Cell Reprogramming: The Many Roads to Success

Aydın, Begüm; Mazzoni, Esteban O.

doi:10.1146/annurev-cellbio-100818-125127

Cited by 51 publications

(32 citation statements)

References 127 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Certain genes that we have identified as candidate FO genes in the current study, such as SIRT5, are strongly related to DNA repair, intracellular homeostasis, redox homeostasis, DNA transcription regulation and microenvironment regulation, all key functions during the process of genetic reprograming. [54][55][56][57][58][59] Such FO genes could be specifically targeted for activation by techniques such as the CRISPRa system, 60 or with small molecule activators of specific pathways.…”

Section: Chromatin Landscape Differences Between Adult and Embryonimentioning

confidence: 99%

Chromatin accessibility in canine stromal cells and its implications for canine somatic cell reprogramming

Questa

Moshref

Jimenez

et al. 2020

Stem Cells Translational Medicine

View full text Add to dashboard Cite

Naturally occurring disease in pet dogs is an untapped and unique resource for stem cell‐based regenerative medicine translational research, given the many similarities and complexity such disease shares with their human counterparts. Canine‐specific regulators of somatic cell reprogramming and pluripotency maintenance are poorly understood. While retroviral delivery of the four Yamanaka factors successfully reprogrammed canine embryonic fibroblasts, adult stromal cells remained resistant to reprogramming in spite of effective viral transduction and transgene expression. We hypothesized that adult stromal cells fail to reprogram due to an epigenetic barrier. Here, we performed assay for transposase‐accessible chromatin using sequencing (ATAC‐seq) on canine stromal and pluripotent stem cells, analyzing 51 samples in total, and establishing the global landscape of chromatin accessibility before and after reprogramming to induced pluripotent stem cells (iPSC). We also studied adult stromal cells that do not yield iPSC colonies to identify potential reprogramming barriers. ATAC‐seq analysis identified distinct cell type clustering patterns and chromatin remodeling during embryonic fibroblast reprogramming. Compared with embryonic fibroblasts, adult stromal cells had a chromatin accessibility landscape that reflects phenotypic differentiation and somatic cell‐fate stability. We ultimately identified 76 candidate genes and several transcription factor binding motifs that may be impeding somatic cell reprogramming to iPSC, and could be targeted for inhibition or activation, in order to improve the process in canines. These results provide a vast resource for better understanding of pluripotency regulators in dogs and provide an unbiased rationale for novel canine‐specific reprogramming approaches.

show abstract

Section: Chromatin Landscape Differences Between Adult and Embryonimentioning

confidence: 99%

Chromatin accessibility in canine stromal cells and its implications for canine somatic cell reprogramming

Questa

Moshref

Jimenez

et al. 2020

Stem Cells Translational Medicine

View full text Add to dashboard Cite

show abstract

“…However, since negative feedback mostly prevents cells which have chosen one path from differentiating into alternative cell types, additional regulatory mechanisms must exist that selectively drive cells onto a unique path and allow cells to robustly assume and maintain a specific differentiated cell identity. A number of studies focusing on directed and transdifferentiation processes showed that differentiation can proceed by multiple routes and yet converge onto similar transcriptional states [11,12], consistent with the view that terminally differentiated cell states are ‘attractor basins’ in a transcriptional and signaling differentiation landscape. The finding that the same differentiated state could be reached by passing through different intermediate states motivated us to ask the question whether a unique attractor basin requires a unique cell identify factor that would allow for the same terminally differentiated state to be reached from different intermediate states.…”

Section: Introductionmentioning

confidence: 61%

Early enforcement of cell identity by a functional component of the terminally differentiated state

Bahrami-Nejad

Chen

Tholen

et al. 2020

Preprint

View full text Add to dashboard Cite

How differentiating progenitor cells can attain a distinct differentiated cell-identity is a challenging problem given the promiscuous nature of critical transcription factors and the typically fluctuating signaling environment in which cells exist. Here we test the hypothesis that a unique and robust differentiated cell identity can result from a core component of the differentiated state doubling up such that it has key functions in the differentiated state and also works at low levels as a positive-feedback signaling mediator that drives progenitor cells to differentiate. Using live single-cell fluorescence imaging analysis in the adipocyte differentiation system, we show that FABP4, one of the most abundant core components that buffers lipids in differentiated adipocytes, regulates at low levels expression of PPARG, the master regulator of adipocyte differentiation. Adipocyte progenitor cells transition from a priming phase of differentiation to a second phase during which low levels of FABP4 and PPARG mutually reinforce each other's expression. In this way both proteins reach a threshold where cells irreversibly commit to the differentiated state. Before and after reaching this threshold, PPARG transcriptionally increases FABP4 expression while fatty-acid loaded FABP4 binds to and increases PPARG activity. Together, our study suggests a control principle for robust cell identity, whereby a core component of the differentiated state also promotes differentiation from its own progenitor state. HIGHLIGHTS• Only a small fraction (~10%) of the maximally reached FABP4 levels in cells is needed to commit cells to the differentiated state.• Mature adipocytes express levels of FABP4 ten times the minimal level needed to commit cells to the differentiated state, thus providing an explanation for why the mature adipocyte state is so stable.• Fatty-acid loaded FABP4 binds to and activates PPARG, thereby turning on PPARG positive feedback loops that increase PPARG expression.• FABP4 critically controls the second phase of adipogenesis between activation of the feedback loops and reaching the threshold to differentiate.

show abstract

“…Regardless of the reprogramming strategy, the acquisition of a new phenotype passes through the modification of gene regulatory networks of the resident cell type to fit the characteristics of the incoming target cell, in terms of cell behavior, proliferation, and metabolic rate [18]. These same changes can also be associated with some pathological cellular states, like tumorigenesis [19,20].…”

Section: Repairing the Failing Heart With Cellular Reprogrammingmentioning

confidence: 99%

Advanced Technologies to Target Cardiac Cell Fate Plasticity for Heart Regeneration

Testa

Benedetto

Passaro

2021

IJMS

View full text Add to dashboard Cite

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.

show abstract

Cell Reprogramming: The Many Roads to Success

Cited by 51 publications

References 127 publications

Chromatin accessibility in canine stromal cells and its implications for canine somatic cell reprogramming

Chromatin accessibility in canine stromal cells and its implications for canine somatic cell reprogramming

Early enforcement of cell identity by a functional component of the terminally differentiated state

Advanced Technologies to Target Cardiac Cell Fate Plasticity for Heart Regeneration

Contact Info

Product

Resources

About