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

Colonic crypt stem cell functions are controlled by tight junction protein claudin‐7 through Notch/Hippo signaling

“…− 53 In this study, we demonstrate that the loss of Cldn7 led to disruption in the large intestine crypt stem cell population, which resulted from decreased Lgr5‐positive active stem cells accompanied by an increase in quiescent and transit‐amplifying cells. Epithelial hyperproliferation seen with in vivo Cldn7 KO is likely a compensatory effect of the loss of the stem cell population, comparable to colonic stem cell damage‐induced hyperproliferation seen with radiation 54 . Without claudin‐7, crypt cells were unable to survive and form colonoids with differentiated epithelial cells in culture, highlighting the vital role of claudin‐7 in IESC survival and differentiation.…”

“…Epithelial hyperproliferation seen with in vivo Cldn7 KO is likely a compensatory effect of the loss of the stem cell population, comparable to colonic stem cell damage-induced hyperproliferation seen with radiation. 54 Without claudin-7, crypt cells were unable to survive and form colonoids with differentiated epithelial cells in culture, highlighting the vital role of claudin-7 in IESC survival and differentiation. Nearly 50% of patients with CRC exhibit chemoresistance and tumor recurrence involving colon cancer stem cells (CSCs).…”

Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization

“…These data are consistent with enhanced radiosensitivity of the gut and bone marrow in ATM -deficient mice ( 59 , 60 ). Asymmetric division of stem cells after radiation is responsible for restoring tissue homeostasis, and the profound sensitization of oral mucosa by AZD1390 likely reflects sensitization of the stem cell compartment ( 61 ). These results contrast with protection against radiation-induced neuronal apoptosis in juvenile ATM -null mice ( 62 ).…”

Renin–Angiotensin Inhibitor, Captopril, Attenuates Growth of Patient-Derived Colorectal Liver Metastasis Organoids

“…Patient #2’s CRLM PDOs demonstrated high levels of the stem cell marker Lgr5 following treatment with captopril and this may indicate resistance to radiotherapy. Studies have shown that although Lgr5+ stem cells in the intestine appear highly sensitive to radiation therapy, those in the colon are not [ 54 , 55 ]. This could inform treatment decisions away from therapies such as SIRT or SBRT and towards other therapies, such as microwave ablation, targeted chemotherapies, or monoclonal antibodies.…”