DNA Damage-Induced Inflammatory Microenvironment and Adult Stem Cell Response

Abstract

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.

Age-Related Changes in the Fibroblastic Differon of the Dermis: Role in Skin Aging

“…The main feature of SCs is the ability to self-renew and differentiate. By doing so, SCs play a key role in maintaining the tissue homeostasis providing the skin (as well as the other body tissues) with differentiated mature descendant cells [ 11 , 12 , 13 , 14 ]. It has been revealed that there is a decrease in the quantity and quality of the SCs functions with age [ 15 , 16 ], which leads to depletion of the SCs pool and, thus, to a decrease in the regenerative abilities of body tissues, one of the main causes of tissue aging [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

“…Disorders in the genetic apparatus of the cell occur under the influence of a number of factors, both internal and external. The internal ones include [ 14 , 18 ]: Reactive oxygen species (ROS) produced by metabolic intermediates and dysfunctional Mt; DNA replication and DNA repair errors; Glycation end products; Dysfunction and shortening of telomeres (the end regions of chromosomes that ensure stable cell replication and protect chromosomes from fusion); Inflammation of the surrounding tissue. …”

“…As a result of these factors action, about 100,000 DNA damages can occur per day in each cell, including various types of nucleotide modifications and single- and double-stranded breaks [ 14 , 42 ]. The second group of external factors includes UV and X-rays, chemicals, tobacco smoke, alcohol, and viral infections [ 12 , 36 , 43 , 44 ].…”

Oxidative Stress and Cancer Heterogeneity Orchestrate NRF2 Roles Relevant for Therapy Response

“…Genotoxic stress has recently been shown to be a trigger of an inflammatory signaling cascade which results in the release of pro-inflammatory factors and an increase in the amount of infiltrating immune cells. These events additionally contribute to ROS production and lead to the occurrence of a vicious circle of carcinogenic oxidative stress [ 15 ].…”

Adipose Stem Cell-Based Treatments for Wound Healing

“…Adult stem cells, which are found in various tissues and organs of the body, are undifferentiated cells in a differentiated tissue that can self-renew and differentiate into the specialized cells composing that tissue. These stem cells include hematopoietic stem cells, bone marrow mesenchymal stem cells, neural stem cells, muscle satellite cells, epidermal stem cells, and adipose stem cells (ASCs) ( Cinat et al, 2021 ; Menche and Farin, 2021 ). In this review, we focus on ASCs.…”