal phenotypes were moderately improved by a plant hormone, kinetin, thus illustrating the potential of drug testing (7, 15).

Predictive drug effects and toxicology

Cell replacement therapy