A classical example of the pluripotent stem cell is embryonic stem (ES) cells found in the inner cell mass of the developing embryo. These cells are capable of multi-lineage differentiation to produce any cell type in the body, and are thus considered not only as an ideal medical tool for tissue regeneration and organ replacement, but also a great research tool to understand molecular basis of genetic disorders. But the ethical issues with the use of human ES cells for research or medical purposes have lead the Bush administration to ban such use, holding back research in this field.
In search for alternative sources of pluripotent stem cells, exasperated researchers began to explore ways to reprogram differentiated somatic cells into the much needed pluripotent stem cells.
Evidence that somatic cells could be reprogrammed into pluripotent stem cells came from initial studies in the 1960s, revealing that reprogramming can be achieved by transferring the nucleus of a pluripotent stem cell into a somatic cell, albeit at a low success rate. This is because the nuclear transfer has erased the key epigenetic program crucial for establishing pluripotency. A breakthrough came in the 1980s with the emergence of cell fusion technology, where reprogramming was achieved at high efficiency by fusing ES cells with somatic cells, without erasing the pluripotent epigenetic program. While the fused cells provide an ideal tool for scientists to understand the molecular basis for pluripotency, the resulting heterokaryons created from the cell fusion are not usable for clinical and disease modelling applications.
Since ethical issues have stalled ES cell research to a frustrating standstill, scientists are beginning to turn to somatic cell reprogramming as an alternative source of pluripotent stem cells suitable for disease modeling and clinical purposes. Using molecular data from insightful cell fusion studies in the past, Yamanaka and colleagues from Kyoto University in 2006 discovered that somatic cells could be reprogrammed into pluripotent stem cells simply by overexpressing the four pluripotency transcription factors OCT4, SOX2, Klf4, Myc, which was soon dubbed the Yamanaka factors. The resulting induced pluripotent stem cells (or IPS cells) generated much excitement in the field at the time, particularly with preliminary studies demonstrating the remarkable similarities between IPS cells and ES cells (Takahashi et al., 2006).
Excitement was soon hampered when researchers further investigated whether IPS cells are truly indistinguishable from ES cells. The research opened a can of worms, revealing the IPS cells have distinctive molecular flaws, including epigenetic codes and microRNA profiles, that make them quite different from the classical ES cells (reviewed in Yamanaka&Blau, 2010). A major blow came from a relative recent study revealing the IPS cells carry a key epigenetic flaw that disrupt their differentiation program and ultimately their ability to produce viable embryos (Statfeld et al., 2010).
In light of these flaws, concerns began to emerge in research labs as well as the clinic. On the research front, scientists have begun to use generate IPS cells from somatic tissue of patients suffering from a genetic disorder known as the LEOPARD syndrome, which is characterized with multiple symptoms including cardiac hypertrophy. The IPS cells from these patients were used to generate cardiac cells that display classical hypertrophy phenotype of the disease, which could be used as a relatively inexpensive in vitro disease model suited for drug screens (Carvajal-Vergara et al., 2010). However, the apparent flaws of IPS cells could have serious implications on the validity of the in vitro disease model and their relevance to the actual disease.
In the clinical end of things, the IPS cell flaws have driven many questions with regards to the safety for the application of IPS cells in the clinic. Could IPS cells differentiate to produce normal tissue for transplantation? Or could they produce cancerous cell types that could cause cancer? These questions suggest that IPS cells may pose a threat to one of the golden rules in medicine, which is to “do no harm”. Clearly, better understanding of IPS flaws, and how to get around them in future generations of IPS cells, are much needed for their safe and ethical clinical applications.
So, can we really reprogram somatic cells into pluripotent stem cells? Generally speaking, the answer is yes, provided pluripotent stem cells are simply defined by their ability to undergo multi-lineage differentiation to generate any cell type in the body. However, as research begins to show disturbing differences between ES cells and IPS cells, it is clear that researchers have not yet totally mastered the molecular secrets of pluripotency. In a perfectionist’s point of view (which is what we require for medical applications), the answer to the question is “not quite”.
Takahashi et al (2006). Cell. 126, 663-76.
Yamanaka&Blau (2010). Nature. 465, 704–712
Statfeld et al. (2010) Nature. 465, 175-181.
Carvajal-Vergara et al (2010). Nature. 465, 808–812
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