Roles for epithelial integrin α3β1 in regulation of the microenvironment during normal and pathological tissue remodeling

Abstract

Integrin receptors for the extracellular matrix activate intracellular signaling pathways that are critical for tissue development, homeostasis, and regeneration/repair, and their loss or dysregulation contributes to many developmental defects and tissue pathologies. This review will focus on tissue remodeling roles for integrin α3β1, a receptor for laminins found in the basement membranes that underlie epithelial cell layers. As a paradigm, we will discuss literature that supports a role for α3β1 in promoting ability of epidermal keratinocytes to modify their tissue microenvironment during skin development, wound healing or tumorigenesis. Preclinical and clinical studies have shown that this role depends largely on ability of α3β1 to govern the keratinocyte's repertoire of secreted proteins, or the "secretome", including (1) matrix proteins and proteases involved in matrix remodeling and (2) paracrine-acting growth factors/cytokines that stimulate other cells with important tissue remodeling functions (e.g., endothelial cells, fibroblasts, inflammatory cells). Moreover, α3β1 signaling controls gene expression that helps epithelial cells carry out these functions, including genes that encode secreted matrix proteins, proteases, growth factors, or cytokines. We will review what is known about α3β1-dependent gene regulation through both transcription and post-transcriptional mRNA stability. Regarding the latter, we will discuss examples of α3β1-dependent alternative splicing or alternative polyadenylation that prevents inclusion of cis-acting mRNA sequences that would otherwise target the transcript for degradation via nonsense-mediated decay or destabilizing AU-rich elements in the 3'-UTR. Finally, we will discuss prospects and anticipated challenges of exploiting α3β1 as a clinical target for the treatment of cancer or wound healing.

Engineering cell-derived extracellular matrix for peripheral nerve regeneration

“…ECMs constitute the microenvironment in which tissue cells live and play a key role in the regulation of various cellular behavior [ 18 , 19 ]. Cell-ECM interaction involves the synergistic effects of the chemical composition, structural organization, and biomechanical properties in ECMs, which enables ECMs to modulate essential physiological processes including the development, homeostasis, and regeneration of various tissues [ [20] , [21] , [22] ]. As naturally sourced biomaterials, ECMs have been continuously explored for decades in tissue engineering and regenerative medicine, and great progress has been made in constructing nerve repair grafts [ 23 ].…”