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The Radiation-Induced Regenerative Response of Adult Tissue-Specific

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The Radiation-Induced Regenerative Response of Adult Tissue-Specific cancers Review The Radiation-Induced Regenerative Response of Adult Tissue-Specific Stem Cells: Models and Signaling Pathways Paola Serrano Martinez 1,2,†, Lorena Giuranno 3,†, Marc Vooijs 3,*,‡ and Robert P. Coppes 1,2,*,‡ 1 Department of Biomedical Sciences of Cells and Systems-Section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands; p.serrano.martinez@umcg.nl 2 Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands 3 Department of Radiation Oncology (Maastro), GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, P.O. Box 616, 6200 MD Maastricht, The Netherlands; l.giuranno@maastrichtuniversity.nl * Correspondence: marc.vooijs@maastrichtuniversity.nl (M.V.); r.p.coppes@umcg.nl (R.P.C.) † These authors contributed equally to the work. ‡ These authors contributed equally to the work. Simple Summary: A common side effect of radiotherapy is the impairment of integrity and functionality of the co-irradiated surrounding normal tissue. Homeostasis and regeneration of many organs are maintained by specific stem/progenitor cells. Radiation can harm these resident stem/progenitor populations involving the disruption of the signaling cascade of pathways known to normally sustain stem/progenitor cellular activity. This review describes the currently existing models used to study the response of stem/progenitor cells to irradiation and the key signaling pathways involved during solid Citation: Serrano Martinez, P.; tissue-specific stem/progenitor driven regeneration. Giuranno, L.; Vooijs, M.; Coppes, R.P. The Radiation-Induced Regenerative Abstract: Radiotherapy is involved in the treatment of many cancers, but damage induced to the Response of Adult Tissue-Specific surrounding normal tissue is often inevitable. Evidence suggests that the maintenance of homeostasis Stem Cells: Models and Signaling and regeneration of the normal tissue is driven by specific adult tissue stem/progenitor cells. These tasks Pathways. Cancers 2021, 13, 855. involve the input from several signaling pathways. Irradiation also targets these stem/progenitor cells, https://doi.org/10.3390/ triggering a cellular response aimed at achieving tissue regeneration. Here we discuss the currently used cancers13040855 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 Academic Editor: Christopher Talbot 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, Received: 12 January 2021 Accepted: 14 February 2021 Hedgehog, and autophagy signaling pathways have been found as crucial for driving stem/progenitor Published: 18 February 2021 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. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Keywords: radiotherapy; stem cells; signaling pathways; regeneration published maps and institutional affil- iations. 1. Introduction One of the main limitations of radiotherapy (RT) is the damage induced to the healthy Copyright: © 2021 by the authors. tissue positioned unavoidably in the radiation field. Radiation-induced side effects can Licensee MDPI, Basel, Switzerland. be linked to the loss of tissue stem cells (SCs) and damage accumulation in the remaining This article is an open access article stem/progenitor cells. This may result in acute or late adverse effects depending on distributed under the terms and the number of surviving stem/progenitor cells. A better understanding of SC response conditions of the Creative Commons and the pathways that orchestrate the regenerative response of the stem/progenitor pool Attribution (CC BY) license (https:// in tissues to RT can help to predict unavoidable toxicity and aid to prevent or repair creativecommons.org/licenses/by/ radiation-induced damage. In this review, we summarize our current understanding of the 4.0/). Cancers 2021, 13, 855. https://doi.org/10.3390/cancers13040855 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 18 Cancers 2021, 13, 855 2 of 17 repair radiation-induced damage. In this review, we summarize our current understand- ingpathways of the pathways that may promote that may solid promote tissue SCsolid response tissue SC to RT response and the to current RT and models the current used to modelscharacterize used to RT characterize response. RT response. 2.2. Models Models to to Study Study SC SC Response Response to to Radiation Radiation ManyMany studies studies have have assessed assessed the the self-renewal self-renewal and and differentiation differentiation potential potential of of SCs SCs uponupon irradiation irradiation (IR). (IR). These These include include two-dimensional two-dimensional (2D) (2D) and and three-dimensional three-dimensional (3D) (3D) in vitroin vitro clonogenicclonogenic studies studies of cell of celllines, lines, spheroids, spheroids, and and organoids, organoids, replating replating assays, assays, and and in vivoin vivo lineagelineage tracing tracing (Figure (Figure 1).1 ).Although Although many many IR IR studies studies have have used used submerged submerged culture culture procedures,procedures, such such as as clonogenic clonogenic and and replating replating st studies,udies, they they are are unable unable to to mimic mimic the the actual actual inin vivo vivo microenvironmentmicroenvironment andand organorgan functionality functionality [1 [1,2].,2]. The The 3D 3D models, models, such such as spheroids,as sphe- roids,organoids, organoids, air–liquid air–liquid interface interface (ALI) (ALI) systems, systems, and organ-on-chips and organ-on-chips recapitulate recapitulate the organ the organstructure, structure, seem toseem better to better reflect reflect the patient-specific the patient-specific response response compared compared to in vitro to in2D vitro cell 2Dline cell models line models and enable and enable assessment assessmen of in vitrot of in SC vitro responses SC responses to IR [3 to]. IR [3]. FigureFigure 1. 1. CurrentCurrent models models use use to toassess assess stem stem cell cell radiation radiation response response in vivoin vivo andand in vitro.in vitro In vitro. In vitro the self-renewalthe self-renewal potential potential of stem of stemcells is cells evaluated is evaluated by assessing by assessing their colony-forming their colony-forming efficiency efficiency in clon- in ogenicclonogenic assays. assays. The stem The cell stem self-renewal cell self-renewal potentia potentiall is also studied is also studied in three-dimensional in three-dimensional (3D) organ- (3D) oidsorganoids and air–liquid and air–liquid interface interface (ALI) systems (ALI) systems that not thatonly not allow only stem allow cell stem radiation cell radiation response responsestudies, butstudies, also their but alsodifferentiation their differentiation capacity upon capacity irradiat uponion. irradiation. In vivo, theIn stem vivo, cell the lineage stem cell tracing lineage remains tracing the most used model that enables to specifically mark stem cells and follow their cell fate. Therefore, remains the most used model that enables to specifically mark stem cells and follow their cell it is possible to characterize how irradiation affects the stem cell self-renewal and differentiation fate. Therefore, it is possible to characterize how irradiation affects the stem cell self-renewal and capacity. Created with BioRender.com. differentiation capacity. Created with BioRender.com. 2.1.2.1. Organoids Organoids OrganoidsOrganoids are are derived derived from from highly highly self-renew self-renewinging tissue tissue SCs SCs that that can can differentiate differentiate in allin of all the of thelineages lineages and andretain retain the genetic the genetic and andphenotypic phenotypic characteristics characteristics of both of bothtumor tumor and normaland normal tissue tissue in vitro.in vitroPassaging. Passaging of the of orga thenoids organoids enriches enriches for cell for population cell population with self- with renewingself-renewing capacities, capacities, such as such stem as and stem progenit and progenitoror cells. SC cells. radiation SC radiation response response may be may re- flectedbe reflected by the by next the passage next passage organoid organoid forming forming potential, potential, which which measures measures the SC the self-re- SC self- newalrenewal potential. potential. Fluorescence-activated Fluorescence-activated cell cell sorting sorting of of cell cell surface surface SC SC markers markers (e.g., (e.g., P63+, P63+, Lgr5+,Lgr5+, Ngfr+, Ngfr+, Nkx2+) Nkx2+) allows allows th thee identification, identification, isolation, isolation, and and enrichment enrichment of of tissue-specific tissue-specific stem/progenitorstem/progenitor cells cells that that can can be be cultured cultured to to study study the the mechanisms mechanisms involved involved in in SC SC DNA DNA Cancers 2021, 13, 855 3 of 17 repair and self-renewal after radiation in experimental conditions closer to the in vivo situation [4,5]. Furthermore, patient-specific tissue-derived
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