Molecular and epigenetic regulatory mechanisms of normal stem cell radiosensitivity

Abstract

Ionizing radiation (IR) therapy is a major cancer treatment modality and an indispensable auxiliary treatment for primary and metastatic cancers, but invariably results in debilitating organ dysfunctions. IR-induced depletion of neural stem/progenitor cells in the subgranular zone of the dentate gyrus in the hippocampus where neurogenesis occurs is considered largely responsible for deficiencies such as learning, memory, and spatial information processing in patients subjected to cranial irradiation. Similarly, IR therapy-induced intestinal injuries such as diarrhea and malabsorption are common side effects in patients with gastrointestinal tumors and are believed to be caused by intestinal stem cell drop out. Hematopoietic stem cell transplantation is currently used to reinstate blood production in leukemia patients and pre-clinical treatments show promising results in other organs such as the skin and kidney, but ethical issues and logistic problems make this route difficult to follow. An alternative way to restore the injured tissue is to preserve the stem cell pool located in that specific tissue/organ niche, but stem cell response to ionizing radiation is inadequately understood at the molecular mechanistic level. Although embryonic and fetal hypersensity to IR has been very well known for many decades, research on embryonic stem cell models in culture concerning molecular mechanisms have been largely inconclusive and often in contradiction of the in vivo observations. This review will summarize the latest discoveries on stem cell radiosensitivity, highlighting the possible molecular and epigenetic mechanism(s) involved in DNA damage response and programmed cell death after ionizing radiation therapy specific to normal stem cells. Finally, we will analyze the possible contribution of stem cell-specific chromatin’s epigenetic constitution in promoting normal stem cell radiosensitivity.

Organoids Reveal That Inherent Radiosensitivity of Small and Large Intestinal Stem Cells Determines Organ Sensitivity

“…A large body of literature reports data on mammalian normal and tumor stem cell radiosensitivity, but correlation with organ/tumor radiosensitivity remains inconclusive (35)(36)(37)(38)(39)(40)(41)(42). A potentially con-founding factor in this analysis is that SI and LI stem cell radiosensitivity is often measured by employing methodologies that did not comply with the rigorous criteria developed and validated in the field of radiobiology over the past four decades (43)(44)(45).…”

Radiotherapy and the immune system: More than just immune suppression

“…Thus, radioprotective measures need to be taken to reduce RT‐mediated side effects. So far, there is only one radioprotective drug approved for the treatment of xerostomia (dry mouth) after irradiation of head and neck cancers 87 . As an alternative, adipose tissue‐derived mesenchymal stem cell transplantation is currently under investigation for the treatment of xerostomia 88,89 .…”

Oral Mucositis: An Update on Innate Immunity and New Interventional Targets

“…During development of chemoradiotherapy-induced OM, the G1/S check point of cell cycle and DNA damage response (DDR) are highly activated, which causes p53-upregulated modulator of apoptosis-dependent (PUMA-dependent) apoptosis in epithelial stem cells (Wei et al 2016; Leibowitz et al 2018). Activation of Wnt/β-catenin by genetic Puma ablation or PUMA inhibition enhances cell proliferation and tissue regeneration following mucosal injury, suggesting that Wnt signaling activators may serve as therapeutic avenue for chemoradiotherapy-induced OM (Fabbrizi et al 2018; Leibowitz et al 2018). Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) has been identified as a functional epithelial stem cell marker that is involved in modulating stem cell self-renewal, proliferation, and homeostasis due to its critical role as an effector of R-spondins (Rspo)/Wnt signaling cascades (Barker et al 2012; Metcalfe et al 2014; Leung et al 2018; Raslan and Yoon 2019).…”