Cell Therapy of Corneal Diseases

Abstract

Mesenchymal stem cells (MSC) isolated from connective tissues are pluripotent and differentiate to phenotypes of connective tissue cell lineages (osteoblasts, chondrocytes, adipocytes) in vitro and in vivo. They have been used to treat mouse models of connective tissue disease such as Lumican null (Lum−/−), and mucopolysaccharidosis (Gusb) mice. MSC have unique immunosuppressive properties allowing evasion of host rejection; thus, they are valuable tools for cell therapy of congenital and acquired diseases involving immune dysfunction of multiple tissues including ocular surface tissues (cornea). We previously showed that human umbilical mesenchymal stem cells (UMSCs) modulated host immune responses, enabling them to survive xenograft transplantations. In vitro UMSCs modulated inflammatory cells by inhibiting adhesion and invasion, and inducing cell death. UMSC also regulated M1/M2 macrophage polarization and induced T-regulatory cell maturation from naïve intraperitoneal cavity lavage cells. UMSCs exposed to inflammatory cells synthesized a rich extracellular glycocalyx composed of hyaluronan (HA) bound to the heavy chains (HCs) of inter-alpha-trypsin inhibitor (HC-HA), which contains tumor necrosis factorα-stimulated gene 6 (TSG6) that catalyzes the transfer of HCs to HA, versican and pentraxin-3. Our in vivo and in vitro results showed that glycocalyx regulated inflammatory cells, allowing UMSCs to survive host immune rejection. Administration of antibodies against glycocalyx constituents or digestion with hyaluronidase and chondroitinase ABC abolished the UMSC ability to modulate immune responses. Treatment with anti-CD44 antibodies also diminished modulation of M2 macrophages by UMSC, indicating cell surface CD44 is required for correct UMSC glycocalyx assembly to modulate inflammatory cells.

Cornea-Derived Mesenchymal Stromal Cells Therapeutically Modulate Macrophage Immunophenotype and Angiogenic Function

“…It is well accepted that the therapeutic effects of MSCs, most commonly derived from the bone marrow, are mediated largely through their immunomodulatory and anti-inflammatory properties [43][44][45][46][47]. MSCs have been shown to modulate both innate and adaptive immune mechanisms [48][49][50][51].…”

Corneal Mesenchymal Stromal Cells Are Directly Antiangiogenic via PEDF and sFLT-1

“…It is well accepted that the therapeutic effects of MSCs in many disease processes are mediated largely through their immunomodulatory and anti-inflammatory properties. 21 , 24 – 26 They have been shown to modulate both innate and adaptive immune mechanisms. 27 – 29 Local tissue derived MSCs, which share many features with other MSCs, can have additional special attributes that may be potentially useful for certain clinical applications.…”

A Retrospective Analysis of the Cartilage and Intervertebral Disc Kunitz Protease Inhibitory Proteins Identifies These as Members of The Inter-α-Trypsin Inhibitor Superfamily with potential roles in the protection of the articulatory surface

“…This may explain a mechanism whereby versican in the surface regions of articular cartilage observed in the present study immobilize HA at the cartilage surface by a means other than through direct interactions between the versican G1 domain and HA (Fig 9). ITI SPIs are also components of such glycocalyx formations in cornea which occur on the corneal surface under inflammatory conditions (134). Thus the ITI isoforms attached to the articular surface previously described by Yoshihara et al 2008 may also be attached to versican at the articular surface which also immobilizes HA in the surface lamina.…”