From Stealing Fire to Cellular Reprogramming: A Scientific History Leading to the 2012 Nobel Prize

Lensch, M. William; Mummery, Christine L.

doi:10.1016/j.stemcr.2013.05.001

Cited by 19 publications

(9 citation statements)

References 69 publications

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“…Observations of the existence of cell fate restriction accompanied the first descriptions of pluripotency itself in the late 19 th century (Lensch and Mummery 2013). Classical embryology experiments involving the division of early newt and sea urchin embryos, in conjunction with subsequent embryonic tissue transplantation experiments by Hans Spemann and Hilde Mangold, were key in demonstrating both the plasticity of early embryonic cells as well as the progressive restriction of their fate as cells progressed through critical stages of development (Lensch and Mummery 2013). Pioneering somatic nuclear transplantation experiments further demonstrated the progressive loss of cell fate plasticity in differentiated cells (Briggs and King 1952; Gurdon 1960; Gurdon 1962).…”

mentioning

confidence: 99%

Restriction of Cellular Plasticity of Differentiated Cells Mediated by Chromatin Modifiers, Transcription Factors and Protein Kinases

Rahe

Hobert²

2019

G3 Genes|Genomes|Genetics

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Ectopic expression of master regulatory transcription factors can reprogram the identity of specific cell types. The effectiveness of such induced cellular reprogramming is generally greatly reduced if the cellular substrates are fully differentiated cells. For example, in the nematode C. elegans , the ectopic expression of a neuronal identity-inducing transcription factor, CHE-1 , can effectively induce CHE-1 target genes in immature cells but not in fully mature non-neuronal cells. To understand the molecular basis of this progressive restriction of cellular plasticity, we screened for C. elegans mutants in which ectopically expressed CHE-1 is able to induce neuronal effector genes in epidermal cells. We identified a ubiquitin hydrolase, usp-48 , that restricts cellular plasticity with a notable cellular specificity. Even though we find usp-48 to be very broadly expressed in all tissue types, usp-48 null mutants specifically make epidermal cells susceptible to CHE-1 -mediated activation of neuronal target genes. We screened for additional genes that allow epidermal cells to be at least partially reprogrammed by ectopic che-1 expression and identified many additional proteins that restrict cellular plasticity of epidermal cells, including a chromatin-related factor (H3K79 methyltransferase, DOT-1.1 ), a transcription factor (nuclear hormone receptor NHR-48 ), two MAPK-type protein kinases ( SEK-1 and PMK-1 ), a nuclear localized O-GlcNAc transferase ( OGT-1 ) and a member of large family of nuclear proteins related to the Rb-associated LIN-8 chromatin factor. These findings provide novel insights into the control of cellular plasticity.

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mentioning

confidence: 99%

Restriction of Cellular Plasticity of Differentiated Cells Mediated by Chromatin Modifiers, Transcription Factors and Protein Kinases

Rahe

Hobert²

2019

G3 Genes|Genomes|Genetics

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“…These experiments have led to an expansion of experimental approaches to manipulate and modify cells to give them multipotent potential [54]. Several adaptations to this original combination of four factors have been shown to result in pluripotent cells, depending on the starting source of cells used as target [55]–[58].…”

Section: Discussionmentioning

confidence: 99%

Differentiated Type II Pneumocytes Can Be Reprogrammed by Ectopic Sox2 Expression

et al. 2014

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The adult lung contains several distinct stem cells, although their properties and full potential are still being sorted out. We previously showed that ectopic Sox2 expression in the developing lung manipulated the fate of differentiating cells. Here, we addressed the question whether fully differentiated cells could be redirected towards another cell type. Therefore, we used transgenic mice to express an inducible Sox2 construct in type II pneumocytes, which are situated in the distal, respiratory areas of the lung. Within three days after the induction of the transgene, the type II cells start to proliferate and form clusters of cuboidal cells. Prolonged Sox2 expression resulted in the reversal of the type II cell towards a more embryonic, precursor-like cell, being positive for the stem cell markers Sca1 and Ssea1. Moreover, the cells started to co-express Spc and Cc10, characteristics of bronchioalveolar stem cells. We demonstrated that Sox2 directly regulates the expression of Sca1. Subsequently, these cells expressed Trp63, a marker for basal cells of the trachea. So, we show that the expression of one transcription factor in fully differentiated, distal lung cells changes their fate towards proximal cells through intermediate cell types. This may have implications for regenerative medicine, and repair of diseased and damaged lungs.

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“…iPSCs were first generated from mouse embryonic and adult fibroblasts following transduction with retroviruses containing four transcription factors, Oct4, Sox2, Klf4 and c-Myc that are normally expressed in ESCs 11 . It was very quickly established that iPSCs could be generated from a variety of adult human cell types 12 . In common with ESCs iPSCs can theoretically be induced to differentiate into any of the 200 or so cell types in the body, and thus like ESCs have the potential to provide an essentially unlimited supply of specific cell types for basic research and transplantation therapies for disease.…”

Section: Future Cell Therapymentioning

confidence: 99%

Cell therapy for type 1 diabetes

Muir

Lima

Docherty

et al. 2014

QJM

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Cell therapy in the form of human islet transplantation has been a successful form of treatment for patients with type 1 diabetes for over 10 years, but is significantly limited by lack of suitable donor material. A replenishable supply of insulin-producing cells has the potential to address this problem; however to date success has been limited to a few preclinical studies. Two of the most promising strategies include differentiation of embryonic stem cells and induced pluripotent stem cells towards insulin-producing cells and transdifferentiation of acinar or other closely related cell types towards β-cells. Here, we discuss recent progress and challenges that need to be overcome in taking cell therapy to the clinic.

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From Stealing Fire to Cellular Reprogramming: A Scientific History Leading to the 2012 Nobel Prize

Cited by 19 publications

References 69 publications

Restriction of Cellular Plasticity of Differentiated Cells Mediated by Chromatin Modifiers, Transcription Factors and Protein Kinases

Restriction of Cellular Plasticity of Differentiated Cells Mediated by Chromatin Modifiers, Transcription Factors and Protein Kinases

Differentiated Type II Pneumocytes Can Be Reprogrammed by Ectopic Sox2 Expression

Cell therapy for type 1 diabetes

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