Loss of Survivin in Intestinal Epithelial Progenitor Cells Leads to Mitotic Catastrophe and Breakdown of Gut Immune Homeostasis

• Published in: Cell reports (Cambridge) Vol. 14; no. 5; pp. 1062 - 1073
• Main Authors: Martini, Eva, Wittkopf, Nadine, Günther, Claudia, Leppkes, Moritz, Okada, Hitoshi, Watson, Alastair J., Podstawa, Eva, Backert, Ingo, Amann, Kerstin, Neurath, Markus F., Becker, Christoph
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09-02-2016; Elsevier
• Subjects: Animals; Cell Death; Cell Division; Cell Survival; Epithelial Cells - pathology; Gene Deletion; Homeostasis; Humans; Inhibitor of Apoptosis Proteins - deficiency; Inhibitor of Apoptosis Proteins - metabolism; Intestines - immunology; Intestines - ultrastructure; Mice; Mitosis; Repressor Proteins - deficiency; Repressor Proteins - metabolism; Stem Cell Niche; Stem Cells - pathology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.01.010

A tightly regulated balance of proliferation and cell death of intestinal epithelial cells (IECs) is essential for maintenance of gut homeostasis. Survivin is highly expressed during embryogenesis and in several cancer types, but little is known about its role in adult gut tissue. Here, we show that Survivin is specifically expressed in transit-amplifying cells and Lgr5+ stem cells. Genetic loss of Survivin in IECs resulted in destruction of intestinal integrity, mucosal inflammation, and death of the animals. Survivin deletion was associated with decreased epithelial proliferation due to defective chromosomal segregation. Moreover, Survivin-deficient animals showed induced phosphorylation of p53 and H2AX and increased levels of cell-intrinsic apoptosis in IECs. Consequently, induced deletion of Survivin in Lgr5+ stem cells led to cell death. In summary, Survivin is a key regulator of gut tissue integrity by regulating epithelial homeostasis in the stem cell niche.
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•Survivin is expressed in stem and progenitor cells of the intestinal epithelium•Deletion of Survivin in IECs leads to death of animals within a few days•Survivin deletion induces loss of transit-amplifying cells and Lgr5+ stem cells•Survivin-deficient cells show cell-cycle defects and signs of mitotic catastrophe
Martini et al. discover an essential role of the IAP protein family member Survivin in the maintenance of tissue homeostasis in the gut. They show that Survivin-deficient epithelial stem and progenitor cells succumb to mitotic catastrophe, leading to secondary inflammation.