The role of DNA repair in the pluripotency and differentiation of human stem cells

Rocha, Clarissa Ribeiro Reily; Lerner, Letícia Koch; Okamoto, Oswaldo Keith; Marchetto, Maria C.; Menck, Carlos Frederico Martins

doi:10.1016/j.mrrev.2012.09.001

Cited by 79 publications

(72 citation statements)

References 132 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inherited polymorphic variants in some DNA repair enzymes are, in fact, closely associated with decreased DNA repair activity and a potentially higher probability of developing cancer. Many proteins involved in the DNA damage response are mutated in cancer [31][32][33]. The absence or lack of fidelity in NHEJ-driven repair increases the diversification of mutational lesions.…”

Section: Dna Repair and Cancer Stem Cellsmentioning

confidence: 99%

“…DNA repair enzymes play a major role in inducing point mutations [11,[31][32][33]. The production of a new cell depends on the duplication of the DNA that is promoted by the DNA polymerases with different efficiency and fidelity.…”

Section: Dna Repair and Cancer Stem Cellsmentioning

confidence: 99%

“…The production of a new cell depends on the duplication of the DNA that is promoted by the DNA polymerases with different efficiency and fidelity. During this process, several types of mutations occur (e.g., exchange of bases, insertions, and deletions) that are corrected precisely by DNA repair enzymes [11,[31][32][33]. Random mistakes are fixed during cell divisions and any failure in this repair can eliminate or disable genes, which leads to gain-of-function or inactivation of their normal function.…”

Section: Dna Repair and Cancer Stem Cellsmentioning

confidence: 99%

“…DNA crosslinks and oxidative DNA damage are repaired by NER, BER, HR, or NHEJ systems [11,30,31,33]. Human ES cells display very low levels of mitochondrial mass and oxidative phosphorylation [30,31,33].…”

Section: Dna Repair and Cancer Stem Cellsmentioning

confidence: 99%

“…Human ES cells display very low levels of mitochondrial mass and oxidative phosphorylation [30,31,33]. They obtain energy preferentially through non-oxidative glycolysis.…”

Section: Dna Repair and Cancer Stem Cellsmentioning

confidence: 99%

See 4 more Smart Citations

Cancer Risks Linked to the Bad Luck Hypothesis and Epigenomic Mutational Signatures

Belizário

2018

Epigenomes

View full text Add to dashboard Cite

Exposure to pathogen infection, and occupational and environmental agents, contributes to induction of most types of cancer through different mechanisms. Cancer is defined and characterized by accumulation of mutations and epimutations that lead to changes in the cellular genome and epigenome. According to a recent Bad Luck Hypothesis, random error mutations during DNA replication in a small population of stem cells may be implicated in two-thirds of variation of cancer risk in 25 organs and tissues. What determines stem cell vulnerability and risk of malignancy across the spectrum of organs, such as the brain, bone marrow, skeletal muscles, skin, and liver? Have stem cells pooled in particular tissues or organs evolved some critical ability to deal with DNA damage in the presence of extrinsic environmental factors? This paper describes how the complex replication and repair DNA systems control mutational events. In addition, recent advances on cancer epigenomic signatures and epigenetic mechanisms are discussed, which will guide future investigation of the origin of cancer initiating cells in tissue and organs in a clinical setting.

show abstract

Section: Dna Repair and Cancer Stem Cellsmentioning

confidence: 99%

Section: Dna Repair and Cancer Stem Cellsmentioning

confidence: 99%

Section: Dna Repair and Cancer Stem Cellsmentioning

confidence: 99%

Section: Dna Repair and Cancer Stem Cellsmentioning

confidence: 99%

“…Human ES cells display very low levels of mitochondrial mass and oxidative phosphorylation [30,31,33]. They obtain energy preferentially through non-oxidative glycolysis.…”

Section: Dna Repair and Cancer Stem Cellsmentioning

confidence: 99%

See 3 more Smart Citations

Cancer Risks Linked to the Bad Luck Hypothesis and Epigenomic Mutational Signatures

Belizário

2018

Epigenomes

View full text Add to dashboard Cite

show abstract

Peribiliary Glands Are Key in Regeneration of the Human Biliary Epithelium After Severe Bile Duct Injury

et al. 2019

View full text Add to dashboard Cite

Peribiliary glands (PBG) are a source of stem/progenitor cells organized in a cellular network encircling large bile ducts. Severe cholangiopathy with loss of luminal biliary epithelium has been proposed to activate PBG, resulting in cell proliferation and differentiation to restore biliary epithelial integrity. However, formal evidence for this concept in human livers is lacking. We therefore developed an ex vivo model using precision‐cut slices of extrahepatic human bile ducts obtained from discarded donor livers, providing an intact anatomical organization of cell structures, to study spatiotemporal differentiation and migration of PBG cells after severe biliary injury. Postischemic bile duct slices were incubated in oxygenated culture medium for up to a week. At baseline, severe tissue injury was evident with loss of luminal epithelial lining and mural stroma necrosis. In contrast, PBG remained relatively well preserved and different reactions of PBG were noted, including PBG dilatation, cell proliferation, and maturation. Proliferation of PBG cells increased after 24 hours of oxygenated incubation, reaching a peak after 72 hours. Proliferation of PBG cells was paralleled by a reduction in PBG apoptosis and differentiation from a primitive and pluripotent (homeobox protein Nanog+/ sex‐determining region Y‐box 9+) to a mature (cystic fibrosis transmembrane conductance regulator+/secretin receptor+) and activated phenotype (increased expression of hypoxia‐inducible factor 1 alpha, glucose transporter 1, and vascular endothelial growth factor A). Migration of proliferating PBG cells in our ex vivo model was unorganized, but resulted in generation of epithelial monolayers at stromal surfaces. Conclusion: Human PBG contain biliary progenitor cells and are able to respond to bile duct epithelial loss with proliferation, differentiation, and maturation to restore epithelial integrity. The ex vivo spatiotemporal behavior of human PBG cells provides evidence for a pivotal role of PBG in biliary regeneration after severe injury.

show abstract

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

The role of DNA repair in the pluripotency and differentiation of human stem cells

Cited by 79 publications

References 132 publications

Cancer Risks Linked to the Bad Luck Hypothesis and Epigenomic Mutational Signatures

Cancer Risks Linked to the Bad Luck Hypothesis and Epigenomic Mutational Signatures

Peribiliary Glands Are Key in Regeneration of the Human Biliary Epithelium After Severe Bile Duct Injury

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

Contact Info

Product

Resources

About