title: Differential mechanisms of x-ray-induced cell death in human endothelial progenitor cells isolated from cord blood and adults.
abstract: Endothelial colony-forming cells (ECFCs) are endothelial progenitor cells that circulate at low concentration in human umbilical cord and adult peripheral blood and are largely resident in blood vessels. ECFCs not only appear to be critical for normal vascular homeostasis and repair but may also contribute to tumor angiogenesis and response to therapy. To begin to characterize the potential role of ECFCs during the treatment of tumors in children and adults with radiation, we characterized the X-ray sensitivity of cord and adult blood-derived ECFCs. We found both cord blood and adult ECFCs to be highly radiation sensitive (3 Gy resulted in >90% killing without induction of apoptosis). The X-ray survival curves suggested reduced potential for repair capacity, but X-ray fractionation studies demonstrated that all the ECFCs exhibited repair when the radiation was fractionated. Finally, the mechanisms of X-ray-induced cell death for cord blood and adult ECFCs were different at low and high dose. At low dose, all ECFCs appear to die by mitotic death/catastrophe. However, at high radiation doses (≥ 10 Gy) cord blood ECFCs underwent p53 stabilization and Bax-dependent apoptosis as well as p21-dependent G₁ and G₂/M cell cycle checkpoints. By contrast, after 10 Gy adult ECFCs undergo only large-scale radiation-induced senescence, which is a cellular phenotype linked to premature development of atherosclerosis and vasculopathies. These data demonstrate that the ECFC response to radiation is dose-dependent and developmentally regulated and may provide potential mechanistic insight into their role in tumor and normal tissue response after ionizing radiation treatment.
authors.affiliation: Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. mmendonc@iupui.edu
authors.forename: Marc S
authors.initials: MS
authors.lastname: Mendonca
authors.forename: Helen
authors.initials: H
authors.lastname: Chin-Sinex
authors.forename: Ryan
authors.initials: R
authors.lastname: Dhaemers
authors.forename: Laura E
authors.initials: LE
authors.lastname: Mead
authors.forename: Merv C
authors.initials: MC
authors.lastname: Yoder
authors.forename: David A
authors.initials: DA
authors.lastname: Ingram
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000166:cytology* / Q000528:radiation effects*; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D002453:Cell Cycle / Q000528:radiation effects; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology*; D005312:Fetal Blood / Q000166:cytology*; D006801:Humans; D051379:Mice; D011836:Radiation Tolerance / Q000528:radiation effects; D013997:Time Factors; D014965:X-Rays / Q000009:adverse effects