Abstract
Murine small intestinal crypt development is initiated during the first postnatal week. Soon after formation, overall increases in the number of crypts occurs through a bifurcating process called crypt fission, which is believed to be driven by developmental increases in the number of intestinal stem cells (ISCs). Recent evidence suggests that a heterogeneous population of ISCs exists within the adult intestine. Actively cycling ISCs are labeled by Lgr5, Ascl2 and Olfm4; whereas slowly cycling or quiescent ISC are marked by Bmi1 and mTert. The goal of this study was to correlate the expression of these markers with indirect measures of ISC expansion during development, including quantification of crypt fission and side population (SP) sorting. Significant changes were observed in the percent of crypt fission and SP cells consistent with ISC expansion between postnatal day 14 and 21. Quantitative real-time polymerase chain reaction (RT-PCR) for the various ISC marker mRNAs demonstrated divergent patterns of expression. mTert surged earliest, during the first week of life as crypts are initially being formed, whereas Lgr5 and Bmi1 peaked on day 14. Olfm4 and Ascl2 had variable expression patterns. To assess the number and location of Lgr5-expressing cells during this period, histologic sections from intestines of Lgr5-EGFP mice were subjected to quantitative analysis. There was attenuated Lgr5-EGFP expression at birth and through the first week of life. Once crypts were formed, the overall number and percent of Lgr5-EGFP positive cells per crypt remain stable throughout development and into adulthood. These data were supported by Lgr5 in situ hybridization in wild-type mice. We conclude that heterogeneous populations of ISCs are expanding as measured by SP sorting and mRNA expression at distinct developmental time points.
Highlights
The structure and physiology of the intestinal tract mature during postnatal growth in order to meet changing absorptive and digestive requirements
Despite this prediction having been made more than 20 years ago, there are no reported studies that have directly investigated the behavior of pluripotent intestinal stem cells (ISCs) during the postnatal period when extensive crypt fission is occurring
Mature bowel possesses an ability to respond to challenges by augmenting several characteristics after a loss of length or functional capacity [23,26,27]
Summary
The structure and physiology of the intestinal tract mature during postnatal growth in order to meet changing absorptive and digestive requirements. The rate of crypt fission was highest between 6–12 months of age as reported by Cummins’ group [3] All of these data indicate that crypt fission is a critical process in intestinal development. Totafurno et al developed a crypt growth model which demonstrates that crypts will bifurcate when their volume doubles [6] Inherent in this model is the prediction that a doubling in the number of stem cells per crypt is the driving force for crypt fission. Despite this prediction having been made more than 20 years ago, there are no reported studies that have directly investigated the behavior of pluripotent intestinal stem cells (ISCs) during the postnatal period when extensive crypt fission is occurring. An in depth review of epithelial stem cells by Wright further highlights the crucial relationship between crypt fission and stem cell number [7]
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