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  • Our study reports that the loss of

    2018-10-24

    Our study reports that the loss of Klf5 from intestinal stem pitavastatin leads to reduction in proliferation eventually resulting in the loss of stem cells. We propose three possible outcomes of Klf5 deletion in stem cells that could elucidate our findings. Firstly, the replenishment of the TA cell population in the EGFP positive crypts could be due to drift from the adjoining non green crypt stem cells. Secondly, the pre-existing quiescent stem cell (Bmi1+) population could be activated due to the lack of proliferation from the native stem cell population and function as the source of TA cell population. Thirdly, in conjunction with the emerging “neutral drift” model for competing stem cells (Snippert et al., 2010; Lopez-Garcia et al., 2010), equipotent competition of stem cells within the EGFP positive crypts could result in clonality arising from a neighboring unlabeled stem cell. The identity of the origin of these replacing crypt epithelial cells remains to be explored.
    Conclusion We have shown that intestinal stem cell proliferation is dependent on Klf5 expression. Stem cells that have lost Klf5 expression show an increase in apoptotic bodies. Disappearance of stem cells was observed as a chronic consequence of Klf5 deletion. Overall, our study shows that Klf5 is necessary and critical for the survival of intestinal crypt cells. The following are the supplementary data related to this article.
    Acknowledgments We thank Dr. Ryozo Nagai for generously providing the floxed Klf5 mice. We also thank the National Institutes of Health for grant support to VWY (DK52230, DK64399, and CA84197).
    Introduction Skeletal muscle maintenance, repair, and regeneration are mediated by skeletal muscle stem cells. Although there are several cell types resident in skeletal muscle that can contribute to these processes under certain circumstances (Dellavalle et al, 2011; Meng et al, 2011), the principal skeletal muscle stem cell is the satellite cell, located underneath the basal lamina of a myofiber (Mauro, 1961; Relaix and Zammit, 2012). Satellite cells are normally mitotically quiescent, but can be activated to produce myoblast progeny that will differentiate to repair muscle. In healthy muscle, repair is normally a remarkably efficient process. However, it is likely that satellite cell function is compromised in muscular dystrophies, inherited disorders in which there is a loss of muscle structure and function, leading to weakness and disability (Emery, 2002; Morgan and Zammit, 2010). In Duchenne muscular dystrophy (DMD), the dystrophin (DMD) gene is mutated, leading to a loss of dystrophin protein. In healthy skeletal muscle, dystrophin is present beneath the basal lamina of muscle myofibers and interacts with other members of the dystrophin-associated protein complex (DAPC) to maintain muscle structure and function. It also has a signaling role, including mechanotransduction of forces and localization of signaling proteins within muscle myofibers (Emery, 2002). The absence of dystrophin renders a myofiber prone to damage by mechanical stress, leading to necrosis. Although muscle regeneration occurs, the regenerated myofibers still lack dystrophin and consequently undergo further cycles of degeneration and regeneration, which eventually completely fails, with the muscle tissue becoming substituted by fibrotic/adipose/connective tissue and unable to generate sufficient force (Webster and Blau, 1990). As dystrophin protein is part of the force transduction apparatus of a muscle fiber, it should not be expressed in satellite cells until after they undergo myogenic differentiation (Hoffman et al, 1987). Thus, the lack of dystrophin in DMD will have only an indirect effect on satellite cell function, as it leads to chronic fiber necrosis and consequent activation, proliferation and then differentiation of nearby satellite cells in an increasing hostile dystrophic microenvironment (Morgan and Zammit 2010).