Local Growth Hormone Facilitates Aging of the Colon Epithelial Microenvironment.
Publication Year:
2025
PubMed ID:
40761135
Funding Grants:
Public Summary:
As we get older, aging cells in our colon begin producing their own localized "growth hormone," and this study reveals how that hormone harms the surrounding healthy tissue. Researchers discovered that this localized hormone acts on both the aging cells and their healthy neighbors, severely disrupting their internal structures and the physical scaffolding that holds the tissue together. This disruption causes the colon cells to behave abnormally, making them more prone to detaching and wandering out of place. Even more concerning, the locally produced hormone prevents nearby cells from properly repairing their DNA, leading to a buildup of genetic damage that increases the risk of normal cells turning cancerous. Ultimately, the study shows that this locally produced hormone creates a toxic environment that actively drives the aging and breakdown of the colon.
Scientific Abstract:
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.