Interaction between Fibroblasts and Immune Cells Following DNA Damage Induced by Ionizing Radiation

Ragunathan, Kalaiyarasi; Upfold, Nikki Lyn Esnardo; Oksenych, Valentyn

doi:10.20944/preprints202011.0339.v2

Cited by 18 publications

(8 citation statements)

References 67 publications

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“…It was previously shown that the expression and activity of DNA-PKcs are increased in the NSPC murine cells when compared to mouse embryonic fibroblasts [ 26 ], suggesting that DNA-PKcs can be essential for homeostasis of NSPCs. Expression and activity of NHEJ vary in different cell types and require closer attention in future research [ 33 ]. Our data further highlighted this observation, and our findings suggest that the DNA-PKcs is required for NSPC proliferation and self-renewal capacities, although its role is partially compensated by XLF ( Figure 2 B,C).…”

Section: Discussionmentioning

confidence: 99%

Non-Homologous End Joining Factors XLF, PAXX and DNA-PKcs Maintain the Neural Stem and Progenitor Cell Population

Gago-Fuentes

Oksenych

2020

Biomolecules

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Non-homologous end-joining (NHEJ) is a major DNA repair pathway in mammalian cells that recognizes, processes and fixes DNA damage throughout the cell cycle and is specifically important for homeostasis of post-mitotic neurons and developing lymphocytes. Neuronal apoptosis increases in the mice lacking NHEJ factors Ku70 and Ku80. Inactivation of other NHEJ genes, either Xrcc4 or Lig4, leads to massive neuronal apoptosis in the central nervous system (CNS) that correlates with embryonic lethality in mice. Inactivation of either Paxx, Mri or Dna-pkcs NHEJ gene results in normal CNS development due to compensatory effects of Xlf. Combined inactivation of Xlf/Paxx, Xlf/Mri and Xlf/Dna-pkcs, however, results in late embryonic lethality and high levels of apoptosis in CNS. To determine the impact of NHEJ factors on the early stages of neurodevelopment, we isolated neural stem and progenitor cells from mouse embryos and investigated proliferation, self-renewal and differentiation capacity of these cells lacking either Xlf, Paxx, Dna-pkcs, Xlf/Paxx or Xlf/Dna-pkcs. We found that XRCC4-like factor (XLF), DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and paralogue of XRCC4 and XLF (PAXX) maintain the neural stem and progenitor cell populations and neurodevelopment in mammals, which is particularly evident in the double knockout models.

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Section: Discussionmentioning

confidence: 99%

Non-Homologous End Joining Factors XLF, PAXX and DNA-PKcs Maintain the Neural Stem and Progenitor Cell Population

Gago-Fuentes

Oksenych

2020

Biomolecules

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“…An important consequence that may take shape because of RT is chronic inflammation that drives fibrosis and leads to an increase in stromal members in the TME as well as more ECM components ( Straub et al, 2015 ). CAFs tolerate relatively high doses (30 Gy) of radiation without apoptosis; however, doses higher than 10–12 Gy often result in a senescent CAF phenotype ( Ragunathan et al, 2020 ). Premature senescence seems to be also induced in normal human fibroblasts as a result of chronic low dose rate (LDR) exposure (5 or 15 mGy/h) of gamma rays ( Fujimori et al, 2005 ).…”

Section: The Effects Of Cancer Therapies On Cancer-associated Fibroblastsmentioning

confidence: 99%

The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth

Manoukian

Bijlsma

Laarhoven

2021

Front. Cell Dev. Biol.

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Pancreatic tumors are known to harbor an abundant and highly desmoplastic stroma. Among the various cell types that reside within tumor stroma, cancer-associated fibroblasts (CAFs) have gained a lot of attention in the cancer field due to their contributions to carcinogenesis and tumor architecture. These cells are not a homogeneous population, but have been shown to have different origins, phenotypes, and contributions. In pancreatic tumors, CAFs generally emerge through the activation and/or recruitment of various cell types, most notably resident fibroblasts, pancreatic stellate cells (PSCs), and tumor-infiltrating mesenchymal stem cells (MSCs). In recent years, single cell transcriptomic studies allowed the identification of distinct CAF populations in pancreatic tumors. Nonetheless, the exact sources and functions of those different CAF phenotypes remain to be fully understood. Considering the importance of stromal cells in pancreatic cancer, many novel approaches have aimed at targeting the stroma but current stroma-targeting therapies have yielded subpar results, which may be attributed to heterogeneity in the fibroblast population. Thus, fully understanding the roles of different subsets of CAFs within the stroma, and the cellular dynamics at play that contribute to heterogeneity in CAF subsets may be essential for the design of novel therapies and improving clinical outcomes. Fortunately, recent advances in technologies such as microfluidics and bio-printing have made it possible to establish more advanced ex vivo models that will likely prove useful. In this review, we will present the different roles of stromal cells in pancreatic cancer, focusing on CAF origin as a source of heterogeneity, and the role this may play in therapy failure. We will discuss preclinical models that could be of benefit to the field and that may contribute to further clinical development.

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“…Cells will immediately initiate apoptosis, once DNA damage repair fails (15,16). 0.5-1Gy irradiation can induce DNA damage and apoptosis for peripheral blood lymphocytes which are very sensitive to irradiation (17,18). P53 signaling pathway plays an extremely important role in both DNA damage repair and the initiation of apoptosis (14).…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, P53 is activated and the stability of P53 is enhanced, which result in cell cycle arrest at G1/S phase and provide a critical opportunity for cells to restore genomic integrity prior to DNA replication. Repairable DNA damage tends to be transient, whereas sustained P53 activation will induce the cells to initiate apoptotic program (17,22). P53 signal plays an important regulatory role in the whole process of ionizing radiation-induced DNA damage and lymphocyte apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Early Biomarkers Associated with P53 Signaling for Acute Radiation Injury

Zhou²,

Meng³

et al. 2022

Life

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Accurate dose assessment within 1 day or even 12 h after exposure through current methods of dose estimation remains a challenge, in response to a large number of casualties caused by nuclear or radiation accidents. P53 signaling pathway plays an important role in DNA damage repair and cell apoptosis induced by ionizing radiation. The changes of radiation-induced P53 related genes in the early stage of ionizing radiation should compensate for the deficiency of lymphocyte decline and γ-H2AX analysis as novel biomarkers of radiation damage. Bioinformatic analysis was performed on previous data to find candidate genes from human peripheral blood irradiated in vitro. The expression levels of candidate genes were detected by RT-PCR. The expressions of screened DDB2, AEN, TRIAP1, and TRAF4 were stable in healthy population, but significantly up-regulated by radiation, with time specificity and dose dependence in 2–24 h after irradiation. They are early indicators for medical treatment in acute radiation injury. Their effective combination could achieve a more accurate dose assessment for large-scale wounded patients within 24 h post exposure. The effective combination of p53-related genes DDB2, AEN, TRIAP1, and TRAF4 is a novel biodosimetry for a large number of people exposed to acute nuclear accidents.

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Interaction between Fibroblasts and Immune Cells Following DNA Damage Induced by Ionizing Radiation

Cited by 18 publications

References 67 publications

Non-Homologous End Joining Factors XLF, PAXX and DNA-PKcs Maintain the Neural Stem and Progenitor Cell Population

Non-Homologous End Joining Factors XLF, PAXX and DNA-PKcs Maintain the Neural Stem and Progenitor Cell Population

The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth

Early Biomarkers Associated with P53 Signaling for Acute Radiation Injury

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