Radiation-induced apoptosis in the small intestine of transgenic mice: additional evidence for cell nonautonomous regulation

C. M. Coppersmith, C. Chandrasekaran, J. I. Gordon

Research output: Contribution to journalArticlepeer-review

Abstract

The intestinal epithelium undergoes rapid and perpetual renewal. A balance between proliferation, differentiation, and death permits cellular census to be maintained at a steady state. Proliferation is limited to crypts of Lieberkühn. Differentiation occurs during an orderly migration along the cryptvillus axis. Programmed cell death is detectable in the crypt and at the villus tip. Proliferating crypt cells are extremely sensitive to γ-irradiation, with an approximately 40-fold increase in apoptosis occurring 4 h after a total body dose of 6 Gy. Post-mitotic, differentiated villus epithelial cells are radioresistant, without any alterations in apoptosis following the same dose of y-radiation or an increased dose of 12 Gy. We have examined the mechanisms underlying this radioresistance of the villus epithelium using transgenic mice with genetically engineered alterations in their "baseline" proliferation, differentiation, and death programs. Transcriptional regulatory elements from the Fabpi gene were used to restrict expression of wild type SV40 TAg to terminally differentiated villus enterocytes in 6-8 week old C57BI/6 (B6) transgenic mice. The viral oncoprotein causes villus enterocytes to proliferate without a detectable change in their state of differentiation. Irradiating these Foip/-SV40 TAg transgenic mice with 6 or 12 Gy produced no alterations in villus apoptosis 4 h later, as defined by quantitative TUNEL and morphologic assays, Apoptosis was increased 40 fold in their SV40 TAg-negative crypts when compared to nonirradiated transgenics. Bi-transgenic animals containing Fabpi-SV40 TAg and fabpt-K.rasVasl2 transgenes exhibit dedifferentiation of their proliferating K-ras/SV40 TAg-posilive villus enterocytes and a 4-8-fold increase in villus apoptosis when compared to single-transgene containing or nontransgenic B6 controls. Irradiating these bi-transgenic mice with 6 Gy produces no alterations in villus apoptosis when compared to nonirradiated bi-transgenic animals while their K-ras/SV40 TAgnegative crypts showed a 40 fold augmentation of cell death. These data demonstrate that the radioresistance of villus cells is independent of their proliferative status, their state of differentiation, or the dose of γ-radiation used. The data suggest that the microenvironment of villus epithelium is not supportive of radiation-induced apoptosis and support other evidence of cell nonautonomous regulation in this system.

Original languageEnglish
Pages (from-to)318a
JournalJournal of Investigative Medicine
Volume44
Issue number3
StatePublished - Jan 1 1996

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