Shinya Yamanaka’s first report of induced pluripotent stem cells (iPSCs) challenged what biologists thought they knew about terminal cell differentiation and caused a wave of excitement and hope for regenerative medicine applications. A second wave of excitement is swooping through the field today, as many researchers shift their focus from iPSC reprogramming to cell fate conversion. A number of studies have described the conversion of skin fibroblasts directly to other somatic cell types including neurons, cardiomyocytes and blood progenitor cells (as described in a previous SCN blog post) by forced expression of tissue specific genes.
The concept of converting cell fate by forced expression of transgenes is not entirely new. In the 1980s, a study was published reporting the induction of myotubes (muscle cells) by forced expression of one gene in fibroblasts (described in this review article).
Recently, the field of cell fate conversion has been picking up momentum. Last month at the International Society for Stem Cell Research meeting in Toronto, unpublished reports of cell fate conversion were presented, including the derivation of cardiomyocytes from cardiac fibroblasts as well as the conversion of fibroblasts to motor neurons. The journal Nature has recently published a number of cell fate conversion studies. Caiazzo et al. described the generation of dopaminergic neurons (dopamine-producing neurons) from mouse and human fibroblasts last month. Additionally, Huang et al. and Sekiya and Suzuki reported two strategies for converting mouse fibroblasts directly into hepatocytes in May and June, respectively.
Cell conversion experiments have been carried out in a similar style to Yamanaka’s initial iPSC experiments. Caiazzo et al., Huang et al., and Sekiya and Suzuki each created a candidate list of genes specific to their cell type of interest and screened their lists to identify the minimal set of lineage-inducing genes required for cell fate conversion. Caiazzo et al. found a combination of three genes capable of converting mouse and human fibroblasts into functional dopaminergic neurons. Mouse fibroblast-derived motor neurons possessed a number of characteristic dopaminergic electrophysiological properties and were able to maintain these properties in vivo following transplantation into a mouse model. In addition, dopaminergic neurons were derived from fibroblasts of two Parkinson’s patients, making this the first study to derive disease-specific cells by cell fate conversion.
In May, Huang et al. published the generation of mouse fibroblast-derived hepatocytes using a combination of three lineage-specific genes. Induced hepatocytes expressed a number of adult drug metabolizing enzymes essential for hepatocyte function. The following month, Sekiya and Suzuki reported the conversion of mouse fibroblasts to hepatocytes using two genes (one of which was used in Huang et al.). In both studies, fibroblast-derived hepatocytes were transplanted into mouse models of liver disease. In both cases, transplantation of induced hepatocytes enhanced the survival of liver deficient mice.
The ability to convert one mature cell type directly into another challenges classic biological concepts. The classic metaphor describing development illustrates a stem cell as a ball at the top of a hill that becomes restricted in its differentiation potential as it rolls down the hill into a valley (or terminally differentiated state). This metaphor, known to biologists as Waddington’s epigenetic landscape, has been challenged by iPSC technology, which has demonstrated that the forced expression of reprogramming genes can drive the metaphorical ball back up the hill, generating undifferentiated pluripotent stem cells. Direct cell conversion calls for another modification to the classic epigenetic landscape. Not only can we force a ball back up the hill, but now we might be able to push it to through into another valley, without first returning to the top of the hill.
One may wonder what Waddington’s take on cellular reprogramming and conversion would be. Would he modify his metaphor to include this exciting new technology? Likely not, as Waddington’s model was based on natural development. However, stem cell biologists can now create their own epigenetic landscape in which we can alter “terminally” differentiated cells by experimental manipulation in the hopes of generating therapeutically relevant cell populations for regenerative medicine.
Angela C. H. McDonald
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