Chesnokova Vera, Zonis Svetlana, Ainsworth Richard, Apaydin Tugce, Valencia Christian Wong, Greiner Elora C, Barrett Robert, Kettenbach Arminja N, Melmed Shlomo
Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Department of Medicine, Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Aging Cell. 2025 Oct;24(10):e70187. doi: 10.1111/acel.70187. Epub 2025 Aug 5.
Aging is associated with the appearance of senescent cells secreting the senescence-associated secretome, facilitating a milieu favoring age-related microenvironmental changes. As we previously showed the production of local nonpituitary growth hormone (npGH) in senescent colon epithelial cells, we now elucidate mechanisms underlying npGH action in the nontumorous colon tissue microenvironment. We demonstrate autocrine npGH action in normal human colon cells (hNCC) infected with lentivirus-expressing hGH (lentiGH), as well as paracrine npGH action in hNCC cocultured with lentiGH hNCC and in intact human 3-dimensional intestinal organoids cocultured with organoids infected with lentiGH. Enriched gene ontology and pathway analysis of intact organoids exposed to paracrine npGH identified distorted extracellular matrix (ECM) and focal adhesion pathways concurrent with altered expression of ECM and cytoskeletal proteins. Significant phosphoprotein changes associated with the cytoskeleton and cell migration pathway occurred in GH-exposed hNCC. Paracrine npGH triggers these changes by activating epithelial-mesenchymal transition, as shown by suppression of E-cadherin and induction of Twist2 in cellular models, as well as in the colon of nude mice inoculated with GH-secreting xenografts. These changes are consistent with observed increased migration of hNCC overexpressing lentiGH, or in those cocultured with GH-secreting hNCC or with GH-secreting normal colon fibroblasts. Furthermore, whole exome sequencing detected increased structural variation in intact organoids cocultured with lentiGH-infected organoids, likely as a consequence of GH-mediated suppressed DNA damage repair, thereby favoring cell transformation. Our results indicate that local growth hormone facilitates aging of the colon epithelial microenvironment.
衰老与分泌衰老相关分泌组的衰老细胞的出现有关，从而促成了有利于与年龄相关的微环境变化的环境。正如我们之前所展示的，衰老的结肠上皮细胞中存在局部非垂体生长激素（npGH）的产生，我们现在阐明npGH在非肿瘤性结肠组织微环境中作用的潜在机制。我们证明了在感染表达hGH的慢病毒（lentiGH）的正常人结肠细胞（hNCC）中存在自分泌npGH作用，以及在与lentiGH hNCC共培养的hNCC中以及在与感染lentiGH的类器官共培养的完整人类三维肠道类器官中存在旁分泌npGH作用。对暴露于旁分泌npGH的完整类器官进行的富集基因本体和通路分析确定，细胞外基质（ECM）和粘着斑通路发生扭曲，同时ECM和细胞骨架蛋白的表达发生改变。在暴露于GH的hNCC中发生了与细胞骨架和细胞迁移通路相关的显著磷酸化蛋白变化。旁分泌npGH通过激活上皮-间质转化触发这些变化，这在细胞模型中以及在接种了分泌GH的异种移植物的裸鼠结肠中表现为E-钙粘蛋白的抑制和Twist2的诱导。这些变化与观察到的过表达lentiGH的hNCC迁移增加一致，或者与那些与分泌GH的hNCC或分泌GH的正常结肠成纤维细胞共培养的hNCC迁移增加一致。此外，全外显子测序检测到与感染lentiGH的类器官共培养的完整类器官中结构变异增加，这可能是由于GH介导的DNA损伤修复受抑制的结果，从而有利于细胞转化。我们的结果表明，局部生长激素促进结肠上皮微环境的衰老。
