Development Unchained: How Cellular Reprogramming is Redefining Our View of Cell Fate and Identity

Cellular reprogramming is a fundamental topic in the research of stem cells and molecular biology. It is widely investigated and its understanding is crucial for learning about different aspects of development such as cell proliferation, determination of cell fate and stem cell renewal. Other factors involved during development include hypoxia and epigenetics, which play major roles in the development of tissues and organs. This review will discuss the involvement of hypoxia and epigenetics in the regulation of cellular reprogramming and how interplay between each factor can contribute to different cellular functions as well as tissue regeneration.

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Advanced Technologies to Target Cardiac Cell Fate Plasticity for Heart Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms22179517 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9517

Author(s):

Gianluca Testa ◽

Giorgia Di Benedetto ◽

Fabiana Passaro

Keyword(s):

Cell Fate ◽

Disease Modeling ◽

Heart Diseases ◽

Cellular Reprogramming ◽

Cardiac Cell ◽

New Paradigm ◽

Cardiovascular Research ◽

Injured Myocardium

The adult human heart can only adapt to heart diseases by starting a myocardial remodeling process to compensate for the loss of functional cardiomyocytes, which ultimately develop into heart failure. In recent decades, the evolution of new strategies to regenerate the injured myocardium based on cellular reprogramming represents a revolutionary new paradigm for cardiac repair by targeting some key signaling molecules governing cardiac cell fate plasticity. While the indirect reprogramming routes require an in vitro engineered 3D tissue to be transplanted in vivo, the direct cardiac reprogramming would allow the administration of reprogramming factors directly in situ, thus holding great potential as in vivo treatment for clinical applications. In this framework, cellular reprogramming in partnership with nanotechnologies and bioengineering will offer new perspectives in the field of cardiovascular research for disease modeling, drug screening, and tissue engineering applications. In this review, we will summarize the recent progress in developing innovative therapeutic strategies based on manipulating cardiac cell fate plasticity in combination with bioengineering and nanotechnology-based approaches for targeting the failing heart.

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FACT sets a barrier for cell fate reprogramming inC. elegansand Human

10.1101/185116 ◽

2017 ◽

Cited By ~ 1

Author(s):

Ena Kolundzic ◽

Andreas Ofenbauer ◽

Bora Uyar ◽

Anne Sommermeier ◽

Stefanie Seelk ◽

...

Keyword(s):

Gene Expression ◽

Cell Fate ◽

Chromatin Accessibility ◽

Genetic Screen ◽

Cellular Reprogramming ◽

Stable Gene ◽

C Elegans ◽

Chromatin Regulator ◽

Evolutionarily Conserved ◽

Stable Gene Expression

The chromatin regulator FACT (Facilitates Chromatin Transcription) is essential for ensuring stable gene expression by promoting transcription. In a genetic screen usingC. eleganswe identified that FACT maintains cell identities and acts as a barrier for transcription factor-mediated cell fate reprogramming. Strikingly, FACTs role as a reprogramming barrier is conserved in humans as we show that FACT depletion enhances reprogramming of fibroblasts into stem cells and neurons. Such activity of FACT is unexpected since known reprogramming barriers typically repress gene expression by silencing chromatin. In contrast, FACT is a positive regulator of gene expression suggesting an unprecedented link of cell fate maintenance with counteracting alternative cell identities. This notion is supported by ATAC-seq analysis showing that FACT depletion results in decreased but also increased chromatin accessibility for transcription factors. Our findings identify FACT as a cellular reprogramming barrier inC. elegansand in Human, revealing an evolutionarily conserved mechanism for cell fate protection.

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Yorkie and JNK revert syncytial muscles into myoblasts during Org-1 dependent lineage reprogramming

10.1101/607820 ◽

2019 ◽

Author(s):

Christoph Schaub ◽

Marcel Rose ◽

Manfred Frasch

Keyword(s):

Cell Fate ◽

Present Report ◽

Cellular Reprogramming ◽

List Type ◽

T Box ◽

Lineage Reprogramming ◽

Kinase Cascade ◽

Alary Muscles

SummaryLineage reprogramming has become a prominent focus in research since it was demonstrated that lineage restricted transcription factors can be used in vitro for direct reprogramming [1]. Recently, we reported that the ventral longitudinal musculature (VLM) of the adult Drosophila heart arises in vivo by direct lineage reprogramming from alary muscles (AM), a process which starts with dedifferentiation and fragmentation of syncytial alary muscles into mononucleate myoblasts. Central upstream activators of the genetic program regulating the development of VLMs from alary muscles are the T-box factor Org-1 (Drosophila Tbx1) and the LIM homeodomain factor Tup (Drosophila Islet1) [2]. However, the events downstream of Org-1 and Tup that exert dedifferentiation and fragmentation of alary muscles have been unknown. In the present report, we shed light on the initiation of this first step of transdifferentiation and show that AM lineage specific activation of Yorkie (Yki), the transcriptional co-activator of the transcription factor Scalloped (Sd), has a key role in initiating AM lineage reprogramming. An additional necessary input comes from active dJNK signaling, which contributes to the inactivation of the Hippo kinase cascade upstream of Yki and furthermore activates dJun. The synergistic activities of the Yki/Sd and dJun/dFos (AP-1) transcriptional activator complexes in the absence of Hippo activity initiate AM dedifferentiation and lead to the expression of Myc and piwi, which are crucial for different aspects of AM transdifferentiation. Our results provide new insights into the mechanisms that mediate muscle lineage plasticity during a cellular reprogramming process occurring in vivo.HighlightsDirect lineage reprogramming of alary muscles depends on Yorkie and JNKYorkie and JNK mediate reversal of syncytial muscle cell fateYki/Sd and AP-1 induce alary muscle dedifferentiation synergisticallyYki dependent Myc induces and Piwi mediates reprogramming of alary muscles

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NETISCE: A Network-Based Tool for Cell Fate Reprogramming

10.1101/2021.12.30.474582 ◽

2022 ◽

Author(s):

Lauren Marazzi ◽

Milan Shah ◽

Shreedula Balakrishnan ◽

Ananya Patil ◽

Paola Vera-Licona

Keyword(s):

Cell Fate ◽

Biological Networks ◽

Cancer Biology ◽

Cellular Reprogramming ◽

Full Model ◽

Computational Tool ◽

Initial State ◽

Large Sets ◽

Model Parameterization ◽

Systems Framework

The search for effective therapeutic targets in fields like regenerative medicine and cancer research has generated interest in cell fate reprogramming. This cellular reprogramming paradigm can drive cells to a desired target state from any initial state. However, methods for identifying reprogramming targets remain limited for biological systems that lack large sets of experimental data or a dynamical characterization. We present NETISCE, a novel computational tool for identifying cell fate reprogramming targets in static networks. NETISCE identifies reprogramming targets through the innovative use of control theory within a dynamical systems framework. Through validations in studies of cell fate reprogramming from developmental, stem cell, and cancer biology, we show that NETISCE can predict previously identified cell fate reprogramming targets and identify potentially novel combinations of targets. NETISCE extends cell fate reprogramming studies to larger-scale biological networks without the need for full model parameterization and can be implemented by experimental and computational biologists to identify parts of a biological system that are relevant for the desired reprogramming task.

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Disentangling a Complex Response in Cell Reprogramming and Probing the Waddington Landscape by Automatic Construction of Petri Nets

10.1101/599191 ◽

2019 ◽

Author(s):

Viktoria Rätzel ◽

Britta Werthmann ◽

Markus Haas ◽

Jan Strube ◽

Wolfgang Marwan

Keyword(s):

Petri Nets ◽

Cell Fate ◽

Single Cells ◽

Genetic Alterations ◽

Basins Of Attraction ◽

Cellular Reprogramming ◽

Automatic Construction ◽

Complex Response ◽

Uncertain Structure ◽

Fate Decision

We analyzed the developmental switch to sporulation of a multinucleate Physarum polycephalum plasmodial cell, a complex response to phytochrome photoreceptor activation. Automatic construction of Petri nets from trajectories of differential gene expression in single cells revealed alternative, genotype-dependent interconnected developmental routes and identified metastable states, commitment points, and subsequent irreversible steps together with molecular signatures associated with cell fate decision and differentiation. Formation of transition-invariants in mutants that are locked in a proliferative state is remarkable considering the view that oncogenic alterations may cause the formation of cancer attractors. We conclude that the Petri net approach is useful to probe the Waddington landscape of cellular reprogramming, to disentangle developmental routes for the reconstruction of the gene regulatory network, and to understand how genetic alterations or physiological conditions reshape the landscape eventually creating new basins of attraction. Unraveling the complexity of pathogenesis, disease progression, and drug response or the analysis of attractor landscapes in other complex systems of uncertain structure might be additional fields of application.

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CellRank for directed single-cell fate mapping

Nature Methods ◽

10.1038/s41592-021-01346-6 ◽

2022 ◽

Author(s):

Marius Lange ◽

Volker Bergen ◽

Michal Klein ◽

Manu Setty ◽

Bernhard Reuter ◽

...

Keyword(s):

Single Cell ◽

Cell Fate ◽

Normal Development ◽

Biological Process ◽

Cellular Reprogramming ◽

Intermediate Cell ◽

Fate Mapping ◽

Directional Information ◽

Development Data ◽

Lung Regeneration

AbstractComputational trajectory inference enables the reconstruction of cell state dynamics from single-cell RNA sequencing experiments. However, trajectory inference requires that the direction of a biological process is known, largely limiting its application to differentiating systems in normal development. Here, we present CellRank (https://cellrank.org) for single-cell fate mapping in diverse scenarios, including regeneration, reprogramming and disease, for which direction is unknown. Our approach combines the robustness of trajectory inference with directional information from RNA velocity, taking into account the gradual and stochastic nature of cellular fate decisions, as well as uncertainty in velocity vectors. On pancreas development data, CellRank automatically detects initial, intermediate and terminal populations, predicts fate potentials and visualizes continuous gene expression trends along individual lineages. Applied to lineage-traced cellular reprogramming data, predicted fate probabilities correctly recover reprogramming outcomes. CellRank also predicts a new dedifferentiation trajectory during postinjury lung regeneration, including previously unknown intermediate cell states, which we confirm experimentally.

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Epigenetic control of cell fate - an interview with Prof. Maria-Elena Torres-Padilla

The International Journal of Developmental Biology ◽

10.1387/ijdb.200176jc ◽

2020 ◽

Vol 52 ◽

Author(s):

Jesús Chimal-Monroy ◽

Diana María Escalante-Alcalde

Keyword(s):

Cell Fate ◽

Cell Biology ◽

Cell Lineage ◽

Cellular Reprogramming ◽

Cell Fate Decision ◽

Cell Embryo ◽

Founding Director ◽

Fate Decision ◽

The One ◽

New Generation

Dr. Maria-Elena Torres-Padilla's research is focused on how cell fate arises from a single-cell embryo, the fertilized egg or zygote. After the initial divisions, cell potency becomes restricted, originating the first cell lineage fates. She studies how epigenetic information controls transitions in cell identity and cellular reprogramming during embryonic development. Currently, she is the founding Director of the Institute of Epigenetics and Stem Cells, Helmholtz Centre, and Professor of Stem Cell Biology at the LMU in Munich. In this interview, Dr. Maria-Elena Torres-Padilla talks to us about her beginnings in the biology field in Mexico. She also tells us about how she became interested in the control of genome regulation within the nucleus during the transition from totipotency to pluripotency and how the control of gene regulation and chromatin organization during the early stages of cell fate decision in the one-cell embryo occurs. She considers that science has no borders; visiting Mexico gives her the possibility to discuss her work with colleagues and the new generation of students trained in Mexico.

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Systems biology of stem cell fate and cellular reprogramming

Nature Reviews Molecular Cell Biology ◽

10.1038/nrm2766 ◽

2009 ◽

Vol 10 (10) ◽

pp. 672-681 ◽

Cited By ~ 239

Author(s):

Ben D. MacArthur ◽

Avi Ma'ayan ◽

Ihor R. Lemischka

Keyword(s):

Stem Cell ◽

Systems Biology ◽

Cell Fate ◽

Cellular Reprogramming ◽

Stem Cell Fate

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Mitochondrial Heterogeneity: Evaluating Mitochondrial Subpopulation Dynamics in Stem Cells

Stem Cells International ◽

10.1155/2017/7068567 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 22

Author(s):

D. C. Woods

Keyword(s):

Stem Cells ◽

Cell Fate ◽

Pluripotent Stem Cells ◽

Cell Biology ◽

Cell Types ◽

Cellular Reprogramming ◽

Cellular Functions ◽

Technical Advances ◽

Mitochondrial Heterogeneity ◽

Key Participants

Although traditionally viewed as the “powerhouse” of the cell, an accruing body of evidence in the rapidly growing field of mitochondrial biology supports additional roles of mitochondria as key participants in a multitude of cellular functions. While it has been well established that mitochondria in different tissues have distinctive ultrastructural features consistent with differential bioenergetic demands, recent and emerging technical advances in flow cytometry, imaging, and “-omics”-based bioinformatics have only just begun to explore the complex and divergent properties of mitochondria within tissues and cell types. Moreover, contemporary studies evaluating the role of mitochondria in pluripotent stem cells, cellular reprogramming, and differentiation point to a potential importance of mitochondrial subpopulations and heterogeneity in the field of stem cell biology. This review assesses the current literature regarding mitochondrial subpopulations within cell and tissue types and evaluates the current understanding of how mitochondrial diversity and heterogeneity might impact cell fate specification in pluripotent stem cells.

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