Intestinal tuft cells regulation mechanisms for crypt restitution following radiation injury: interplay between stem cells and diverse cell types

Developers

Parthasarathy Chandrakesan, Randal May, Michael S. Bronze, Courtney W. Houchen, etc.

Description of the technology

Crypt epithelial survival and regeneration after injury require highly coordinated complex interplay between resident stem cells and diverse cell types. The function of Dclk1 expressing tuft cells regulating intestinal epithelial DNA damage response for cell survival/self-renewal after radiation-induced injury is unclear. Intestinal epithelial cells were isolated and purified and utilized for experimental analysis. Then it was found that small intestinal crypts of VillinCre;Dclk1f/f mice were hypoplastic and more apoptotic 24 h post-total body irradiation, a time when stem cell survival was p53-independent. Injury-induced ATM-mediated DNA damage response, pro-survival genes, stem cell markers, and self-renewal ability for survival and restitution were reduced in the isolated intestinal epithelial cells. An even greater reduction in these signaling pathways was observed 3.5 days post-total body irradiation, when peak crypt regeneration occurred. It was found that interaction with Dclk1 is critical for ATM and COX2 activation in response to injury. Dclk1 expressing tuft cells regulate the whole intestinal epithelial cells following injury through paracrine mechanism. These findings suggest that intestinal tuft cells play an important role in regulating the ATM-mediated DNA damage response, for epithelial cell survival/self-renewal via a Dclk1 dependent mechanism, and these processes are indispensable for restitution and function after severe radiation-induced injury.

Practical application

These findings may give new insight into the functional role of Dclk1 expression in tuft cells in maintaining cell and genome integrity and survival for epithelial remodeling and cell fate decision after injury. Specific pharmacological activation of Dclk1 expression in tuft cells could form a new technology for treatment of severe injuries, for example, radiation traumas.

Laboratories

• Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (USA)
• OU Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City (USA)
• Department of Veterans Affairs Medical Center, Oklahoma City (USA)

Links

Publications

• Chandrakesan, P. et al. «Intestinal tuft cells regulate the ATM mediated DNA Damage response via Dclk1 dependent mechanism for crypt restitution following radiation injury." 6 Scientific Reports, (2016): 37667.
• Chandrakesan, P. et al. «Dclk1+ small intestinal epithelial tuft cells display the hallmarks of quiescence and self-renewal." 6 Oncotarget, (2015): 30876–30886.
• Chandrakesan, P. et al. «Utility of a bacterial infection model to study epithelial-mesenchymal transition, mesenchymal-epithelial transition or tumorigenesis." 33 Oncogene, (2014): 2639–2654.