Local Growth Hormone Facilitates Aging of the Colon Epithelial Microenvironment

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.