DNA Damage and Checkpoint Responses in Adult Stem Cells

2014 ◽  
pp. 74-82
Author(s):  
Vasily Romanov ◽  
Aruna Shukla ◽  
Zhenyu Ju
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Adult Stem Cells

scholarly journals Lack of DNA Damage Response at Low Radiation Doses in Adult Stem Cells Contributes to Organ Dysfunction

2018 ◽  
Vol 24 (24) ◽  
pp. 6583-6593 ◽  
Author(s):  
Peter W. Nagle ◽  
Nynke A. Hosper ◽  
Lara Barazzuol ◽  
Anne L. Jellema ◽  
Mirjam Baanstra ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Organ Dysfunction ◽  
Dna Damage Response ◽  
Adult Stem Cells ◽  
Radiation Doses ◽  
Damage Response ◽  
Low Radiation Doses

scholarly journals Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells

Aging ◽  
2014 ◽  
Vol 6 (6) ◽  
pp. 481-495 ◽  
Author(s):  
Aleksandra Borodkina ◽  
Alla Shatrova ◽  
Polina Abushik ◽  
Nikolay Nikolsky ◽  
Elena Burova
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
P38 Mapk ◽  
Adult Stem Cells ◽  
Human Adult

scholarly journals DNA Damage-Induced Inflammatory Microenvironment and Adult Stem Cell Response

2021 ◽  
Vol 9 ◽  
Author(s):  
Davide Cinat ◽  
Robert P. Coppes ◽  
Lara Barazzuol
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Stem Cell ◽  
Adult Stem Cells ◽  
Genotoxic Stress ◽  
Inflammatory Factors ◽  
Functional Requirements ◽  
Tissue Specific ◽  
Inflammatory Microenvironment ◽  
Age Related

Adult stem cells ensure tissue homeostasis and regeneration after injury. Due to their longevity and functional requirements, throughout their life stem cells are subject to a significant amount of DNA damage. Genotoxic stress has recently been shown to trigger a cascade of cell- and non-cell autonomous inflammatory signaling pathways, leading to the release of pro-inflammatory factors and an increase in the amount of infiltrating immune cells. In this review, we discuss recent evidence of how DNA damage by affecting the microenvironment of stem cells present in adult tissues and neoplasms can affect their maintenance and long-term function. We first focus on the importance of self-DNA sensing in immunity activation, inflammation and secretion of pro-inflammatory factors mediated by activation of the cGAS-STING pathway, the ZBP1 pathogen sensor, the AIM2 and NLRP3 inflammasomes. Alongside cytosolic DNA, the emerging roles of cytosolic double-stranded RNA and mitochondrial DNA are discussed. The DNA damage response can also initiate mechanisms to limit division of damaged stem/progenitor cells by inducing a permanent state of cell cycle arrest, known as senescence. Persistent DNA damage triggers senescent cells to secrete senescence-associated secretory phenotype (SASP) factors, which can act as strong immune modulators. Altogether these DNA damage-mediated immunomodulatory responses have been shown to affect the homeostasis of tissue-specific stem cells leading to degenerative conditions. Conversely, the release of specific cytokines can also positively impact tissue-specific stem cell plasticity and regeneration in addition to enhancing the activity of cancer stem cells thereby driving tumor progression. Further mechanistic understanding of the DNA damage-induced immunomodulatory response on the stem cell microenvironment might shed light on age-related diseases and cancer, and potentially inform novel treatment strategies.

DNA damage response in adult stem cells: pathways and consequences

2011 ◽  
Vol 12 (3) ◽  
pp. 198-202 ◽  
Author(s):  
Pankaj K. Mandal ◽  
Cédric Blanpain ◽  
Derrick J. Rossi
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Adult Stem Cells ◽  
Damage Response

scholarly journals Ongoing repair of migration-coupled DNA damage allows planarian adult stem cells to reach wound sites

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Sounak Sahu ◽  
Divya Sridhar ◽  
Prasad Abnave ◽  
Noboyoshi Kosaka ◽  
Anish Dattani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Dna Repair ◽  
Stem Cell ◽  
Cell Migration ◽  
Adult Stem Cells ◽  
Adult Stem Cell ◽  
Wound Site ◽  
Stem Cell Migration

Mechanical stress during cell migration may be a previously unappreciated source of genome instability, but the extent to which this happens in any animal in vivo remains unknown. We consider an in vivo system where the adult stem cells of planarian flatworms are required to migrate to a distal wound site. We observe a relationship between adult stem cell migration and ongoing DNA damage and repair during tissue regeneration. Migrating planarian stem cells undergo changes in nuclear shape and exhibit increased levels of DNA damage. Increased DNA damage levels reduce once stem cells reach the wound site. Stem cells in which DNA damage is induced prior to wounding take longer to initiate migration and migrating stem cell populations are more sensitive to further DNA damage than stationary stem cells. RNAi mediated knockdown of DNA repair pathway components blocks normal stem cell migration, confirming that active DNA repair pathways are required to allow successful migration to a distal wound site. Together these findings provide evidence that levels of Migration-Coupled-DNA-Damage (MCDD) are significant in adult stem cells and that ongoing migration requires DNA repair mechanisms. Our findings reveal that migration of normal stem cells in vivo represent an unappreciated source of damage, that could be a significant source of mutations in animals during development or during long term tissue homeostasis.

scholarly journals The role of DNA damage repair in aging of adult stem cells

2007 ◽  
Vol 35 (22) ◽  
pp. 7557-7565 ◽  
Author(s):  
J. Kenyon ◽  
S. L. Gerson
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Adult Stem Cells ◽  
Dna Damage Repair ◽  
Damage Repair

scholarly journals Ongoing repair of migration-coupled DNA damage allows stem cells to reach wound sites

2019 ◽  
Author(s):  
Sounak Sahu ◽  
Divya Sridhar ◽  
Prasad Abnave ◽  
Nobuyoshi Kosaka ◽  
Anish Dattani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Dna Repair ◽  
Stem Cell ◽  
Cell Migration ◽  
Adult Stem Cells ◽  
Wound Site ◽  
Stem Cell Migration ◽  
The Impact

AbstractThe impact of mechanical stress during cell migration may be a previously unappreciated source of genome instability [1–3], but to what extent this happens in vivo remains unknown. Here we consider an in vivo system where the adult stem cells of planarian flatworms are required to migrate to a distal wound site [4]. We observe a relationship between adult stem cell migration and ongoing DNA damage and repair during tissue regeneration. Migrating planarian stem cells undergo changes in nuclear shape and increased levels of DNA damage. Increased DNA damage levels resolve once stem cells reach the wound site and stop migrating. Stem cells in which DNA damage is induced prior to wounding take longer to initiate migration suggesting migration activity is sensitive to DNA damage. Migrating stem cells populations are more sensitive to further DNA damage than stationary stem cells, providing evidence that levels of migration-coupled-DNA-damage (MCDD) are significant. RNAi mediated knockdown of DNA repair pathway components blocks normal stem cell migration, confirming that DNA repair pathways are required to allow successful migration to a distal wound site. Together these lines of evidence demonstrate that migration leans to DNA damage in vivo and requires DNA repair mechanisms. Our findings reveal that migration of stem cells represents an unappreciated source of damage, that could be a significant source of mutations in animals during development or during long term tissue homeostasis.

Stem Cell Replicative Stress and Clonal Exhaustion

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-41-SCI-41
Author(s):  
Michael D. Milsom
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Stem Cell ◽  
Malignant Transformation ◽  
Fanconi Anemia ◽  
Adult Stem Cells ◽  
Adult Stem Cell ◽  
Cellular Aging ◽  
Replicative Stress ◽  
Associated Diseases

In humans, the process of aging is characterized by a gradual decline in the functional capacity of multiple tissues, either directly precipitating age-associated diseases or increasing the risk of an individual developing disease, such as in the case of persistent infections or cancer. In regenerating organs, the process of aging is likely driven by the progressive depletion of adult stem cell populations that are responsible for maintaining tissues throughout the lifetime of an organism. One mechanism thought to be a primary cause of progressive adult stem cell depletion with ongoing time, is the accumulation of DNA damage in the stem cell compartment and the subsequent response to this insult. As well as potentially driving the loss of adult stem cells, DNA damage in this cell population is the likely mechanism behind the sequential acquisition of transforming mutations that lead to malignant transformation. Critically, to date, no one has identified the universal physiologic source of DNA damage in adult stem cells that leads to age-associated functional decline and transformation. An in depth interrogation of the mechanism via which adult stem cells acquire DNA damage under physiologic conditions and subsequently respond to this insult is therefore warranted in order to understand the aging process and how this is a critical factor in determining risk of developing cancer and other age-associated diseases. Historically, almost all studies of DNA damage and it's relevance to aging of stem cells either compare young versus aged cells and/or characterize the DNA damage response to artificial experimental agonists such as ionizing radiation, chemotherapy, serial bone marrow transplantation or in vitro culture. Although these approaches have been valuable in furthering our understanding of the relationship between DNA damage and stem cell biology, their physiologic relevance is debatable. The comparison of young versus aged cells assesses the consequences of cellular aging as opposed to the cause of aging, and non-physiologic experimental conditions of DNA damage evaluate a cellular response to an agonist of a type and magnitude that adult stem cells are unlikely to encounter in a normal lifetime. We have recently developed an in vivo model of DNA damage in hematopoietic stem cells (HSCs), which is precipitated by exposure of mice to agonists that mimic physiologic stress such as infection and chronic blood loss. These stress agonists drive HSCs out of their homeostatic quiescent status, resulting in de novo DNA damage as a consequence of increased replicative stress associated with dynamic changes in HSC energy metabolism. Importantly, this stress-induced DNA damage results in a phenotype of cumulative HSC attrition and a myeloid differentiation bias, which is akin to accelerated aging. In the setting of a clinically relevant mouse model of defective DNA repair (Fanconi anemia), stress hematopoiesis leads to a premature collapse of the entire hematopoietic system, fully recapitulating the progression of this disease in Fanconi anemia patients. Such a model is an ideal platform to study the response of HSCs to physiologic DNA damage and will allow us to better understand how environmental stress stimuli such as infections can impact upon both the rate of aging of tissues and the incidence of malignant transformation. This may have important clinical implications relevant to the study of age-related hematopoietic defects in patients. Disclosures No relevant conflicts of interest to declare.

DNA damage response in adult stem cells

2014 ◽  
Vol 52 (4) ◽  
pp. 147-151 ◽  
Author(s):  
Alessandra Insinga ◽  
Angelo Cicalese ◽  
Pier Giuseppe Pelicci
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Adult Stem Cells ◽  
Damage Response
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