Abstract
This chapter addresses the genetic instability in stem cells, a central feature that is an important determinant for the safety and effectiveness of cell-based therapies. First, DNA damage response mechanism and the gene network that regulates the DNA integrity homeostasis are revisited, focusing on relationship between genetic integrity and stemness maintenance. Also, several factors have been included that influence genetic instability in vivo, i.e., ROS generation and inflammation, and in vitro regarding cell isolation, culture conditions, i.e., oxygen levels and the use of feeder layers and different carriers, splitting procedures, passage number, etc. Telomere shortening, replicative senescence aneuploidy, and the senescence-associated secretory phenotype are different processes involved in deterioration of stem cells abilities for homing, reparability, and paracrine modulation. Moreover, less effective DNA repair upon senescence increases the propensity of developing tumors for stem cells that is one the main concerns related to genetic instability in stem cells. Nuclear organization and their determinants linked to chromosome aberrations and aneuploidy in stem cells and those epigenetic changes affecting stability are addressed. Differences between adipose, embryonic, and induced pluripotent stem cells are analyzed regarding to their ontogeny, changes in culture, and variation in proliferative capacity and stemness. The effect of reprogramming methods in genetic instability and variation in mutagenicity according to genes utilized for pluripotency induction, i.e., Yamanaka’s factors and others, is discussed. Donor-related factors, i.e., age, smoking, and alcohol consumption, comorbidities, i.e., obesity, insulin resistance, diabetes, are mentioned for wide evaluation of genetic instability. The next years must witness consensus protocols that will contribute to control the effects of factors that alter stem cell genetic stability to increase the security and applicability of cell-based therapy.
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Abbreviations
- ASC:
-
Adipose stem cells
- AT:
-
Adipose tissue
- ATM:
-
Ataxia telangiectasia mutated
- ATR:
-
ATM- and Rad3-related serine/threonine kinase
- BATF:
-
Basic leucine zipper transcription factor – ATF-like
- BER:
-
Base excision repair
- BID:
-
BH3 interacting domain death agonist
- BM-hMSC:
-
Bone marrow human mesenchymal stem cell
- BRCA1:
-
BReast CAncer gene 1
- CASP:
-
Caspase
- Cdc25a:
-
Cycle regulator phosphatase
- CDK:
-
Cyclin-dependent kinase p16Ink4a
- CENP-A:
-
Centromere histone H3 variant
- Cernunnos/XLF:
-
Nonhomologous end-joining factor 1
- CHK1/2:
-
Checkpoint kinase 1 and 2
- c-MYC:
-
Transcription factor, proto-oncogene
- CNVs:
-
Copy number variations
- CT:
-
Chromosome territories
- DBC1:
-
Deleted in bladder cancer protein 1
- DDR:
-
DNA damage response
- DDT:
-
DNA damage tolerance
- DNA-PKcs:
-
DNA-dependent protein kinase
- DPPA3:
-
Developmental pluripotency-associated protein-3
- DSBs:
-
Double-stranded breaks
- EPC:
-
Endothelial progenitor cells
- ESCs:
-
Embryonic stem cells
- Exo1:
-
Exonuclease 1
- FISH:
-
Fluorescent in situ hybridization
- FOXO:
-
Forkhead box O1 transcription factor
- hADSC:
-
Human adipose-derived stem cells
- hESCs:
-
Human ESCs
- HIF-1α:
-
Hypoxia-inducible factor-1α
- hiPSCs:
-
Human induced pluripotent stem cells
- hPSCs:
-
Human pluripotent stem cells
- HR:
-
Homologous recombination
- HSC:
-
Hematopoietic stem cells
- hTR:
-
Noncoding human telomerase RNA
- ICLR:
-
Interstrand cross-link repair
- IDH2:
-
Isocitrate dehydrogenase-2
- iPSCs:
-
Induced pluripotent stem cells
- Klf4:
-
KrĂĽppel-like factor 4
- LIN28A:
-
Lin-28 homolog A, RNA-binding protein
- MAPK p38:
-
Mitogen-activated protein kinase 38
- MDC1:
-
Mediator of DNA damage checkpoint 1
- mESC:
-
Mouse embryonic stem cells
- MMR:
-
Mismatch repair
- MN/CB:
-
Micronucleus with cytochalasin B
- MNR:
-
Trimeric complex (Mre11, Rad50, and Nbs1)
- MRE11:
-
Homolog double-strand break repair nuclease
- MSCs:
-
Mesenchymal stem cells
- mTOR:
-
Mammalian target of rapamycin
- MUSE:
-
Multilineage-differentiating stress-enduring
- NANOG:
-
Nanog homeobox transcription factor
- NBS1:
-
Nijmegen breakage syndrome 1
- NER:
-
Nucleotide excision repair
- NF-ÎşB:
-
Nuclear factor ÎşB
- NHEJ:
-
Nonhomologous end joining
- NPM2:
-
Nucleoplasmin-2
- NSC:
-
Neural stem cells
- Oct-4:
-
Octamer-binding transcription factor 4, POU5F1
- p21/WAF1:
-
Cyclin-dependent kinase inhibitor 1A
- p53:
-
p53 tumor suppressor gene
- PARP1:
-
Poly-ADP ribose polymerase 1
- PBMC:
-
Peripheral blood mononuclear cells
- Pi3KK:
-
Phosphatidylinositol 3-kinase-related kinase
- PPR:
-
Post-replication repair
- PSCs:
-
Pluripotent stem cells
- RAD17:
-
Checkpoint clamp loader component
- RAD18:
-
RAD18 E3 ubiquitin protein ligase
- RAD50:
-
Double-strand break repair protein
- RAD9:
-
Cell cycle checkpoint control gene RAD9A
- Rb:
-
Rb tumor suppressor gene
- ROS:
-
Reactive oxygen species
- RS:
-
Replicative stress
- RT:
-
Replication-timing
- SASP:
-
Senescence-associated secretory phenotype
- SNP:
-
Single nucleotide polymorphism
- SOX-2:
-
Transcription factor SRY (sex determining region Y)-box
- TAD:
-
Topological associated domains
- TCR:
-
Transcription coupled repair
- TLS:
-
Trans-lesion synthesis
- TRA-1-60:
-
Pluripotency stem cell marker
- USSCs:
-
Human unrestricted somatic stem cells
- XPA XPA:
-
DNA damage recognition and repair factor
- ÎłH2AX:
-
Histone H2AX
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Prieto Gonzalez, E.A. (2022). A Multilevel Approach to the Causes of Genetic Instability in Stem Cells. In: Haider, K.H. (eds) Handbook of Stem Cell Therapy. Springer, Singapore. https://doi.org/10.1007/978-981-16-6016-0_26-1
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DOI: https://doi.org/10.1007/978-981-16-6016-0_26-1
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