Constitutively Active SMAD2/3 Are Broad-Scope Potentiators of Transcription-Factor-Mediated Cellular Reprogramming

Ruetz, Tyson Joel; Pfisterer, Ulrich; Stefano, Bruno Di; Ashmore, James; Beniazza, Meryam; Tian, Tian V.; Kaemena, Daniel F.; Tosti, Luca; Tan, Wenfang; Manning, Jonathan; Chantzoura, Eleni; Ottosson, Daniella Rylander; Collombet, Samuel; Johnsson, Anna; Cohen, Erez; Yusa, Kosuke; Linnarsson, Sten; Graf, Thomas; Parmar, Malin; Kaji, Keisuke

doi:10.1016/j.stem.2017.10.013

Cited by 38 publications

(44 citation statements)

References 72 publications

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“…Another report showed that the constitutively active SMAD2/3 can interact with other factors on OCT4 target loci and potentiate DR conversion with multiple types of transcription factors from myoblasts to adipocytes, B cells to macrophages, and fibroblasts to neurons. Thus, they might be the common cofactors that potentiate diverse cell fate conversions with master genes [57]. …”

Section: Introductionmentioning

confidence: 99%

Potential application of cell reprogramming techniques for cancer research

Saito

Lin

Nakamura

et al. 2018

Cell. Mol. Life Sci.

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The ability to control the transition from an undifferentiated stem cell to a specific cell fate is one of the key techniques that are required for the application of interventional technologies to regenerative medicine and the treatment of tumors and metastases and of neurodegenerative diseases. Reprogramming technologies, which include somatic cell nuclear transfer, induced pluripotent stem cells, and the direct reprogramming of specific cell lineages, have the potential to alter cell plasticity in translational medicine for cancer treatment. The characterization of cancer stem cells (CSCs), the identification of oncogene and tumor suppressor genes for CSCs, and the epigenetic study of CSCs and their microenvironments are important topics. This review summarizes the application of cell reprogramming technologies to cancer modeling and treatment and discusses possible obstacles, such as genetic and epigenetic alterations in cancer cells, as well as the strategies that can be used to overcome these obstacles to cancer research.

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Section: Introductionmentioning

confidence: 99%

Potential application of cell reprogramming techniques for cancer research

Saito

Lin

Nakamura

et al. 2018

Cell. Mol. Life Sci.

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“…Our data also suggest that functional maturation can, at least in part, be controlled separately from neuronal specification during iN conversion. Supporting this, increased and accelerated maturation via external factors during iN conversion can also be achieved via the constitutive expression of SMAD3 [17,34,35]. We anticipate that these findings, as well as continued studies seeking to identify molecular regulators of neuronal maturation, will enable more refined and possibly accelerated studies of disease-related functional properties in vitro.…”

Section: Discussionmentioning

confidence: 76%

Dual modulation of neuron‐specific microRNAs and the REST complex promotes functional maturation of human adult induced neurons

et al. 2019

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Direct neuronal reprogramming can be achieved using different approaches: by expressing neuronal transcription factors or microRNAs; and by knocking down neuronal repressive elements. However, there still exists a high variability in terms of the quality and maturity of the induced neurons obtained, depending on the reprogramming strategy employed. Here, we evaluate different long‐term culture conditions and study the effect of expressing the neuronal‐specific microRNAs, miR124 and miR9/9*, while reprogramming with forced expression of the transcription factors Ascl1, Brn2, and knockdown of the neuronal repressor REST. We show that the addition of microRNAs supports neuronal maturation in terms of gene and protein expression, as well as in terms of electrophysiological properties.

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“…The switching implementation imposes an instantaneous change of the conditions to the desired ones, so our observations may correspond to the extremes, where the transitions between cell fates are strongly favored. With rapid developments in improving the reprogramming efficiency [83,84,85,86], we anticipate that the predictions present here can be tested by the experiments in the future.…”

Section: Discussionmentioning

confidence: 83%

Microscopic Chromosomal Structural and Dynamical Origin of Cell Differentiation and Reprogramming

Chu

Wang

2020

Preprint

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As an essential and fundamental process of life, cell development involves large-scale reorganization of the three-dimensional genome architecture, which forms the basis of gene regulation. Here, we develop a landscape-switching model to explore the microscopic chromosomal structural origin of the embryonic stem cell (ESC) differentiation and the somatic cell reprogramming. We show that chromosome structure exhibits significant compartment-switching in the unit of topologically associating domain. We find that the chromosome during differentiation undergoes monotonic compaction with spatial re-positioning of active and inactive chromosomal loci towards the chromosome surface and interior, respectively. In contrast, an over-expanded chromosome, which exhibits universal localization of loci at the chromosomal surface with erasing the structural characteristics formed in the somatic cells, is observed during reprogramming. We suggest an early distinct differentiation pathway from the ESC to the terminally differentiated cell, giving rise to early bifurcation on the Waddington landscape for the ESC differentiation. Our theoretical model including the non-equilibrium effects, draws a picture of the highly irreversible cell differentiation and reprogramming processes, in line with the experiments. The predictions from our model provide a physical understanding of cell differentiation and reprogramming from the chromosomal structural and dynamical perspective and can be tested by future experiments.

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Constitutively Active SMAD2/3 Are Broad-Scope Potentiators of Transcription-Factor-Mediated Cellular Reprogramming

Cited by 38 publications

References 72 publications

Potential application of cell reprogramming techniques for cancer research

Potential application of cell reprogramming techniques for cancer research

Dual modulation of neuron‐specific microRNAs and the REST complex promotes functional maturation of human adult induced neurons

Microscopic Chromosomal Structural and Dynamical Origin of Cell Differentiation and Reprogramming

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