Stem Cells: The Pursuit of Genomic Stability

Wyles, Saranya P.; Brandt, Emma B.; Nelson, T. J. N.

doi:10.3390/ijms151120948

Cited by 30 publications

(29 citation statements)

References 122 publications

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“…As mentioned earlier, genomic stability can be achieved by the coordination of multiple processes referred to as DDR which includes cell cycle checkpoints, DNA repair and cell death (62, 64). Recent reviews describing DDR in adult stem cells (90) including hematopoietic stem cells (91) as well as multipotent and pluripotent stem cells (92) have been reported. This review article will mainly focus on DDR signaling in embryonic and induced pluripotent stem cells.…”

Section: Dna Damage Response (Ddr) and Stem Cellsmentioning

confidence: 99%

“…Studies describing DDR in pluripotent stem cells (PSCs) and either derived differentiated cells or other somatic cells provide a wide range of outcomes (Table 1). However, it is clear that ES cells and PSCs have an enhanced activity of DNA repair proteins and DNA DSB repair (92). Upon exposure to DNA damaging agents (UV, IR, H 2 O 2 , psoralen), human ESCs showed efficient DNA repair as compared to fibroblast and HeLa cells (93).…”

Section: Dna Damage Response (Ddr) and Stem Cellsmentioning

confidence: 99%

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Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations

et al. 2016

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Pluripotent stem cells (PSCs) hold great promise in regenerative medicine, disease modeling, functional genomics, toxicological studies and cell-based therapeutics due to their unique characteristics of self-renewal and pluripotency. Novel methods for generation of pluripotent stem cells and their differentiation to the specialized cell types such as neuronal cells, myocardial cells, hepatocytes, and beta cells of the pancreas and many other cells of the body are constantly being refined. Pluripotent stem cell derived differentiated cells, including neuronal cells or cardiac cells are ideal for stem cell transplantation as autologous or allogeneic cells from healthy donors due to their minimum risks of rejection. DNA damage induced by ionizing radiation (IR), ultraviolet (UV) light, genotoxic stress, and other intrinsic and extrinsic factors trigger a series of biochemical reactions termed as DNA damage response (DDR). In order to maintain genomic stability, and avoid transmission of mutations into progenitors cells, stem cells have robust DNA damage response signaling – a contrast to somatic cells. Stem cell transplantation may over come the late effects related to radiation. This review will particularly focus on differential DNA damage response between stem cells and derived differentiated cells and the possible pathways that determine such differences.

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Section: Dna Damage Response (Ddr) and Stem Cellsmentioning

confidence: 99%

Section: Dna Damage Response (Ddr) and Stem Cellsmentioning

confidence: 99%

Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations

et al. 2016

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“…Compared to somatic cells, very few studies have been conducted in pluripotent cells regarding their DDR network components. Limited reports suggested that PSCs employed distinct strategies to cope with DNA damage (Wyles et al, 2014). For instance, mouse ESCs bypass the G1/S cell cycle checkpoint due to a extremely short G1 phase (van der Laan et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability

et al. 2015

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Summary Pluripotent stem cells (PSCs) hold great promise in cell-based therapy, but the genomic instability seen in culture hampers full application. Greater understanding of the factors that regulate genomic stability in PSCs could help address this issue. Here we describe the identification of Filia as a specific regulator of genomic stability in mouse embryonic stem cells (ESCs). Filia expression is induced by genotoxic stress. Filia promotes centrosome integrity and regulates DNA damage response (DDR) through multiple pathways, including DDR signaling, cell cycle checkpoints and damage repair, ESC differentiation and apoptosis. Filia depletion causes ESC genomic instability, induces resistance to apoptosis and promotes malignant transformation. As part of its role in the DDR, Filia interacts with PARP1 and stimulates its enzymatic activity. Filia also constitutively resides on centrosomes and translocates to DNA damage sites and mitochondria, consistent with its multifaceted roles in regulating centrosome integrity, damage repair and apoptosis.

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“…Differences in genomic stability and differentiation potential among reprogrammed PSCs A fundamental concern about stem cells and their differentiated derivatives is their ability to restore physiological functionality and to resist neoplastic transformation in response to endogenous genotoxic stress (Wyles et al, 2014). Variations in differentiation potential were recently observed among isogenic PSCs generated by different reprogramming approaches (Fig.…”

Section: Resultsmentioning

confidence: 99%

Pluripotent stem cells with low differentiation potential contain incompletely reprogrammed DNA replication

Paniza

Deshpande

Wang

et al. 2020

Journal of Cell Biology

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Reprogrammed pluripotent stem cells (PSCs) are valuable for research and potentially for cell replacement therapy. However, only a fraction of reprogrammed PSCs are developmentally competent. Genomic stability and accurate DNA synthesis are fundamental for cell development and critical for safety. We analyzed whether defects in DNA replication contribute to genomic instability and the diverse differentiation potentials of reprogrammed PSCs. Using a unique single-molecule approach, we visualized DNA replication in isogenic PSCs generated by different reprogramming approaches, either somatic cell nuclear transfer (NT-hESCs) or with defined factors (iPSCs). In PSCs with lower differentiation potential, DNA replication was incompletely reprogrammed, and genomic instability increased during replicative stress. Reprogramming of DNA replication did not correlate with DNA methylation. Instead, fewer replication origins and a higher frequency of DNA breaks in PSCs with incompletely reprogrammed DNA replication were found. Given the impact of error-free DNA synthesis on the genomic integrity and differentiation proficiency of PSCs, analyzing DNA replication may be a useful quality control tool.

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Stem Cells: The Pursuit of Genomic Stability

Cited by 30 publications

References 122 publications

Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations

Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations

Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability

Pluripotent stem cells with low differentiation potential contain incompletely reprogrammed DNA replication

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