DNA damage repair response in mesenchymal stromal cells: From cellular senescence and aging to apoptosis and differentiation ability

doi:10.1016/j.arr.2020.101125

Ageing Research Reviews

Volume 62, September 2020, 101125

https://doi.org/10.1016/j.arr.2020.101125 Get rights and content

Highlights

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MSCs sense localized tissue damages and release repairing and regenerative secretome to maintain tissue homeostasis.
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Deficient DNA repair pathway limits MSCs regeneration capability by reducing stemness and self-renewal capability.
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Telomeres participate in DNA damage response of MSCs through modifying of cell cycle checkpoints.

Abstract

Mesenchymal stromal cells (MSCs) are heterogeneous and contain several populations, including stem cells. MSCs' secretome has the ability to induce proliferation, differentiation, chemo-attraction, anti-apoptosis, and immunomodulation activities in stem cells. Moreover, these cells recognize tissue damage caused by drugs, radiation (e.g., Ultraviolet, infra-red) and oxidative stress, and respond in two ways: either MSCs differentiate into particular cell lineages to preserve tissue homeostasis, or they release a regenerative secretome to activate tissue repairing mechanisms. The maintenance of MSCs in quiescence can increase the incidence and accumulation of various forms of genomic modifications, particularly upon environmental insults. Thus, dysregulated DNA repair pathways can predispose MSCs to senescence or apoptosis, reducing their stemness and self-renewal properties. For instance, DNA damage can impair telomere replication, activating DNA damage checkpoints to maintain MSC function. In this review, we aim to summarize the role of DNA damage and associated repair responses in MSC senescence, differentiation and programmed cell death.

Introduction

The number and function of stem cells (SCs), in addition to their compartmentalization, contribute to the pathophysiological status of tissues (Vitale et al., 2017a). Adult stem cells (ASCs) can promote tissue repair and regeneration upon injury and sustain inter-cellular heterogeneity for physiological homeostasis. Endogenous and exogenous factors can cause damage onto the DNA and these genetic lesions may challenge ASCs survival and function. The significant roles of DNA in living organisms necessitate precise control of DNA damage repair mechanisms through recruitment of repair factors to damage sites and activation of checkpoint regulators to halt cell-cycle progression. These mechanisms, which are known collectively as the DNA damage response (DDR), can execute full repair or promote the elimination of damaged cells to protect host organisms against possible carcinogenesis (Bielak-Zmijewska et al., 2018). Adult stem and progenitor cells in various tissues are equipped with several regulatory mechanisms to guarantee genome integrity and tissue homeostasis. Dysregulation of DNA repair pathways in SCs can reduce tissue regeneration capacity by limiting the self-renewal and differentiation properties of SCs and by inducing senescence or apoptosis in these cells (Weeden and Asselin-Labat, 2018).

The secretome of MSCs contains tissue repairing elements that play an essential role in regulating local and remote progenitor and stem cell (SC) function. In response to tissue damage, MSCs can release factors that activate tissue repair mechanisms or that direct differentiation of SCs into certain cell lineages (Fitzsimmons et al., 2018; Moravej et al., 2019; Xi et al., 2013). In the present review, we summarize the contributions of the DDR in MSC senescence and apoptosis and highlight its pathophysiological relevance.

Section snippets

Mesenchymal stromal cells

Mesenchymal stromal cells (MSCs) are characterized by ﬁbroblast-like morphology, these cells are derived from bone marrow (BM) and different tissues (Horwitz et al., 2005). The International Society for Cell & Gene Therapy (ISCT) defines MSCs as a heterogeneous population of stromal cells that are capable of self-renewal and tri-lineage differentiation (to osteoblast, adipocyte, and chondrocyte). These cells are plastic-adherent under routine culture conditions and express CD73, CD90, and CD105

Effect of DNA damage in MSCs

In contrast to somatic cells, which typically undergo terminal differentiation, SCs can survive and duplicate for an extended period, which can increase the possibility of incidence and accumulation of damages onto the DNA of these cells (Mani et al., 2019). Chemical reactions between DNA and active molecules, including intracellular reactive oxygen species (ROSs), can cause a wide range of DNA damage (Chatterjee and Walker, 2017). The main endogenous DNA-damages result from metabolic processes

Role of DNA damage in stemness and differentiation of MSCs

Irradiation can trigger ROS accumulation in cells and cause DNA damage and eventually lead to the loss of stemness in MSCs. BM-MSCs show a different response upon exposure to low or high dose radiation. Low dose radiation can induce senescence, a defense response against tumorigenesis, and reduce the stemness of MSCs by attenuating autophagy activity (Alessio et al., 2015). Autophagy is an active mechanism to maintain the stemness of MSCs by decreasing ROS accumulation and DNA damage.

DNA damage in senescence and apoptosis of MSCs

DDR proteins are responsible for the detection of DNA damage as well as for executing the appropriate cellular responses toward repair, senescence or apoptosis (Lombard et al., 2005; Roos and Kaina, 2006). Senescence is a unique state of cell-cycle arrest, which can be induced by various cellular stresses, including DNA damage accumulation. This process is one of the critical defense mechanisms to avoid malignancy in mammalian cells. Although senescent cells are non-replicative, they are

DNA-repair mechanisms in MSCs

Various proteins involved in the DDR and DNA repair recognize DNA damage and either restore DNA integrity or induce senescence, differentiation, or apoptosis in MSCs (Krokan and Bjørås, 2013). In all cells, there are different DNA repair pathways that respond based on the DNA damage type. DNA repair activity is under the influence of many modulators, including epigenetics and other factors, which can regulate the gene expression and post-transcriptional modification (ubiquitination,

Conclusion

MSCs can modulate tissue homeostasis. Also, they can control tissue repair and regeneration capacity in aging-associated degenerative diseases. Although MSCs are located in hypoxic niches to keep away from oxidative stressors and maintain their stemness properties, they are still susceptible to intrinsic and extrinsic DNA-damaging agents. The primary responses of MSCs to DNA damage are the production of a considerable amount of anti-oxidants and activation of the DDR to reduce genotoxicity.

Declaration of Competing Interest

The authors have no conflict of interest to declare relevant to the content of this review.

Acknowledgment

There were no funding resources for the current study.

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¹: These authors are contributed equally to this study.

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ReviewDNA damage repair response in mesenchymal stromal cells: From cellular senescence and aging to apoptosis and differentiation ability

Highlights

Abstract

Introduction

Section snippets

Mesenchymal stromal cells

Effect of DNA damage in MSCs

Role of DNA damage in stemness and differentiation of MSCs

DNA damage in senescence and apoptosis of MSCs

DNA-repair mechanisms in MSCs

Conclusion

Declaration of Competing Interest

Acknowledgment

Int. J. Biochem. Cell Biol.

Mech. Ageing Dev.

Exp. Cell Res.

Mol. Cell

J. Radiat. Res. Appl. Sci.

Cytotherapy

Mol. Cell

Cell

J. Biol. Chem.

Mol. Cell

Cytotherapy

DNA Repair (Amst).

Mutat. Res. Mutat. Res.

Cell

Stem Cell Res.

Mol. Ther. Nucleic Acids

J. Nutr.

Exp. Cell Res.

Noncoding RNA Res.

Cancer Lett.

Trends Mol. Med.

DNA Repair (Amst)

DNA Repair (Amst)

Cell

Cytotherapy

Low dose radiation induced senescence of human mesenchymal stromal cells and impaired the autophagy process

Oncotarget

Mesenchymal stromal cells having inactivated RB1 survive following low irradiation and accumulate damaged DNA: hints for side effects following radiotherapy

Cell Cycle

A link between the accumulation of DNA damage and loss of multi-potency of human mesenchymal stromal cells

J. Cell. Mol. Med.

Dietary pesticides (99.99% all natural)

Proc. Natl. Acad. Sci. U. S. A.

Effects of mesenchymal stem cell derivatives on hematopoiesis and hematopoietic stem cells

Adv. Pharm. Bull.

Age-related changes in rat bone-marrow mesenchymal stem cell plasticity

BMC Cell Biol.

Age-related changes in rat bone-marrow mesenchymal stem cell plasticity

BMC Cell Biol.

Toward an understanding of mechanism of aging-induced oxidative stress in human mesenchymal stem cells

Biomed. Mater. Eng.

Mycotoxins

Clin. Microbiol. Rev.

Telomere states and cell fates

Nature

DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells

Aging Cell

Different protective mechanisms of human embryonic and endometrium-derived mesenchymal stem cells under oxidative stress

Cell tissue biol.

TNF-aα and IL-1β-activated human mesenchymal stromal cells increase airway epithelial wound healing in vitro via activation of the epidermal growth factor receptor

Respir. Res.

Why are MSCs therapeutic? New data: new insight

J. Pathol.

Mechanisms of DNA damage, repair, and mutagenesis

Environ. Mol. Mutagen.

Radiation-induced Micro-RNA modulation in glioblastoma cells differing in DNA-Repair pathways

DNA Cell Biol.

Resistance to neoplastic transformation of &i&ex-vivo&/i& expanded human mesenchymal stromal cells after exposure to supramaximal physical and chemical stress

Oncotarget

Doxorubicin induces the DNA damage response in cultured human mesenchymal stem cells

Int. J. Hematol.

The DNA-Damage Response to γ-Radiation Is Affected by miR-27a in A549 Cells

Int. J. Mol. Sci.

The DNA-Damage Response to γ-radiation is affected by miR-27a in A549 cells

Int. J. Mol. Sci.

Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice

Age (Omaha)

Review
DNA damage repair response in mesenchymal stromal cells: From cellular senescence and aging to apoptosis and differentiation ability