Corneal Wound Healing Effects of Mesenchymal Stem Cell Secretome Delivered Within a Viscoelastic Gel Carrier

Abstract

Severe corneal injuries often result in permanent vision loss and remain a clinical challenge. Human bone marrow‐derived mesenchymal stem cells (MSCs) and their secreted factors (secretome) have been studied for their antiscarring, anti‐inflammatory, and antiangiogeneic properties. We aimed to deliver lyophilized MSC secretome (MSC‐S) within a viscoelastic gel composed of hyaluronic acid (HA) and chondroitin sulfate (CS) as a way to enhance corneal re‐epithelialization and reduce complications after mechanical and chemical injuries of the cornea. We hypothesized that delivering MSC‐S within HA/CS would have improved wound healing effects compared the with either MSC‐S or HA/CS alone. The results showed that a once‐daily application of MSC‐S in HA/CS enhances epithelial cell proliferation and wound healing after injury to the cornea. It also reduced scar formation, neovascularization, and hemorrhage after alkaline corneal burns. We found that combining MSC‐S and HA/CS increased the expression of CD44 receptors colocalized with HA, suggesting that the observed therapeutic effects between the MSC‐S and HA/CS are in part mediated by CD44 receptor upregulation and activation by HA. The results from this study demonstrate a reproducible and efficient approach for delivering the MSC‐S to the ocular surface for treatment of severe corneal injuries. stem cells translational medicine 2019;8:478–489

Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration

“…For example, in preclinical models, MSC‐CM distributed within a hyaluronic acid (HA) hydrogel enhanced tissue regeneration after endometrial injury, [ 21 ] while a hydrogel composed of HA and chondroitin sulfate incorporating MSC‐CM achieved corneal wound healing. [ 208 ] Additionally, injection of MSC‐CM encapsulated in a platelet‐rich plasma hydrogel ameliorated renal healing and function in an acute kidney injury model, [ 209 ] while MSC‐CM delivered in synthetic PLGA nanoparticles coated with red blood cell membranes enhanced liver regeneration. [ 210 ] Several studies have demonstrated the potential of biomaterial‐based delivery of MSC‐EVs [ 211 ] for repair in indications such as peripheral nerve injury, [ 212 ] epidural fibrosis, [ 213 ] and incisional hernia [ 214 ] ( Table 2 ).…”

Characterizing the impact of 2D and 3D culture conditions on the therapeutic effects of human mesenchymal stem cell secretome on corneal wound healing in vitro and ex vivo

“…Fluorescein dye strips (Haag-Streit, Koeniz, Switzerland) were infused in saline (2 strips per 1 mL saline), and then the liquid mixture was applied to the corneas to determine the location and degree of the ocular surface staining under cobalt blue illumination. Photographs of fluorescein-stained corneas were taken with a smartphone ophthalmic imaging adapter (Paxos Scope, by Digisight Technologies, now Verana Health, San Francisco, CA, USA) equipped with a 15 × magnifying lens and a blue LED in the same manner as done in previous research [22].…”

Effects of Amniotic Membrane–Derived Fibroblast Supernatant on Corneal Epithelium

“…18 Human bone marrow-derived MSC secretome, consisting of cellderived soluble factors and extracellular vesicles delivered within a viscoelastic gel carrier combining HA and chondroitin sulfate, enhanced epithelial cell proliferation and wound healing following mechanical and chemical injuries to the cornea. 63 HA was present at higher levels in the AM stroma, and AM-derived stromal cells produced more HA in medium than did AM epithelial cells and skin-derived fibroblasts. 9,64 These data imply that the secretome contained within AMF-sup and HA promoted wound healing in the in vitro and in vivo models used in this study.…”