Knudsen Collin, Moriya Ayano, Nakato Eriko, Gulati Rishi, Akiyama Takuya, Nakato Hiroshi
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, United States of America.
Department of Biology, The Porter Cancer Research Center, Indiana State University, Terre Haute, Indiana, United States of America.
PLoS Genet. 2025 May 9;21(5):e1011686. doi: 10.1371/journal.pgen.1011686. eCollection 2025 May.
The basement membrane (BM) plays critical roles in stem cell maintenance and activity control. Here we show that chondroitin sulfate (CS), a major component of the Drosophila midgut BM, is required for proper control of intestinal stem cells (ISCs). Loss of Chsy, a critical CS biosynthetic gene, resulted in elevated levels of ISC proliferation during homeostasis, leading to midgut hyperplasia. Regeneration assays demonstrated that Chsy mutant ISCs failed to properly downregulate mitotic activity at the end of regeneration. We also found that CS is essential for the barrier integrity to prevent leakage of the midgut epithelium. CS is known to be polymerized by the action of the complex of Chsy and another critical protein, Chondroitin polymerizing factor (Chpf). We found that Chpf mutants show increased ISC division during midgut homeostasis and regeneration, similar to Chsy mutants. As Chpf is induced by a tissue damage during regeneration, our data suggest that Chpf functions with Chsy to facilitate CS remodeling and stimulate tissue repair. We propose that the completion of the repair of CS-containing BM acts as a prerequisite to properly terminate the regeneration process.
基底膜（BM）在干细胞维持和活性控制中起着关键作用。在此我们表明，硫酸软骨素（CS）作为果蝇中肠BM的主要成分，是正确控制肠道干细胞（ISC）所必需的。Chsy（一个关键的CS生物合成基因）的缺失导致稳态期间ISC增殖水平升高，从而导致中肠增生。再生试验表明，Chsy突变体ISC在再生结束时未能正确下调有丝分裂活性。我们还发现CS对于维持屏障完整性以防止中肠上皮渗漏至关重要。已知CS通过Chsy与另一种关键蛋白硫酸软骨素聚合因子（Chpf）的复合物作用而聚合。我们发现Chpf突变体在中肠稳态和再生期间显示出ISC分裂增加，类似于Chsy突变体。由于Chpf在再生过程中由组织损伤诱导，我们的数据表明Chpf与Chsy共同作用以促进CS重塑并刺激组织修复。我们提出，含CS的BM修复的完成是正确终止再生过程的先决条件。
