Mesenchymal stem cells (MSCs) have been utilized to rescue disease phenotypes in genetic disorders, to direct healing after traumatic injury and to suppress the immune response in a variety of autoimmune disorders. We have demonstrated that corneal UMSC (umbilical mesenchymal stem cells) transplantation rescues the cloudy, thin cornea stroma of lumican knockout (Lum-/-) mice. Thus, transplantation of UMSC can be beneficial to ameliorate corneal pathology caused by genetic defects. UMSC can suppress host inflammation and immune responses and have been used in solid organ co-transplantation to improve graft success rates. Our preliminary studies have showed that intrastromal UMSC transplantation allow the alkali- burned corneas to regain transparency, to prevent the formation retro-corneal membrane when UMSC are transplanted into the anterior chamber. Our hypothesis is that modulation of inflammation and suppression of autoimmunity by UMSC transplantation are beneficial for regeneration/repair and survival of progenitor/stem cells in traumatized corneas.
The specific aims will determine the efficacy of utilizing UMSCs for the treatment of three models of human corneal dysfunction: trauma, limbal deficiency due to persistent inflammation and/or immune disorders, and genetic disease.
Specific Aim 1 : To examine the efficacy of UMSC in treating traumatized mouse corneas. The hypothesis is that UMSC will modulate the inflammatory response and facilitate regeneration;
Specific Aim 2 : To examine the efficacy of UMSC transplantation in treating limbal stem cell deficiency. The hypothesis is persistent inflammation leading to progenitor/stem cell deficiency can be ameliorated by UMSC transplantation;
Specific Aim 3 : To determine whether UMSC transplantation can restore function in a corneal stroma with a congenital defect. The hypothesis is that UMSC will remodel and repair stromal defects resulting from mutant proteins in genetic disease thereby restoring function. The outcome of our proposed studies will lend support to the notion that UMSC transplantation can serve as an alternative treatment in lieu of penetrating keratoplasty for cornea dysfunction caused by trauma and mutation by the preservation of progenitor/stem cells in persistent inflammation and/or immune disorders. Thus, the UMSC transplantation can be a potential treating regimen for dry eyes, Sjogren and Stevens-Johnson syndromes that are characterized by persistent inflammation and autoimmune disorder.

Public Health Relevance

Corneal transplantation is still the most effective treatment for vision restoration of corneal blindness due to congenital gene mutation and acquired diseases such as trachoma, microbial infections, laceration, chemical burns. We are developing alternative treatment regimens using umbilical mesenchymal stem cell in lieu of corneal transplantation to ameliorate corneal diseases complicated by persistent and severe inflammation e.g., alkali burn, limbal deficiency and genetic mutation. The success of the proposed studies will lead to new strategies for treating eye diseases such as dry eye, Sjogren and Steve-Johnson syndromes, and corneal dystrophy caused by genetic mutation.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01EY021768-04
Application #
8722564
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Coulson-Thomas, Vivien Jane; Gesteira, Tarsis Ferreira; Hascall, Vincent et al. (2014) Umbilical cord mesenchymal stem cells suppress host rejection: the role of the glycocalyx. J Biol Chem 289:23465-81
Ksander, Bruce R; Kolovou, Paraskevi E; Wilson, Brian J et al. (2014) ABCB5 is a limbal stem cell gene required for corneal development and repair. Nature 511:353-7
Kao, Winston W-Y; Liu, Hongshan; Zhang, Jianhua (2013) Wakayama symposium: challenges of future research in ocular surface cell biology. Ocul Surf 11:19-24
Coulson-Thomas, Vivien Jane; Caterson, Bruce; Kao, Winston W-Y (2013) Transplantation of human umbilical mesenchymal stem cells cures the corneal defects of mucopolysaccharidosis VII mice. Stem Cells 31:2116-26