Abstract
Leukemia inhibitory factor (LIF) is a cytokine essential for maintaining pluripotency of mouse embryonic stem cells. However, its role in adult intestinal stem cells (ISCs) is unclear. The adult intestinal epithelium has a high self-renewal rate driven by ISCs in crypts. Here, we find that LIF is present in the ISC niche in crypts and critical for the function of ISCs in maintaining the intestinal epithelial homeostasis and regeneration. Mechanistically, LIF maintains β-catenin activity through the AKT/GSK3β signaling to regulate ISC functions. LIF deficiency in mice impairs the renewal of the intestinal epithelium under the physiological condition. Further, LIF deficiency in mice impairs the regeneration of intestinal epithelium in response to radiation and shortens the lifespan of mice after high doses of radiation due to gastrointestinal (GI) syndrome, which can be rescued by administering recombinant LIF (rLIF). Importantly, LIF exhibits a radioprotective role in wild-type (WT) mice by protecting mice from lethal radiation-induced GI syndrome; administering rLIF promotes intestinal epithelial regeneration and prolongs survival in WT mice after radiation. These results reveal a previously unidentified and a crucial role of LIF in ensuring ISC function, promoting regeneration of the intestinal epithelium in response to radiation and protecting against radiation-induced GI syndrome.
Highlights
Leukemia inhibitory factor (LIF) is a multi-functional cytokine and plays an important role in various biological processes[1,2]
LIF is expressed in intestinal crypts We investigated the expression pattern of LIF in the mouse intestinal tissue by immunohistochemistry (IHC) and immunofluorescent (IF) staining using a LIF antibody
The expression of LIF in the intestinal epithelium was readily observed after birth as determined at P7 and P15, with majority of LIF positive cells localized in the crypt (Supplementary Fig. S1)
Summary
LIF is a multi-functional cytokine and plays an important role in various biological processes[1,2]. We found that LIF is a target gene of tumor suppressor p53, and mediates p53’s function in regulation of embryonic implantation in mice and humans[3,4]. LIF binds to its receptor complex composed of LIF receptor and glycoprotein gp[130] to activate several signaling pathways, including the JAK/STAT, MAPK, and PI3K/AKT pathways, in a highly cell- and tissue-specific manner[1,2,5]. LIF is crucial in maintaining the pluripotency of mouse embryonic stem cells[6]. Basal LIF expression levels are generally low in normal adult tissues. The intestinal crypt drives rapid self-renewal of the intestinal epithelium, which is one of the best-defined adult stem cell models[7]. The intestinal crypt contains Lgr5+ intestinal stem cells (ISCs), transit-amplifying (TA)
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