Novel regenerative peptide TP508 mitigates radiation-induced gastrointestinal damage by activating stem cells and preserving crypt integrity.
In recent years, increasing threats of radiation exposure and nuclear disasters have become a significant concern for the United States and countries worldwide. Exposure to high doses of radiation triggers a number of potentially lethal effects. Among the most severe is the gastrointestinal (GI) toxicity syndrome caused by the destruction of the intestinal barrier, resulting in bacterial translocation, systemic bacteremia, sepsis, and death. The lack of effective radioprotective agents capable of mitigating radiation-induced damage has prompted a search for novel countermeasures that can mitigate the effects of radiation post exposure, accelerate tissue repair in radiation-exposed individuals, and prevent mortality. We report that a single injection of regenerative peptide TP508 (rusalatide acetate, Chrysalin) 24 h after lethal radiation exposure (9 Gy, LD100/15) appears to significantly increase survival and delay mortality by mitigating radiation-induced intestinal and colonic toxicity. TP508 treatment post exposure prevents the disintegration of GI crypts, stimulates the expression of adherens junction protein E-cadherin, activates crypt cell proliferation, and decreases apoptosis. TP508 post-exposure treatment also upregulates the expression of DCLK1 and LGR5 markers of stem cells that have been shown to be responsible for maintaining and regenerating intestinal crypts. Thus, TP508 appears to mitigate the effects of GI toxicity by activating radioresistant stem cells and increasing the stemness potential of crypts to maintain and restore intestinal integrity. These results suggest that TP508 may be an effective emergency nuclear countermeasure that could be delivered within 24 h post exposure to increase survival and delay mortality, giving victims time to reach clinical sites for advanced medical treatment.
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
Carla
C
Kantara
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
Stephanie M
SM
Moya
Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Courtney W
CW
Houchen
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
Shahid
S
Umar
Department of Radiation Oncology, University of Texas Medical Branch, Galveston, TX, USA.
Robert L
RL
Ullrich
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
Pomila
P
Singh
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.|Chrysalis BioTherapeutics, Inc., Galveston, TX, USA.
Darrell H
DH
Carney
D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D041981:Gastrointestinal Tract / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010446:Peptide Fragments / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D016019:Survival Analysis; D013917:Thrombin / Q000494:pharmacology*
D010446:Peptide Fragments; C412222:rusalatide acetate; D013917:Thrombin