Article

Molecular Roadblocks for Cellular Reprogramming

Institute for Stem Cell Biology and Regenerative Medicine, Department of Pathology, and Cancer Biology Program, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
Molecular cell (Impact Factor: 14.46). 09/2012; 47(6):827-38. DOI: 10.1016/j.molcel.2012.09.008
Source: PubMed

ABSTRACT During development, diverse cellular identities are established and maintained in the embryo. Although remarkably robust in vivo, cellular identities can be manipulated using experimental techniques. Lineage reprogramming is an emerging field at the intersection of developmental and stem cell biology in which a somatic cell is stably reprogrammed into a distinct cell type by forced expression of lineage-determining factors. Lineage reprogramming enables the direct conversion of readily available cells from patients (such as skin fibroblasts) into disease-relevant cell types (such as neurons and cardiomyocytes) or into induced pluripotent stem cells. Although remarkable progress has been made in developing novel reprogramming methods, the efficiency and fidelity of reprogramming need to be improved in order increase the experimental and translational utility of reprogrammed cells. Studying the mechanisms that prevent successful reprogramming should allow for improvements in reprogramming methods, which could have significant implications for regenerative medicine and the study of human disease. Furthermore, lineage reprogramming has the potential to become a powerful system for dissecting the mechanisms that underlie cell fate establishment and terminal differentiation processes. In this review, we will discuss how transcription factors interface with the genome and induce changes in cellular identity in the context of development and reprogramming.

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    • "This new direct reprograming method featuring defined factors indicates that transdifferentiation can occur across germ layers. Transdifferentiation can be controlled through epigenetic regulation and gene activation [57], [58]. In 2012, Ladewig et al. reported that inhibiting GSK-3β and SMAD signaling during reprogramming increased the efficiency of human iN generation as well as the purity of the resulting iNs [59]. "
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    • "The transformation of differentiated somatic cells to induced pluripotent cells (iPSCs) has opened a new horizon of regenerative medicine in cell transplantation therapies; however, there are several limitations in using iPSCs as a valuable tool for studying disease modeling. For example, not all clones that appear in the induced process are fully reprogramminged (Hanna et al., 2009; Vierbuchen and Wernig, 2012). In addition , the difficulty of picking clones and the generation of Oct4 promoter–labeled iPSCs are processes that are too expensive for use by researchers. "
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    • "The observed initial mistargeting of the reprogramming factors is a plausible explanation for the low efficiencies and slow kinetics of iPS cell reprogramming. By analogy, it could be assumed that other types of lineage reprogramming also involve transcription factor cooperativity and positive feedback activation (Vierbuchen and Wernig, 2012). "
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