Sepsis reveals compartment‐specific responses in intestinal proliferation and apoptosis in transgenic mice whose enterocytes re‐enter the cell cycle

Cell production and death are tightly regulated in the rapidly renewing gut epithelium, with proliferation confined to crypts and apoptosis occurring in villi and crypts. This study sought to determine how stress alters these compartmentalized processes. Wild‐type mice made septic via cecal ligation and puncture had decreased crypt proliferation and increased crypt and villus apoptosis. Fabpi‐TAg mice expressing large T‐antigen solely in villi had ectopic enterocyte proliferation with increased villus apoptosis in unmanipulated animals. Septic Fabpi‐TAg mice had an unexpected increase in villus proliferation compared with unmanipulated littermates, whereas crypt proliferation was decreased. Cell cycle regulators cyclin D1 and cyclin D2 were decreased in jejunal tissue in septic transgenic mice. In contrast, villus and crypt apoptosis were increased in septic Fabpi‐TAg mice. To examine the relationship between apoptosis and proliferation in a compartment‐specific manner, Fabpi‐TAg mice were crossed with fabpl‐Bcl‐2 mice, resulting in expression of both genes in the villus but Bcl‐2 alone in the crypt. Septic bitransgenic animals had decreased crypt apoptosis but had a paradoxical increase in villus apoptosis compared with septic fabpi‐TAg mice, associated with decreased proliferation in both compartments. Thus, sepsis unmasks compartment‐specific proliferative and apoptotic regulation that is not present under homeostatic conditions.— Lyons, J. D., Klingensmith, N. J., Otani, S., Mittal, R., Liang, Z., Ford, M. L., Coopersmith, C. M. Sepsis reveals compartment‐specific responses in intestinal proliferation and apoptosis in transgenic mice whose enterocytes reenter the cell cycle. FASEB J. 31, 5507–5519 (2017). www.fasebj.org