LIF is essential for ISC function and protects against radiation-induced gastrointestinal syndrome

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.

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

“…Analogous to CNTF, LIF signals through LIFRa and gp130 to induce JAK/STAT dependent gene transcription. It was first described as a suppressor of proliferation in a myeloid leukemia cell line, but has since been associated to functions in multiple peripheral organs (252)(253)(254)(255)(256)(257). In addition, LIF has been recognized as neuropoetic cytokine, regulating the differentiation and activation of multiple cell types in the CNS (258)(259)(260)(261)(262).…”

MiRNA-29c-3p Promotes Intestinal Inflammation via Targeting Leukemia Inhibitory Factor in Ulcerative Colitis

“… 16 In another study, LIF deficiency impaired the renewal and shortened the lifespan of intestinal epithelium, which could be rescued by LIF administration. 31 In the current study, we investigated the effect of miR-29c-3p/LIF axis on cell proliferation and apoptosis. We found that overexpression of miR-29c-3p inhibited Caco-2 cells proliferation and drove cell apoptosis via suppressing LIF, while knockdown of miR-29c-3p showed totally opposite effects.…”

Tumor suppressor p53 regulates intestinal type 2 immunity

“…Intestinal tissues were flushed with PBS and coiled into “Swiss rolls” to make formalin-fixed, paraffin-embedded (FFPE) tissue sections. H&E and IHC staining were performed using standard procedures as previously described 52 . For the tuft cell staining, an anti-Dclk1 (Abcam, ab88484, 1:400 dilution) antibody was used as a primary antibody.…”

“…IF staining of organoids was performed as we described in the published paper 52 . In brief, organoids were fixed with 4% paraformaldehyde, treated with 0.5% TritonX-100, and then blocked with 10% goat serum in IF buffer (0.1% BSA, 0.2% Triton X100, 0.05% Tween-20, and 0.05% NaN 3 in PBS) for 2 h. Organoids were incubated with the anti-Dclk1 (Abcam, ab88484, 1:400 dilution) or anti-LRMP (Biorbyt, orb166443, 1:200 dilution) antibodies overnight at room temperature and then incubated with Alexa Fluor® 555 Goat Anti-Mouse IgG (H + L) (Invitrogen, 1:200 dilution) and Alexa Fluor® 488 Goat Anti-Rabbit IgG (H + L) (Invitrogen, 1:200 dilution), respectively.…”

“…IF staining of mouse intestine tissues was performed as previously described 52 . Briefly, tissue sections were deparaffinized in xylene and rehydrated with ethanol.…”