Abstract
The effect of local and systemic injections of mesenchymal stem cells derived from adipose tissue (AD-MSC) into rabbit models of corneal allograft rejection with either normal-risk or high-risk vascularized corneal beds was investigated. The models we present in this study are more similar to human corneal transplants than previously reported murine models. Our aim was to prevent transplant rejection and increase the length of graft survival. In the normal-risk transplant model, in contrast to our expectations, the injection of AD-MSC into the graft junction during surgery resulted in the induction of increased signs of inflammation such as corneal edema with increased thickness, and a higher level of infiltration of leukocytes. This process led to a lower survival of the graft compared with the sham-treated corneal transplants. In the high-risk transplant model, in which immune ocular privilege was undermined by the induction of neovascularization prior to graft surgery, we found the use of systemic rabbit AD-MSCs prior to surgery, during surgery, and at various time points after surgery resulted in a shorter survival of the graft compared with the non-treated corneal grafts. Based on our results, local or systemic treatment with AD-MSCs to prevent corneal rejection in rabbit corneal models at normal or high risk of rejection does not increase survival but rather can increase inflammation and neovascularization and break the innate ocular immune privilege. This result can be partially explained by the immunomarkers, lack of immunosuppressive ability and immunophenotypical secretion molecules characterization of AD-MSC used in this study. Parameters including the risk of rejection, the inflammatory/vascularization environment, the cell source, the time of injection, the immunosuppression, the number of cells, and the mode of delivery must be established before translating the possible benefits of the use of MSCs in corneal transplants to clinical practice.
Highlights
Corneal transplantation has been performed successfully for over 100 years, and it is the most common form of solid tissue transplantation in humans [1]
In the rabbits subjected to transplant surgery that received stromal injections of rabbit AD-mesenchymal stem cells (MSCs) (n = 9), none of the grafts survived over the follow-up period of 8 weeks, with a mean time to rejection of 26.5±4.5 days
We investigated the effect of AD-MSC pre-treatment and/or as an adjuvant to the surgery on the modulation of rejection response in normal- and high-risk models of rabbit corneal transplantation
Summary
Corneal transplantation has been performed successfully for over 100 years, and it is the most common form of solid tissue transplantation in humans [1]. Unlike other solid organ transplantation, human leukocyte antigen (HLA) typing and systemic immunosuppressive drugs are not used, yet 90% of those considered normal-risk transplants such as first-time grafts in avascular graft beds and non-inflamed graft beds can survive 5 years after surgery [3]. This number decreases with time, to 43% corneal graft survival at 15 years for low-risk corneal dystrophies and 77% for keratoconus. In these high-risk recipients, graft survival is even poorer: for herpetic eye, 72% survival is achieved at 5 years, and 49% at 15 years; for corneal ulcers, 48% survival at 5 years is reported and decreases to 21% at 15 years [4]
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