title: The In Vitro Response of Tissue Stem Cells to Irradiation With Different Linear Energy Transfers.
abstract: OBJECTIVE
  A reduction in the dose, irradiated volume, and sensitivity of, in particular, normal tissue stem cells is needed to advance radiation therapy. This could be obtained with the use of particles for radiation therapy. However, the radiation response of normal tissue stem cells is still an enigma. Therefore, in the present study, we developed a model to investigate the in vitro response of stem cells to particle irradiation.
  
  
  METHODS
  We used the immortalized human salivary gland (HSG) cell line resembling salivary gland (SG) cells to translate the radiation response in 2-dimensional (2D) to 3-dimensional (3D) conditions. This response was subsequently translated to the response of SG stem cells (SGSCs). Dispersed single cells were irradiated with photons or carbon ions at different linear energy transfers (LETs; 48.76 ± 2.16, 149.9 ± 10.8, and 189 ± 15 keV/μm). Subsequently, 2D or 3D clonogenicity was determined by counting the colonies or secondary stem cell-derived spheres in Matrigel. γH2AX immunostaining was used to assess DNA double strand break repair.
  
  
  RESULTS
  The 2D response of HSG cells showed a similar increase in dose response to increasing higher LET irradiation as other cell lines. The 3D response of HSG cells to increasing LET irradiation was reduced compared with the 2D response. Finally, the response of mouse SGSCs to photons was similar to the 3D response of HSG cells. The response to higher LET irradiation was reduced in the stem cells.
  
  
  CONCLUSIONS
  Mouse SGSC radiosensitivity seems reduced at higher LET radiation compared with transformed HSG cells. The developed model to assess the radiation response of SGSCs offers novel possibilities to study the radiation response of normal tissue in vitro.
authors.affiliation: Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Nagle
authors.affiliation: Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Nynke A
authors.initials: NA
authors.lastname: Hosper
authors.affiliation: Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Ploeg
authors.affiliation: Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; KVI-Center for Advanced Radiation Research, University of Groningen, Groningen, The Netherlands.
authors.forename: Marc-Jan
authors.initials: MJ
authors.lastname: van Goethem
authors.affiliation: KVI-Center for Advanced Radiation Research, University of Groningen, Groningen, The Netherlands.
authors.forename: Sytze
authors.initials: S
authors.lastname: Brandenburg
authors.affiliation: Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Langendijk
authors.affiliation: Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Roland K
authors.initials: RK
authors.lastname: Chiu
authors.affiliation: Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: r.p.coppes@umcg.nl.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Coppes
mesh_terms: D018929:Cell Culture Techniques; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000528:radiation effects; D002588:Cesium Radioisotopes; D003094:Collagen; D003114:Colony-Forming Units Assay / Q000379:methods; D053903:DNA Breaks, Double-Stranded; D004338:Drug Combinations; D063193:Heavy Ion Radiotherapy; D006657:Histones / Q000032:analysis; D006801:Humans; D066298:In Vitro Techniques; D007797:Laminin; D018499:Linear Energy Transfer; D017785:Photons; D011509:Proteoglycans; D011836:Radiation Tolerance; D018874:Spheroids, Cellular / Q000166:cytology / Q000528:radiation effects; D013234:Stem Cells / Q000528:radiation effects*; D013363:Submandibular Gland / Q000166:cytology*
chemical_list: D002588:Cesium Radioisotopes; D004338:Drug Combinations; C468783:H2AX protein, human; D006657:Histones; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen