Cellular Reprogramming: A New Technology Frontier in Pharmaceutical Research

Brock, Amy; Goh, Hui Tong; Yang, Binxia; Lu, Yu; Hu, Li; Loh, Yuin-Han

doi:10.1007/s11095-011-0618-z

Cited by 10 publications

(9 citation statements)

References 105 publications

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“…Pluripotent stem cell (hPSC)‐derived neural stem cells (hNSC) appear as one of the most promising source of human neurons for various biomedical applications, including drug discovery , disease modeling , and cell replacement therapies . Consequently, mass cell production has become a major goal in this field , calling for robustness and cost‐effectiveness, parameters that need to be optimized using rational and systematic approaches.…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase-A Inhibition Is Sufficient to Support Human Neural Stem Cells Self-Renewal

Georges¹,

Boissart²,

Poulet³

et al. 2015

Stem Cells

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Human pluripotent stem cell-derived neural stem cells offer unprecedented opportunities for producing specific types of neurons for several biomedical applications. However, to achieve it, protocols of production and amplification of human neural stem cells need to be standardized, cost effective, and safe. This means that small molecules should progressively replace the use of media containing cocktails of protein-based growth factors. Here we have conducted a phenotypical screening to identify pathways involved in the regulation of hNSC self-renewal. We analyzed 80 small molecules acting as kinase inhibitors and identified compounds of the 5-isoquinolinesulfonamide family, described as protein kinase A (PKA) and protein kinase G inhibitors, as candidates to support hNSC self-renewal. Investigating the mode of action of these compounds, we found that modulation of PKA activity was central in controlling the choice between self-renewal or terminal neuronal differentiation of hNSC. We finally demonstrated that the pharmacological inhibition of PKA using the small molecule HA1004 was sufficient to support the full derivation, propagation, and long-term maintenance of stable hNSC in absence of any other extrinsic signals. Our results indicated that tuning of PKA activity is a core mechanism regulating hNSC self-renewal and differentiation and delineate the minimal culture media requirement to maintain undifferentiated hNSC in vitro. STEM CELLS 2015;33:3666-3672 SIGNIFICANCE STATEMENTPluripotent stem cells-derived neural stem cells offer unprecedented opportunities for producing human neurons for several biomedical applications. However, defining the minimal requirement to maintain neural stem cells self-renewal in vitro, using small molecules rather than protein based cocktails, is a pre-requisite to fully achieve the potential of these cells. Here, we have used high throughput screening to find small molecules able to replace the prototypical EGF/FGF-2 based cocktail uses to support neural stem cells self-renewal. This screen identified Protein Kinase A inhibitors and allowed us to delineate the minimal culture media requirement to maintain undifferentiated hNSC in vitro.

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Section: Introductionmentioning

confidence: 99%

Protein Kinase-A Inhibition Is Sufficient to Support Human Neural Stem Cells Self-Renewal

Georges¹,

Boissart²,

Poulet³

et al. 2015

Stem Cells

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“…Focusing on human biology can address adverse reactions in humans, which were unnoticed in animal models [79]. Improved preclinical models can empower to access human biology.…”

Section: Complementary Approachesmentioning

confidence: 99%

“…The idea was to use stem cell-based assays for toxicity evaluation in heart, liver, muscle, skin, and nerves. Recently new methods and tools have been used to culture human cells, reprogram them to specific phenotype and perform clinical trials [79,80,81]. The study published by Cell Reports show that induced pluripotent stem cells (iPSCs) derived from patients with frontotemporal dementia were genetically corrected and converted to cortical neurons [82].…”

Section: Complementary Approachesmentioning

confidence: 99%

Complementary Approaches to Existing Target Based Drug Discovery for Identifying Novel Drug Targets

Vasaikar

Bhatia

et al. 2016

Biomedicines

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In the past decade, it was observed that the relationship between the emerging New Molecular Entities and the quantum of R&D investment has not been favorable. There might be numerous reasons but few studies stress the introduction of target based drug discovery approach as one of the factors. Although a number of drugs have been developed with an emphasis on a single protein target, yet identification of valid target is complex. The approach focuses on an in vitro single target, which overlooks the complexity of cell and makes process of validation drug targets uncertain. Thus, it is imperative to search for alternatives rather than looking at success stories of target-based drug discovery. It would be beneficial if the drugs were developed to target multiple components. New approaches like reverse engineering and translational research need to take into account both system and target-based approach. This review evaluates the strengths and limitations of known drug discovery approaches and proposes alternative approaches for increasing efficiency against treatment.

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“…Retroviral vectors were used to induce the ectopic expression of the four defined transcription factors that initiated events that reactivated genes associated with pluripotency. These reprogrammed cells were, like ESCs, found to be able to contribute to the germ-line in chimeric mice [ 17 ], and were capable of forming teratomas containing tissues derived from the three main germ layers [ 8 ]. Subsequently, it was also shown that the overexpression of other combinations of transcription factors, such as combinations including Nanog or Lin28, could trigger cellular reprogramming [ 18 ].…”

Section: Cellular Reprogrammingmentioning

confidence: 99%

“…The discovery that somatic cells can be reprogrammed to form iPSCs, which share similar characteristics with ESCs, has expanded the prospect for development of cellular therapies for degenerative diseases [ 8 ]. iPSCs face less ethical controversy as compared to ESCs, and as patient-specific iPSCs can be generated from patients of most genotypes, it is easier to model a wide range of diseases with iPSCs.…”

Section: Introductionmentioning

confidence: 99%

Induced Pluripotency and Gene Editing in Disease Modelling: Perspectives and Challenges

Seah

Farran

Warrier

et al. 2015

IJMS

Self Cite

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Embryonic stem cells (ESCs) are chiefly characterized by their ability to self-renew and to differentiate into any cell type derived from the three main germ layers. It was demonstrated that somatic cells could be reprogrammed to form induced pluripotent stem cells (iPSCs) via various strategies. Gene editing is a technique that can be used to make targeted changes in the genome, and the efficiency of this process has been significantly enhanced by recent advancements. The use of engineered endonucleases, such as homing endonucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and Cas9 of the CRISPR system, has significantly enhanced the efficiency of gene editing. The combination of somatic cell reprogramming with gene editing enables us to model human diseases in vitro, in a manner considered superior to animal disease models. In this review, we discuss the various strategies of reprogramming and gene targeting with an emphasis on the current advancements and challenges of using these techniques to model human diseases.

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Cellular Reprogramming: A New Technology Frontier in Pharmaceutical Research

Cited by 10 publications

References 105 publications

Protein Kinase-A Inhibition Is Sufficient to Support Human Neural Stem Cells Self-Renewal

Protein Kinase-A Inhibition Is Sufficient to Support Human Neural Stem Cells Self-Renewal

Complementary Approaches to Existing Target Based Drug Discovery for Identifying Novel Drug Targets

Induced Pluripotency and Gene Editing in Disease Modelling: Perspectives and Challenges

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