Context‐Dependent Enhancement of Induced Pluripotent Stem Cell Reprogramming by Silencing Puma

Lake, Blue B.; Fink, J. Lynn; Klemetsaune, Liv; Fu, Xuemei; Jeffers, John; Zambetti, Gerard P.; Xu, Yang

doi:10.1002/stem.1054

Cited by 24 publications

(25 citation statements)

References 35 publications

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“…[21][22][23][24][25][26][27][28][29] Thus, we asked whether p53 is also activated in p63 À / À MEFs. However, neither p53 protein nor its sensitive targets p21 and miR34a/b/c, also known reprogramming barriers, [40][41][42][43] (Figure 5g). Moreover, the tumor suppressors p19-Arf and p16-Ink4A, which are known reprogramming barriers in mouse and human fibroblasts, 23,24 were shown to partially mediate skin and limb defects of p63 À / À mice.…”

Section: Resultsmentioning

confidence: 99%

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

Petrenko

Nemajerová

et al. 2013

Cell Death Differ

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Somatic cells can be converted into induced pluripotent stem cells (iPSCs) by forced expression of various combinations of transcription factors, but the molecular mechanisms of reprogramming are poorly understood. Specifically, evidence that the reprogramming process can take many distinct routes only begins to emerge. It is definitively established that p53 deficiency greatly enhances reprogramming, revealing p53's barrier function for induced pluripotency, but the role of its homologs p63 and p73 are unknown. Here we report that in stark contrast to p53, p73 has no role in reprogramming. However, p63 is an enabling (rather than a barrier) factor for Oct4, Sox2 and Klf4 (OSK) and Oct4 and Sox2 (OS), but not for Oct4 and Klf4 (OK) reprogramming of mouse embryonic fibroblasts. Specifically, p63 is essential during reprogramming for maximum efficiency, albeit not for the ability to reprogram per se, and is dispensable for maintaining stability and pluripotency of established iPSC colonies. DNp63, but not TAp63, is the principal isoform involved. Loss of p63 can affect reprogramming via several mechanisms such as reduced expression of mesenchymal-epithelial transition and pluripotency genes, hypoproliferation and loss of the most reprogrammable cell populations. During OSK and OS reprogramming, different mechanisms seem to be critical, such as regulation of epithelial and pluripotency genes in OSK reprogramming versus regulation of proliferation in OS reprogramming. Finally, our data reveal three different routes of reprogramming by OSK, OS or OK, based on their differential p63 requirements for iPSC efficiency and pluripotency marker expression. This supports the concept that many distinct routes of reprogramming exist.

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Section: Resultsmentioning

confidence: 99%

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

Petrenko

Nemajerová

et al. 2013

Cell Death Differ

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“…One of the main challenges of the reprogramming process is interference owing to genome instability or apoptosis induction [20, 21]. During this process, p53 protein, a crucial monitor of genome integrity, accumulates in response to the ectopic overexpression of reprogramming factors [22]; thus, p53 strictly regulates the reprogramming of somatic cells and can impede this process overall.…”

Section: Genetic Defects That Affect Reprogrammingmentioning

confidence: 99%

Integrating Gene Correction in the Reprogramming and Transdifferentiation Processes: A One‐Step Strategy to Overcome Stem Cell‐Based Gene Therapy Limitations

Lee

Chung

2016

Stem Cells International

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The recent advent of induced pluripotent stem cells (iPSCs) and gene therapy tools has raised the possibility of autologous cell therapy for rare genetic diseases. However, cellular reprogramming is inefficient in certain diseases such as ataxia telangiectasia, Fanconi anemia, LIG4 syndrome, and fibrodysplasia ossificans progressiva syndrome, owing to interference of the disease-related genes. To overcome these therapeutic limitations, it is necessary to fundamentally correct the abnormal gene during or prior to the reprogramming process. In addition, as genetic etiology of Parkinson's disease, it has been well known that induced neural stem cells (iNSCs) were progressively depleted by LRRK2 gene mutation, LRRK2 (G2019S). Thus, to maintain the induced NSCs directly derived from PD patient cells harboring LRRK2 (G2019S), it would be ideal to simultaneously treat the LRRK2 (G2019S) fibroblast during the process of TD. Therefore, simultaneous reprogramming (or TD) and gene therapy would provide the solution for therapeutic limitation caused by vulnerability of reprogramming or TD, in addition to being suitable for general application to the generation of autologous cell-therapy products for patients with genetic defects, thereby obviating the need for the arduous processes currently required.

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“…The p21 protein is required for p53-dependent cell cycle arrest, and p53 upregulated modulator of apoptosis (PUMA) is required for p53-dependent apoptosis [64]. Depletion of PUMA and p21 greatly promotes reprogramming efficiency without increasing reprogramming-associated DNA damage by activating the senescence pathway [65]. Therefore, with improved understanding of the mechanisms involved in induced pluripotency and reprogramming-induced DNA damage responses, it may be possible to optimize reprogramming strategies to minimize the genetic instability in iPSCs.…”

Section: The Genomic and Functional Stability Of Pluripotent Stem Cellsmentioning

confidence: 99%

Challenges to the clinical application of pluripotent stem cells: towards genomic and functional stability

2012

Genome Med

Self Cite

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Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and are pluripotent, retaining the ability to differentiate into all cell types in the body. As a renewable source of various types of human cells, hESCs hold great therapeutic potential. Although significant advances have been achieved in defining the conditions needed to differentiate hESCs into various types of biologically active cells, many challenges remain in the clinical development of hESC-based cell therapy, such as the immune rejection of allogeneic hESC-derived cells by recipients. Breakthroughs in the generation of induced pluripotent stem cells (iPSCs), which are reprogrammed from somatic cells with defined factors, raise the hope that autologous cells derived from patient-specific iPSCs can be transplanted without immune rejection. However, recent genomic studies have revealed epigenetic and genetic abnormalities associated with induced pluripotency, a risk of teratomas, and immunogenicity of some iPSC derivatives. These findings have raised safety concerns for iPSC-based therapy. Here, we review recent advances in understanding the genomic and functional stability of human pluripotent stem cells, current challenges to their clinical application and the progress that has been made to overcome these challenges.

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Context‐Dependent Enhancement of Induced Pluripotent Stem Cell Reprogramming by Silencing Puma

Cited by 24 publications

References 35 publications

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

Integrating Gene Correction in the Reprogramming and Transdifferentiation Processes: A One‐Step Strategy to Overcome Stem Cell‐Based Gene Therapy Limitations

Challenges to the clinical application of pluripotent stem cells: towards genomic and functional stability

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