Heuberger Julian, Liu Lichao, Berger Hilmar, van den Heuvel Joop, Lin Manqiang, Müllerke Stefanie, Bayram Safak, Beccaceci Giulia, de Jonge Hugo, Gherardi Ermanno, Sigal Michael
Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Nat Commun. 2025 May 3;16(1):4131. doi: 10.1038/s41467-025-59474-y.
The colon epithelium frequently incurs damage through toxic influences. Repair is rapid, mediated by cellular plasticity and acquisition of the highly proliferative regenerative state. However, the mechanisms that promote the regenerative state are not well understood. Here, we reveal that upon injury and subsequent inflammatory response, IFN-γ drives widespread epithelial remodeling. IFN-γ promotes rapid apoptotic extrusion of fully differentiated surface colonocytes, while simultaneously causing differentiation of crypt-base stem and progenitor cells towards a colonocyte-like lineage. However, unlike homeostatic colonocytes, these IFN-γ-induced colonocytes neither respond to nor produce BMP-2 but retain regenerative capacity. The reduction of BMP-2-producing epithelial surface cells causes a remodeling of the surrounding mesenchymal niche, inducing high expression of HGF, which promotes proliferation of the IFN-γ-induced colonocytes. This mechanism of lineage replacement and subsequent remodeling of the mesenchymal niche enables tissue-wide adaptation to injury and efficient repair.
结肠上皮经常因毒性影响而受损。修复过程迅速，由细胞可塑性和获得高度增殖的再生状态介导。然而，促进再生状态的机制尚不清楚。在这里，我们发现，在损伤及随后的炎症反应后，IFN-γ驱动广泛的上皮重塑。IFN-γ促进完全分化的表面结肠细胞快速凋亡性排出，同时使隐窝底部干细胞和祖细胞向结肠细胞样谱系分化。然而，与稳态结肠细胞不同，这些IFN-γ诱导的结肠细胞既不响应也不产生BMP-2，但保留再生能力。产生BMP-2的上皮表面细胞减少导致周围间充质微环境重塑，诱导HGF高表达，从而促进IFN-γ诱导的结肠细胞增殖。这种谱系替代及随后间充质微环境重塑的机制使组织能够在全组织范围内适应损伤并实现高效修复。
