Article

Robinton, DA and Daley, GQ. The promise of induced pluripotent stem cells in research and therapy. Nature 481: 295-305

Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 01/2012; 481(7381):295-305. DOI: 10.1038/nature10761
Source: PubMed

ABSTRACT

The field of stem-cell biology has been catapulted forward by the startling development of reprogramming technology. The ability to restore pluripotency to somatic cells through the ectopic co-expression of reprogramming factors has created powerful new opportunities for modelling human diseases and offers hope for personalized regenerative cell therapies. While the field is racing ahead, some researchers are pausing to evaluate whether induced pluripotent stem cells are indeed the true equivalents of embryonic stem cells and whether subtle differences between these types of cell might affect their research applications and therapeutic potential.

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    • "Since then, many studies have focused on understanding how intrinsic factors, such as transcriptional factors and chromatin regulators, govern cellular reprogramming (reviewed in Apostolou and Hochedlinger, 2013; Jaenisch and Young, 2008). However, detailed analysis of reprogrammed cells also revealed genetic and epigenetic aberrations (reviewed in Robinton and Daley, 2012), raising concerns regarding medical applications. That said, many organs with short-lived cells, such as blood, skin, intestine, and testis, are maintained by continuous activity of adult stem cells. "
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    ABSTRACT: Extrinsic cues from the niche are known to regulate adult stem cell self-renewal versus differentiation. Here, we report that an aminopeptidase Slamdance (Sda) acts in the Drosophila testicular niche to maintain germline stem cells (GSCs) and regulate progenitor germ cell dedifferentiation. Mutations in sda lead to dramatic testicular niche deterioration and stem cell loss. Recombinant Sda has specific aminopeptidase activity in vitro, and the in vivo function of Sda requires an intact aminopeptidase domain. Sda is required for accumulation of mature DE-cadherin, and overexpression of DE-cadherin rescues most sda mutant phenotypes, suggesting that DE-cadherin is an important target of Sda. Finally, Sda is both necessary and sufficient to promote dedifferentiation during aging and recovery from genetically manipulated depletion of GSCs. Together, our results suggest that a niche factor promotes both stem cell maintenance and progenitor cell dedifferentiation.
    Full-text · Article · Oct 2015 · Cell Reports
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    • "The ability to reprogram adult somatic cells into pluripotent stem cells by a set of transcription factors has revolutionized biomedical research (Takahashi et al., 2007; Takahashi and Yamanaka, 2006). The generated human-induced pluripotent stem cells (hiPSCs) can be coaxed to differentiate into a variety of cell lineages (including cardiomyocytes [Zhang et al., 2009; Zwi et al., 2009]) that can then be utilized for the development of autologous cell-replacement therapies, disease modeling, and drug discovery (Robinton and Daley, 2012). "
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    ABSTRACT: The advent of the human-induced pluripotent stem cell (hiPSC) technology has transformed biomedical research, providing new tools for human disease modeling, drug development, and regenerative medicine. To fulfill its unique potential in the cardiovascular field, efficient methods should be developed for high-resolution, large-scale, long-term, and serial functional cellular phenotyping of hiPSC-derived cardiomyocytes (hiPSC-CMs). To achieve this goal, we combined the hiPSC technology with genetically encoded voltage (ArcLight) and calcium (GCaMP5G) fluorescent indicators. Expression of ArcLight and GCaMP5G in hiPSC-CMs permitted to reliably follow changes in transmembrane potential and intracellular calcium levels, respectively. This allowed monitoring short- and long-term changes in action-potential and calcium-handling properties and the development of arrhythmias in response to several pharmaceutical agents and in hiPSC-CMs derived from patients with different inherited arrhythmogenic syndromes. Combining genetically encoded fluorescent reporters with hiPSC-CMs may bring a unique value to the study of inherited disorders, developmental biology, and drug development and testing.
    Full-text · Article · Sep 2015 · Stem Cell Reports
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    • "The possibility of such control would offer clear opportunities. For example, under the widely supported stochastic model for induced pluripotent stem cell generation [13], a majority of cells have the possibility of being reprogrammed, even though existing technologies have achieved substantially smaller yields [14]. The ability to control the response to noise of differentiated and stem-cell states (e.g., inhibiting transitions to the first and promoting transitions to the second) could lead to enhanced procedures to create induced pluripotent stem cells. "
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    ABSTRACT: Noise caused by fluctuations at the molecular level is a fundamental part of intracellular processes. While the response of biological systems to noise has been studied extensively, there has been limited understanding of how to exploit it to induce a desired cell state. Here we present a scalable, quantitative method based on the Freidlin-Wentzell action to predict and control noise-induced switching between different states in genetic networks that, conveniently, can also control transitions between stable states in the absence of noise. We apply this methodology to models of cell differentiation and show how predicted manipulations of tunable factors can induce lineage changes, and further utilize it to identify new candidate strategies for cancer therapy in a cell death pathway model. This framework offers a systems approach to identifying the key factors for rationally manipulating biophysical dynamics, and should also find use in controlling other classes of noisy complex networks.
    Full-text · Article · Sep 2015 · Physical Review X
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