Collagen Mimetic Peptides Promote Corneal Epithelial Cell Regeneration

Abstract

The cornea of the eye is at risk for injury through constant exposure to the extraocular environment. A highly collagenous structure, the cornea contains several different types distributed across multiple layers. The anterior-most layer contains non-keratinized epithelial cells that serve as a barrier to environmental, microbial, and other insults. Renewal and migration of basal epithelial cells from the limbus involve critical interactions between secreted basement membranes, composed primarily of type IV collagen, and underlying Bowman’s and stromal layers, which contain primarily type I collagen. This process is challenged in many diseases and conditions that insult the ocular surface and damage underlying collagen. We investigated the capacity of a collagen mimetic peptide (CMP), representing a fraction of a single strand of the damaged triple helix human type I collagen, to promote epithelial healing following an acute corneal wound. In vitro, the collagen mimetic peptide promoted the realignment of collagen damaged by enzymic digestion. In an in vivo mouse model, topical application of a CMP-containing formulation following a 360° lamellar keratectomy targeting the corneal epithelial layer accelerated wound closure during a 24 h period, compared to vehicle. We found that the CMP increased adherence of the basal epithelium to the underlying substrate and enhanced density of epithelial cells, while reducing variability in the regenerating layer. These results suggest that CMPs may represent a novel therapeutic to heal corneal tissue by repairing underlying collagen in conditions that damage the ocular surface.

Restoring the Extracellular Matrix: A Neuroprotective Role for Collagen Mimetic Peptides in Experimental Glaucoma

“…We have argued earlier that a tissue repair technology that reestablishes collagen fibrillar organization could restore both biomechanical and structural functions of collagen membranes and normal and healthy cell signaling ( Baratta R. O. et al, 2021 ), and ECM is increasingly viewed as an avenue for therapeutics ( Ren et al, 2015 ). The results we describe here for DRG cultures and in our experimental glaucoma model support the idea that CMP treatment could accelerate repair or protect against further axonal injury through the established action of CMPs intercalating into damaged collagen strands ( Chattopadhyay et al, 2012 ).…”

“…The small number of CMPs tested here demonstrate modest reparative properties; we are examining whether other CMPs will show similar properties as we continue our studies with more extensive experimentation that incorporates additional outcome measures. A corollary is that this therapeutic approach could also reduce secondary inflammation that accelerates RGC degeneration in optic neuropathy that often arises with collagen degradation ( Baratta R. O. et al, 2021 ). A simple intravitreal injection of CMP that could affect wide-spread repair of ECM and promote RGC survival could offer an alternative for millions suffering from optic neuropathies, both chronic and acute.…”

Intraocular Delivery of a Collagen Mimetic Peptide Repairs Retinal Ganglion Cell Axons in Chronic and Acute Injury Models

“…Recently, we found that a collagen mimetic peptide (CMP 03A) prevented degradation of RGC axonal transport to the superior colliculus (SC), the primary target for RGC axons in rodents [ 24 , 25 ], following three weeks of microbead-induced elevations in intraocular pressure (IOP) [ 19 ]. This same CMP promoted healing of the corneal epithelium following acute corneal surface injury [ 58 ]. Additional members of the CMP family were efficacious in promoting neurite outgrowth from dorsal root ganglia cultures challenged by matrix metalloproteinase (MMP) digestion of collagen plating [ 19 ].…”

Collagen Mimetic Peptides Promote Adherence and Migration of ARPE-19 Cells While Reducing Inflammatory and Oxidative Stress

“…This is important work not only from the standpoint of restoring ECM structure, but also for reducing inflammation in local tissues [1]. We found that a CMP was efficacious in promoting the repair and structural integrity of the corneal epithelium following an acute injury [18]. Additional members of this CMP family promoted neurite outgrowth from dorsal root ganglia cultures following MMP-induced damage to the underlying collagen substrate [19].…”

“…Following treatment, adherence with CMP 13A was similar to that of intact collagen (p = 018). Recently, we found that a similarly structured CMP promoted repair of the corneal surface by enhancing migration of epithelial cells in vivo [18]. Here, we tested whether this same CMP(CMP 03A) similarly promotes adherence and migration of ARPE-19 cells using a transwell assay consisting of membrane inserts in which we coated only the basal (distal) side.…”