12-O-tetradecanoylphorbol-13-acetate (TPA) increases murine intestinal crypt stem cell survival following radiation injury

Abstract

Radiation enteropathy is a common complication in cancer patients following radiation therapy. Thus, there is a need for agents that can protect the intestinal epithelium against radiation. 12-O-tetradecanoylphorbol-13-acetate (TPA) has been shown to induce differentiation and/or apoptosis in multiple cell lines and primary cells. In the current report, we studied the function of TPA in radiation induced enteropathy in cultured rat intestinal epithelial cell line IEC-6 after ionizing radiation (IR) and in mice after high dose total-body gamma-IR (TBI). In IEC-6 cells, there were reduced apoptosis and cell cycle arrest in TPA treated cells after IR. We detected a four-fold increase in crypt cell survival and a two-fold increase in animal survival post TBI in TPA treated mice. The beneficial effects of TPA were accompanied by upregulation of stem cells markers and higher level of proteins that are involved in PKC signaling pathway. In addition, TPA also decreased the TBI-augmented levels of the DNA damage indicators. The effects were only observed when TPA was given before irradiation. These results suggest that TPA has the ability to modulate intestinal crypt stem cells survival and this may represent a promising countermeasure against radiation induced enteropathy.

Radiation-Induced Intestinal Damage: Latest Molecular and Clinical Developments

“…SCs are distinguished from other cell types by their ability to renew and divide after long periods of inactivity, and their induction into tissues with specialized biological functions in response to well-characterized physiological stimuli [21]. The GI epithelial villus/crypt and the neighbouring pericryptal fibroblasts and mesenchyme constitute a well-characterized anatomical unit that is responsible for the production of four major cell lineages, including absorptive enterocytes, goblet cells, enteroendocrine cells and tuft cells [27][28][29]. The crypt encompasses a pocket of epithelial cells at the villus base, at which GI SCs (ISCs) are activated to produce progenitor cells committed to mature cell lineages [27].…”

“…They can be identified through the expression of LGR5, ASCL2, OLFM4, SMOC2, PROM1 and SOX9lo (reviewed in [25]). aISCs termed crypt base columnar cells, rapidly divide to progenitor cells in the transit-amplifying (TA) region [28]. The second type of ISCs are stress-resistant quiescent SCs, in other words, reserve ISCs (rISCs) which are activated in response to perturbations to aISCs [25].…”

“…The apoptotic phase in mice undergoing RIID constitutes crypt loss, shrinkage and shortening of the villi [16,56,57]. This is followed by the regenerative phase during which the surviving crypt cells act in unison to regenerate entire crypt [28,58]. The total number of crypts subsequently decrease in the intestine and the crypts undergoing regeneration enlarge and divide more rapidly [59].…”

A Non-redundant Role for T cell-derived IL-22 in Antibacterial Defense of Colonic Crypts

“…N. Berger et al, 2017; Bergstrom et al, 2008; Borenshtein et al, 2009; Chan et al, 2013; Ma et al, 2006; Papapietro et al, 2013), the distal part of which is the infectious niche of C.r in mice as opposed to the ileum and transverse colon of E. coli (EPEC and EHEC respectively) in humans (Croxen et al, 2013). Elongation of the colonic crypts is thought to isolate intestinal stem cells (ISCs) that reside in the base of crypts from physical and metabolic damage that results from infection, thereby preventing destruction of the progenitors that give rise to all cells of the intestinal epithelial monolayer (Kaiko et al, 2016; Y. Liang et al, 2017; Matsuki et al, 2013; Okada et al, 2013).…”

Polysaccharides extracted fromRheum tanguticumameliorate radiation-induced enteritis via activation of Nrf2/HO-1

“…Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. Radiation therapy is an effective treatment for cancer but is associated with side effects caused by the exposure of healthy tissues adjacent to the radiation field [ 1 , 2 ]. The gastrointestinal tract, especially the small intestine, is particularly sensitive to radiation, which renders it vulnerable to collateral radiation during radiotherapy for abdominal and pelvic cancers [ 3 ].…”