The Radiation-Induced Regenerative Response of Adult Tissue-Specific Stem Cells: Models and Signaling Pathways

Abstract

Radiotherapy is involved in the treatment of many cancers, but damage induced to the surrounding normal tissue is often inevitable. Evidence suggests that the maintenance of homeostasis and regeneration of the normal tissue is driven by specific adult tissue stem/progenitor cells. These tasks involve the input from several signaling pathways. Irradiation also targets these stem/progenitor cells, triggering a cellular response aimed at achieving tissue regeneration. Here we discuss the currently used in vitro and in vivo models and the involved specific tissue stem/progenitor cell signaling pathways to study the response to irradiation. The combination of the use of complex in vitro models that offer high in vivo resemblance and lineage tracing models, which address organ complexity constitute potential tools for the study of the stem/progenitor cellular response post-irradiation. The Notch, Wnt, Hippo, Hedgehog, and autophagy signaling pathways have been found as crucial for driving stem/progenitor radiation-induced tissue regeneration. We review how these signaling pathways drive the response of solid tissue-specific stem/progenitor cells to radiotherapy and the used models to address this.

Keywords: radiotherapy; regeneration; signaling pathways; stem cells.

Figure 1

Current models use to assess stem cell radiation response in vivo and in vitro. In vitro the self-renewal potential of stem cells is evaluated by assessing their colony-forming efficiency in clonogenic assays. The stem cell self-renewal potential is also studied in three-dimensional (3D) organoids and air–liquid interface (ALI) systems that not only allow stem cell radiation response studies, but also their differentiation capacity upon irradiation. In vivo, the stem cell lineage tracing remains the most used model that enables to specifically mark stem cells and follow their cell fate. Therefore, it is possible to characterize how irradiation affects the stem cell self-renewal and differentiation capacity. Created with BioRender.com.

Figure 2

Principal signaling pathways involved in the response of stem/progenitor cells to irradiation. (a) The activation of the Notch signaling pathway in intestinal stem cells (ISCs) drives the post-irradiation in vivo regeneration of the murine gut. (b) Notch inhibition hampers the maintenance of stem/progenitor cells of the murine mammary gland after irradiation in vitro, while it promotes the response of mouse lung stem/progenitor cells. (c) The activity from the hedgehog (Hh) signaling pathway orchestrates the regeneration driven by stem/progenitor cells in the mouse brain, intestine, salivary gland (SG), and liver. (d) SG radiation-induced dysfunction is rescued by cues from the Hh signaling pathway in a pig model. (e) Activation of the Wnt canonical pathway results in stem/progenitor driven regeneration of the murine intestine, taste bud, and mammary gland post-irradiation. (f) The activation of the Wnt pathway hampers the repair response of human acinar cells to irradiation. (g) The absence of Hippo signaling through Yap1 nuclear translocation promotes the intestinal and cerebellar recovery after irradiation. However, nuclear Yap1 localization impairs the parotid gland regeneration. (h) The activation of the autophagy pathway protects the mouse kidney, intestine, and parotid gland from irradiation. Reactive oxygen species (ROS). Created with BioRender.com.