https://doi.org/10.4081/ejh.2021.3236
DNA damage and repair in differentiation of stem cells and cells of connective cell lineages: A trigger or a complication?
Submitted: 24 February 2021
Accepted: 16 April 2021
Published: 3 May 2021
Accepted: 16 April 2021
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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The review summarizes literature data on the role of DNA breaks and DNA repair in differentiation of pluripotent stem cells (PSC) and connective cell lineages. PSC, including embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC), are rapidly dividing cells with highly active DNA damage response (DDR) mechanisms to ensure the stability and integrity of the DNA. In PSCs, the most common DDR mechanism is error-free homologous recombination (HR) that is primarily active during S phase of the cell cycle, whereas in quiescent, slow-dividing or non-dividing tissue progenitors and terminally differentiated cells, error-prone non-homologous end joining (NHEJ) mechanism of the double-strand break (DSB) repair is dominating. Thus, it seems that reprogramming and differentiation induce DNA strand breaks in stem cells which itself may trigger the differentiation process. Somatic cell reprogramming to iPSCs is preceded by a transient increase of the DSBs induced presumably by the caspase-dependent DNase or reactive oxygen species (ROS). In general, pluripotent stem cells possess stronger DNA repair systems compared to the differentiated cells. Nonetheless, during a prolonged cell culture propagation, DNA breaks can accumulate due to the DNA polymerase stalling. Consequently, the DNA damage might trigger the differentiation of stem cells or a replicative senescence of somatic cells. Differentiation process per se is often accompanied by a decrease of the DNA repair capacity. Thus, the differentiation might be triggered by DNA breaks, alternatively the breaks can be a consequence of the decay in the DNA repair capacity of differentiated cells.
Vitale I, Manic G, De Maria R, Kroemer G, Galluzzi L. DNA damage in stem cells. Mol Cell 2017;66:306-19.
DOI: https://doi.org/10.1016/j.molcel.2017.04.006
Mani C, Reddy PH, Palle K. DNA repair fidelity in stem cell maintenance, health, and disease. Biochim Biophys Acta Mol Basis Dis 2020;1866:165444.
DOI: https://doi.org/10.1016/j.bbadis.2019.03.017
Sjakste N, Sjakste T. Possible involvement of DNA strand breaks in regulation of cell differentiation. Eur J Histochem 2007;51:81-94.
Alt FW, Schwer B. DNA double-strand breaks as drivers of neural genomic change, function, and disease. DNA Repair (Amst) 2018;71:158-63.
DOI: https://doi.org/10.1016/j.dnarep.2018.08.019
Arya R, Bassing CH. V(D)J recombination exploits DNA damage responses to promote immunity. Trends Genet 2017;33:479-89.
DOI: https://doi.org/10.1016/j.tig.2017.04.006
Oster S, Aqeilan RI. Programmed dna damage and physiological DSBs: Mapping, biological significance and perturbations in disease states. Cells 2020;9:1870.
DOI: https://doi.org/10.3390/cells9081870
Larsen BD, Megeney LA. Parole terms for a killer: directing caspase3/CAD induced DNA strand breaks to coordinate changes in gene expression. Cell Cycle 2010;9:2940-5.
Larsen BD, Rampalli S, Burns LE, Brunette S, Dilworth FJ, Megeney LA. Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks. Proc Natl Acad Sci USA 2010;107:4230-5.
DOI: https://doi.org/10.1073/pnas.0913089107
Larsen BD, Sørensen CS. The caspase-activated DNase: apoptosis and beyond. FEBS J 2017;284:1160-70.
DOI: https://doi.org/10.1111/febs.13970
Bell RAV, Megeney LA. Evolution of caspase-mediated cell death and differentiation: twins separated at birth. Cell Death Differ 2017;24:1359-68.
DOI: https://doi.org/10.1038/cdd.2017.37
Azqueta A, Ladeira C, Giovannelli L, Boutet-Robinet E, Bonassi S, Neri M, et al. Application of the comet assay in human biomonitoring: An hCOMET perspective. Mutat Res 2020;783:108288.
DOI: https://doi.org/10.1016/j.mrrev.2019.108288
Fung H, Weinstock DM. Repair at single targeted DNA double-strand breaks in pluripotent and differentiated human cells. PLoS One 2011;6:e20514.
DOI: https://doi.org/10.1371/journal.pone.0020514
Oster S, Aqeilan RI. Mapping the breakome reveals tight regulation on oncogenic super-enhancers. Mol Cell Oncol 2020;7:1698933.
DOI: https://doi.org/10.1080/23723556.2019.1698933
Baranello L, Kouzine F, Wojtowicz D, Cui K, Zhao K, Przytycka TM, et al. Mapping DNA breaks by next-generation sequencing. Methods Mol Biol 2018;1672:155-66.
DOI: https://doi.org/10.1007/978-1-4939-7306-4_13
Canela A, Sridharan S, Sciascia N, Tubbs A, Meltzer P, Sleckman BP, et al. DNA breaks and end resection measured genome-wide by end sequencing. Mol Cell 2016;63:898-911.
DOI: https://doi.org/10.1016/j.molcel.2016.06.034
Choi EH, Yoon S, Koh YE, Seo YJ, Kim KP. Maintenance of genome integrity and active homologous recombination in embryonic stem cells. Exp Mol Med 2020;52:1220-9.
DOI: https://doi.org/10.1038/s12276-020-0481-2
Fujita J, Crane AM, Souza MK, Dejosez M, Kyba M, Flavell RA et al. Caspase activity mediates the differentiation of embryonic stem cells. Cell Stem Cell 2008;2:595-601.
DOI: https://doi.org/10.1016/j.stem.2008.04.001
Abdul-Ghani M, Megeney LA. Rehabilitation of a contract killer: caspase-3 directs stem cell differentiation. Cell Stem Cell 2008;2:515-6.
DOI: https://doi.org/10.1016/j.stem.2008.05.013
Hussein S, Batada N, Vuoristo S, Ching RW, Autio R, Närvä E et al. Copy number variation and selection during reprogramming to pluripotency. Nature 2011:471;58–62.
DOI: https://doi.org/10.1038/nature09871
Simara P, Tesarova L, Rehakova D, Matula P, Stejskal S, Hampl A et al. DNA double-strand breaks in human induced pluripotent stem cell reprogramming and long-term in vitro culturing. Stem Cell Res Ther 2017;8:73.
DOI: https://doi.org/10.1186/s13287-017-0522-5
Li F, He Z, Shen J, Huang Q, Li W, Liu X et al. Apoptotic caspases regulate induction of iPSCs from human fibroblasts. Cell Stem Cell 2010;7:508-20.
DOI: https://doi.org/10.1016/j.stem.2010.09.003
Martin U. Genome stability of programmed stem cell products. Adv Drug Deliv Rev 2017;120:108-17.
DOI: https://doi.org/10.1016/j.addr.2017.09.004
Gu N, Tamada Y, Imai A, Palfalvi G, Kabeya Y Shigenobu S, et al. DNA damage triggers reprogramming of differentiated cells into stem cells in Physcomitrella. Nat Plants 2020;6:1098-105.
DOI: https://doi.org/10.1038/s41477-020-0745-9
Vallabhaneni H, Lynch PJ, Chen G, Park K, Liu Y, Goehe R, et al. High basal levels of γH2AX in human induced pluripotent stem cells are linked to replication-associated DNA damage and repair. Stem Cells 2018;36:1501-13.
DOI: https://doi.org/10.1002/stem.2861
Gómez-Cabello D, Checa-Rodríguez C, Abad M, Serrano M, Huertas P. CtIP-specific roles during cell reprogramming have long-term consequences in the survival and fitness of induced pluripotent stem cells. Stem Cell Rep 2017;8:432-45.
DOI: https://doi.org/10.1016/j.stemcr.2016.12.009
Liu X, Li C, Zheng K, Zhao X, Xu X, Yang A, et al. Chromosomal aberration arises during somatic reprogramming to pluripotent stem cells. Cell Div 2020;15:12.
DOI: https://doi.org/10.1186/s13008-020-00068-z
Shimada M, Tsukada K, Kagawa N, Matsumoto Y. Reprogramming and differentiation-dependent transcriptional alteration of DNA damage response and apoptosis genes in human induced pluripotent stem cells. J Radiat Res 2019;60:719-28.
DOI: https://doi.org/10.1093/jrr/rrz057
Suchorska WM, Augustyniak E, Łukjanow M. Comparison of the early response of human embryonic stem cells and human induced pluripotent stem cells to ionizing radiation. Mol Med Rep 2017;15:1952-62.
DOI: https://doi.org/10.3892/mmr.2017.6270
Mujoo K, Pandita RK, Tiwari A, Charaka V, Chakraborty S, Singh DK, et al. Differentiation of human induced pluripotent or embryonic stem cells decreases the DNA damage repair by homologous recombination. Stem Cell Rep 2017;9:1660-74.
DOI: https://doi.org/10.1016/j.stemcr.2017.10.002
Pittenger MF, Discher DE, Péault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med 2019;4:22.
DOI: https://doi.org/10.1038/s41536-019-0083-6
Caplan AI. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol 2007;213:341-7.
DOI: https://doi.org/10.1002/jcp.21200
Neri S. Genetic stability of mesenchymal stromal cells for regenerative medicine applications: A fundamental biosafety aspect. Int J Mol Sci 2019;20:2406.
DOI: https://doi.org/10.3390/ijms20102406
Tichy ED, Pillai R, Deng L, Liang L, Tischfield J, Schwemberger SJ, et al. Mouse embryonic stem cells, but not somatic cells, predominantly use homologous recombination to repair double-strand DNA breaks. Stem Cells Dev 2010;19:1699-711.
DOI: https://doi.org/10.1089/scd.2010.0058
Hare I, Gencheva M, Evans R, Fortney J, Piktel D, Vos JA, et al. In vitro expansion of bone marrow derived mesenchymal stem cells alters DNA double strand break repair of etoposide induced DNA damage. Stem Cells Int 2016;2016:8270464.
DOI: https://doi.org/10.1155/2016/8270464
Bao X, Wang J, Zhou G, Aszodi A, Schönitzer V, Scherthan H, et al. Extended in vitro culture of primary human mesenchymal stem cells downregulates Brca1-related genes and impairs DNA double-strand break recognition. FEBS Open Bio 2020;10:1238-50.
DOI: https://doi.org/10.1002/2211-5463.12867
Wu PK, Wang JY, Chen CF, Chao KY, Chang MC, Chen WM, et al. Early passage mesenchymal stem cells display decreased radiosensitivity and increased DNA repair activity. Stem Cells Transl Med 2017;6:1504-14.
DOI: https://doi.org/10.1002/sctm.15-0394
Lützkendorf J, Wieduwild E, Nerger K, Lambrecht N, Schmoll HJ, Müller-Tidow C, et al. Resistance for genotoxic damage in mesenchymal stromal cells is increased by hypoxia but not generally dependent on p53-regulated cell cycle arrest. PLoS One 2017;12:e0169921.
DOI: https://doi.org/10.1371/journal.pone.0169921
He N, Xiao C, Sun Y, Wang Y, Du L, Feng Y, et al. Radiation responses of human mesenchymal stem cells derived from different sources. Dose Response 2019;17:1559325819893210.
DOI: https://doi.org/10.1177/1559325819893210
Fekete N, Erle A, Amann EM, Fürst D, Rojewski MT, Langonné A. Effect of high-dose irradiation on human bone-marrow-derived mesenchymal stromal cells. Tissue Eng Part C Methods 2015;21:112-22.
DOI: https://doi.org/10.1089/ten.tec.2013.0766
Qadir A, Liang S, Wu Z, Chen Z, Hu L, Qian A. Senile osteoporosis: The involvement of differentiation and senescence of bone marrow stromal cells. Int J Mol Sci 2020;21:349.
DOI: https://doi.org/10.3390/ijms21010349
Duer M, Cobb AM, Shanahan CM. DNA damage response: A molecular lynchpin in the pathobiology of arteriosclerotic calcification. Arterioscler Thromb Vasc Biol 2020;40:e193-e202.
DOI: https://doi.org/10.1161/ATVBAHA.120.313792
Kostyuk S, Smirnova T, Kameneva L, Porokhovnik L, Speranskij A, Ershova E et al. GC-rich extracellular DNA induces oxidative stress, double-strand DNA breaks, and DNA damage response in human adipose-derived mesenchymal stem cells. Oxid Med Cell Longev 2015;2015:782123.
DOI: https://doi.org/10.1155/2015/782123
Kostyuk SV, Porokhovnik LN, Ershova ES, Malinovskaya EM Konkova MS, Kameneva LV et al. Changes of KEAP1/NRF2 and IKB/NF-κB expression levels induced by cell-free DNA in different cell types. Oxid Med Cell Longev 2018;2018:1052413.
DOI: https://doi.org/10.1155/2018/1052413
Valverde M, Lozano-Salgado J, Fortini P, Rodriguez-Sastre MA, Rojas E, Dogliotti E. Hydrogen peroxide-induced DNA damage and repair through the differentiation of human adipose-derived mesenchymal stem cells. Stem Cells Int 2018;2018:1615497.
DOI: https://doi.org/10.1155/2018/1615497
Doan-Xuan QM, Sarvari AK, Fischer-Posovszky P, Wabitsch M, Balajthy Z, Fesus L, et al. High content analysis of differentiation and cell death in human adipocytes. Cytometry A 2013;83:933-43.
Meulle A, Salles B, Daviaud D, Valet P, Muller C. Positive regulation of DNA double strand break repair activity during differentiation of long life span cells: the example of adipogenesis. PLoS One 2008;3:e3345.
DOI: https://doi.org/10.1371/journal.pone.0003345
Erener S, Hesse M, Kostadinova R, Hottiger MO. Poly(ADP-ribose)polymerase-1 (PARP1) controls adipogenic gene expression and adipocyte function. Mol Endocrinol 2012;26:79-86.
DOI: https://doi.org/10.1210/me.2011-1163
Chen YW, Harris RA, Hatahet Z, Chou KM. Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities. Proc Natl Acad Sci USA 2015;112:E4556-64.
DOI: https://doi.org/10.1073/pnas.1506954112
Oliver L, Hue E, Séry Q, Lafargue A, Pecqueur C, Paris F, et al. Differentiation-related response to DNA breaks in human mesenchymal stem cells. Stem Cells 2013;31:800-7.
DOI: https://doi.org/10.1002/stem.1336
Kim HN, Chang J, Shao L, Han L, Iyer S, Manolagas SC, et al. DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age. Aging Cell 2017;16:693-703.
DOI: https://doi.org/10.1111/acel.12597
Li J, Zuo B, Zhang L, Dai L, Zhang X: Osteoblast versus adipocyte: Bone marrow microenvironment-guided epigenetic control. Case Rep Orthop Res 2018;1:2-18.
DOI: https://doi.org/10.1159/000489053
Li J, Dong S. The signaling pathways involved in chondrocyte differentiation and hypertrophic differentiation. Stem Cells Int 2016;2016:2470351.
DOI: https://doi.org/10.1155/2016/2470351
Jeon OH, David N, Campisi J, Elisseeff JH. Senescent cells and osteoarthritis: a painful connection. J Clin Invest 2018;128:1229-37.
DOI: https://doi.org/10.1172/JCI95147
Coryell PR, Diekman BO, Loeser RF. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat Rev Rheumatol 2021;17:47-57.
DOI: https://doi.org/10.1038/s41584-020-00533-7
Copp ME, Flanders MC, Gagliardi R, Gilbertie JM, Sessions GA, Chubinskaya S, et al. The combination of mitogenic stimulation and DNA damage induces chondrocyte senescence. Osteoarthritis Cartilage 2021;29:402-12.
DOI: https://doi.org/10.1016/j.joca.2020.11.004
Minguzzi M, Cetrullo S, D'Adamo S, Silvestri Y, Flamigni F, Borzì RM. Emerging players at the intersection of chondrocyte loss of maturational arrest, oxidative stress, senescence and low-grade inflammation in osteoarthritis. Oxid Med Cell Longev 2018;2018:3075293.
DOI: https://doi.org/10.1155/2018/3075293
Stelcer E, Kulcenty K, Rucinski M, Jopek K, Richter M, Trzeciak T, et al. Forced differentiation in vitro leads to stress-induced activation of DNAdamage response in hiPSC-derived chondrocyte-like cells. PLoS One 20184;13:e0198079.
DOI: https://doi.org/10.1371/journal.pone.0198079
Stelcer E, Kulcenty K, Suchorska WM. Chondrocytes differentiated from humaninduced pluripotent stem cells: Response to ionizing radiation. PLoS One 2018;13:e0205691.
DOI: https://doi.org/10.1371/journal.pone.0205691
Beerman I, Seita J, Inlay MA, Weissman IL, Rossi DJ. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 2014;15:37-50.
DOI: https://doi.org/10.1016/j.stem.2014.04.016
Beerman I. Accumulation of DNA damage in the aged hematopoietic stem cell compartment. Semin Hematol 2017;54:12-18.
DOI: https://doi.org/10.1053/j.seminhematol.2016.11.001
Beerman I. Cell umbrella protects stem cells from DNA damage. Nature 2018;558:374-5.
DOI: https://doi.org/10.1038/d41586-018-05166-1
Wingert S, Rieger MA. Terminal differentiation induction as DNA damage response in hematopoietic stem cells by GADD45A. Exp Hematol 2016;44:561-6.
DOI: https://doi.org/10.1016/j.exphem.2016.04.006
Wingert S, Thalheimer FB, Haetscher N, Rehage M, Schroeder T, Rieger MA. DNA-damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival. Stem Cells 2016;34:699-710.
DOI: https://doi.org/10.1002/stem.2282
Bai L, Shi G, Zhang X, Dong W, Zhang L. Transgenic expression of BRCA1 disturbs hematopoietic stem and progenitor cells quiescence and function. Exp Cell Res 2013;319:2739-46.
DOI: https://doi.org/10.1016/j.yexcr.2013.06.014
Berte N, Eich M, Heylmann D, Koks C, Van Gool SW, Kaina B. Impaired DNA repair in mouse monocytes compared to macrophages and precursors. DNA Repair (Amst) 2020;98:103037.
DOI: https://doi.org/10.1016/j.dnarep.2020.103037
Kraft D, Rall M, Volcic M, Metzler E, Groo A, Stahl A et al. NF-κB-dependent DNA damage-signaling differentially regulates DNA double-strand break repair mechanisms in immature and mature human hematopoietic cells. Leukemia 2015;29:1543-54.
DOI: https://doi.org/10.1038/leu.2015.28
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University of LatviaHow to Cite
Sjakste, N., & Riekstiņa, U. (2021). DNA damage and repair in differentiation of stem cells and cells of connective cell lineages: A trigger or a complication?. European Journal of Histochemistry, 65(2). https://doi.org/10.4081/ejh.2021.3236
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