Overcoming Pluripotent Stem Cell Dependence on the Repair of Endogenous DNA Damage

Chlon, Timothy M.; Ruiz-Torres, Sonya; Maag, Logan; Mayhew, Christopher N.; Wikenheiser-Brokamp, Kathryn A.; Davies, Stella M.; Mehta, Parinda A.; Myers, Kasiani C.; Wells, James M.; Wells, Susanne I.

doi:10.1016/j.stemcr.2015.12.001

Cited by 29 publications

(32 citation statements)

References 20 publications

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“…However, other study showed that although irradiated hESCs undergo significant apoptosis after irradiation, they continue to remain pluripotent and maintain the ability to form all three germ layers (such as the formation of teratomas in vivo ). Such studies are thought to have implications for tracking cellular regenerative therapies using radiotracer reporter probes (104). Many DNA damaging metabolites, including ROS and aldehydes, cause interstrand crosslinks (ICLs).…”

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%

“…A recent report established that iPSCs require FA pathway for their growth in vitro and CHK1 was shown to be a critical regulator iPSCs hypersensitivity to DNA damage. Hyperactive CHK1 signaling restricts iPSC self-renewal in the absence of error free DNA repair (104), hence maintaining the genomic stability.…”

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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“…Moreover, with the advent of high-precision irradiation using protons and heavier ions such as carbon ions at HIT [14,16], we sought to evaluate the feasibility of this approach to decipher the transcriptome response as a surrogate for RBE of different radiation qualities (RQ). To evaluate whether potential differences in the transcriptional response to radiation is influenced by the genetic predisposition of the patients we have compared radiation-associated gene expression patterns in normal to FANCA deficient HIO which were derived from iPSC of individuals with FA [17]. The sensitivity of FA patients to chemotherapy agents involved in DNA damaging processes such as cisplatin and mitomycin C is well known.…”

Section: Introductionmentioning

confidence: 99%

Personalized Assessment of Normal Tissue Radiosensitivity via Transcriptome Response to Photon, Proton and Carbon Irradiation in Patient-Derived Human Intestinal Organoids

Nowrouzi

Sertorio

Akbarpour

et al. 2020

Cancers

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Radiation-induced normal tissue toxicity often limits the curative treatment of cancer. Moreover, normal tissue relative biological effectiveness data for high-linear energy transfer particles are urgently needed. We propose a strategy based on transcriptome analysis of patient-derived human intestinal organoids (HIO) to determine molecular surrogates for radioresponse of gastrointestinal (GI) organs at risk in a personalized manner. HIO were generated from induced pluripotent stem cells (iPSC), which were derived from skin biopsies of three patients, including two patients with FANCA deficiency as a paradigm for enhanced radiosensitivity. For the two Fanconi anemia (FA) patients (HIO-104 and 106, previously published as FA-A#1 IND-iPS1 and FA-A#2 IND-iPS3), FANCA expression was reconstituted as a prerequisite for generation of HIO via lentiviral expression of a doxycycline inducible construct. For radiosensitivity analysis, FANCA deficient and FANCA rescued as well as wtHIO were sham treated or irradiated with 4Gy photon, proton or carbon ions at HIT, respectively. Immunofluorescence staining of HIO for 53BP1-foci was performed 1 h post IR and gene expression analyses was performed 12 and 48 h post IR. 53BP1-foci numbers and size correlated with the higher RBE of carbon ions. A FANCA dependent differential gene expression in response to radiation was found (p < 0.01, ANOVA; n = 1071 12 h; n = 1100 48 h). Pathways associated with FA and DNA-damage repair i.e., transcriptional coupled nucleotide excision repair, homology-directed repair and translational synthesis were found to be differentially regulated in FANCA deficient HIO. Next, differential regulated genes were investigated as a function of radiation quality (RQ, p < 0.05, ANOVA; n = 742 12 h; n = 553 48 h). Interestingly, a gradual increase or decrease of gene expression was found to correlate with the three main qualities, from photon to proton and carbon irradiation. Clustering separated high-linear energy transfer irradiation with carbons from proton and photon irradiation. Genes associated with dual incision steps of TC-NER were differentially regulated in photon vs. proton and carbon irradiation. Consequently, SUMO3, ALC1, POLE4, PCBP4, MUTYH expression correlated with the higher RBE of carbon ions. An interaction between the two studied parameters FA and RQ was identified (p < 0.01, 2-way ANOVA n = 476). A comparison of genes regulated as a function of FA, RQ and RBE suggest a role for p53 interacting genes BRD7, EWSR1, FBXO11, FBXW8, HMGB1, MAGED2, PCBP4, and RPS27 as modulators of FA in response to radiation. This proof of concept study demonstrates that patient tailored evaluation of GI response to radiation is feasible via generation of HIO and comparative transcriptome profiling. This methodology can now be further explored for a personalized assessment of GI radiosensitivity and RBE estimation.

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“…Inherent traits that increase the risk for introduction of mutations and/or for increased genomic instability may facilitate the process of transformation. Indeed, the mutation rates in pluripotent stem cells have been shown to be relatively lower than the mutation rates in somatic cells, which are believed to be due at least partly to the extensive use of the mechanism for homologous recombination for DNA repair (Cervantes et al 2002, Chlon et al 2016). The latter is less error-prone than the other mechanisms of DNA repair, mainly because it uses the highaccuracy DNA polymerases of replication (Chakarov et al 2014b).…”

Section: The Role Of Irc In the Establishment Maintenance Of Pluripomentioning

confidence: 99%

The success of stem cell transplantations and the potential post-transplantation complications may be dependent, among other factors, on the capacity of the recipient and the transplanted cells to repair DNA damage

Reynolds¹

2016

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Cell therapy is presently a treatment of choice for many types of haematological and metabolic diseases and is likely to become a therapeutic option for other severe human diseases and conditions in the near future. The success of cell transplantation depends on a variety of factors, including the degree of HLA match between the donor and the recipient, the infectious burden of the graft, cell dosage, age, general state of the recipient and other incompletely characterised features of the donor and the recipient. It is likely that the individual capacity for identification and repair of DNA damage and maintenance of genomic integrity may account, at least in part, for these elusive factors that modulate transplantation outcome in terms of success rate and both long and short term posttransplantation complications. This paper outlines the role of individual repair capacity of the donor and recipient in cell transplantations, summarising the little knowledge already accumulated in the field whilst analysing the known major issues of the use of different types of stem cells. Attention will be given to their capacity to maintain the integrity of their genome, the ability to renew their own population, differentiate into various cell types and in ‡

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Overcoming Pluripotent Stem Cell Dependence on the Repair of Endogenous DNA Damage

Cited by 29 publications

References 20 publications

Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations

Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations

Personalized Assessment of Normal Tissue Radiosensitivity via Transcriptome Response to Photon, Proton and Carbon Irradiation in Patient-Derived Human Intestinal Organoids

The success of stem cell transplantations and the potential post-transplantation complications may be dependent, among other factors, on the capacity of the recipient and the transplanted cells to repair DNA damage

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