Local growth hormone facilitates the aging colon epithelial microenvironment

ABSTRACT: Aging is associated with appearance of senescent cells secreting the senescence-associated secretome facilitating a milieu favoring age-related changes in microenvironment. Previously, we showed accumulation and secretion of local non-pituitary growth hormone (npGH) in senescent colon epithelial cells. Here, we elucidate mechanisms underlying npGH action in the non-tumorous 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 co-cultured 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 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 harboring GH-secreting xenografts. These changes are consistent with observed increased migration of hNCC overexpressing lentiGH, or in those co-cultured with GH-secreting hNCC or with GH-secreting normal colon fibroblasts. Furthermore, whole exome sequencing detected increased cell copy number alterations in intact organoids co-cultured with lentiGH-infected organoids, likely as a consequence of GH-mediated suppressed DNA damage repair thereby favoring cell transformation. Our results indicate that accumulated npGH in aging tissue enables a microenvironment landscape favoring age-associated pro-proliferative changes.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Arminja Kettenbach  

PROVIDER: MSV000096807 | MassIVE | Wed Jan 08 13:56:00 GMT 2025

SECONDARY ACCESSION(S): PXD059561

REPOSITORIES: MassIVE