Modeling radiation injury-induced cell death and countermeasure drug responses in a human Gut-on-a-Chip

Sasan Jalili-Firoozinezhad; Rachelle Prantil-Baun; Amanda Jiang; Ratnakar Potla; Tadanori Mammoto; James C Weaver; Thomas C Ferrante; Hyun Jung Kim; Joaquim M S Cabral; Oren Levy; Donald E Ingber

doi:10.1038/s41419-018-0304-8

Modeling radiation injury-induced cell death and countermeasure drug responses in a human Gut-on-a-Chip

Cell Death Dis. 2018 Feb 14;9(2):223. doi: 10.1038/s41419-018-0304-8.

Authors

Affiliations

¹ Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA.
² Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.
³ Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
⁵ Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA. [email protected].
⁶ Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. [email protected].
⁷ Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA 02139, USA. [email protected].

Abstract

Studies on human intestinal injury induced by acute exposure to γ-radiation commonly rely on use of animal models because culture systems do not faithfully mimic human intestinal physiology. Here we used a human Gut-on-a-Chip (Gut Chip) microfluidic device lined by human intestinal epithelial cells and vascular endothelial cells to model radiation injury and assess the efficacy of radiation countermeasure drugs in vitro. Exposure of the Gut Chip to γ-radiation resulted in increased generation of reactive oxygen species, cytotoxicity, apoptosis, and DNA fragmentation, as well as villus blunting, disruption of tight junctions, and compromise of intestinal barrier integrity. In contrast, pre-treatment with a potential prophylactic radiation countermeasure drug, dimethyloxaloylglycine (DMOG), significantly suppressed all of these injury responses. Thus, the human Gut Chip may serve as an in vitro platform for studying radiation-induced cell death and associate gastrointestinal acute syndrome, in addition to screening of novel radio-protective medical countermeasure drugs.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Amino Acids, Dicarboxylic / pharmacology*
Animals
Apoptosis / drug effects
Apoptosis / radiation effects
Caco-2 Cells
Cells, Cultured
DNA Fragmentation / drug effects
DNA Fragmentation / radiation effects
Gamma Rays / adverse effects*
Human Umbilical Vein Endothelial Cells / cytology
Human Umbilical Vein Endothelial Cells / drug effects
Human Umbilical Vein Endothelial Cells / metabolism
Human Umbilical Vein Endothelial Cells / radiation effects
Humans
Intestinal Mucosa / cytology
Intestinal Mucosa / drug effects
Intestinal Mucosa / metabolism
Intestinal Mucosa / radiation effects
Lab-On-A-Chip Devices*
Lipid Peroxidation / drug effects
Lipid Peroxidation / radiation effects
Models, Biological*
Permeability / drug effects
Permeability / radiation effects
Radiation Injuries / metabolism
Radiation Injuries / pathology
Radiation Injuries / prevention & control*
Radiation-Protective Agents / pharmacology*
Reactive Oxygen Species / agonists
Reactive Oxygen Species / antagonists & inhibitors
Reactive Oxygen Species / metabolism
Tight Junctions / drug effects
Tight Junctions / metabolism
Tight Junctions / radiation effects

Substances

Amino Acids, Dicarboxylic
Radiation-Protective Agents
Reactive Oxygen Species
oxalylglycine

Grants and funding

HHSF223201310079C/FD/FDA HHS/United States