Intravenous Mesenchymal Stem Cells Prevented Rejection of Allogeneic Corneal Transplants by Aborting the Early Inflammatory Response

Abstract

Mesenchymal stem/progenitor cells (MSCs) were reported to enhance the survival of cellular and organ transplants. However, their mode of action was not established. We here used a mouse model of corneal allotransplantation and demonstrated that peri-transplant intravenous (i.v.) infusion of human MSCs (hMSCs) decreased the early surgically induced inflammation and reduced the activation of antigen-presenting cells (APCs) in the cornea and draining lymph nodes (DLNs). Subsequently, immune rejection was decreased, and allograft survival was prolonged. Quantitative assays for human GAPDH revealed that <10 hMSCs out of 1 × 10(6) injected cells were recovered in the cornea 10 hours to 28 days after i.v. infusion. Most of hMSCs were trapped in lungs where they were activated to increase expression of the gene for a multifunctional anti-inflammatory protein tumor necrosis factor-α stimulated gene/protein 6 (TSG-6). i.v. hMSCs with a knockdown of TSG-6 did not suppress the early inflammation and failed to prolong the allograft survival. Also, i.v. infusion of recombinant TSG-6 reproduced the effects of hMSCs. Results suggest that hMSCs improve the survival of corneal allografts without engraftment and primarily by secreting TSG-6 that acts by aborting early inflammatory responses. The same mechanism may explain previous reports that MSCs decrease rejection of other organ transplants.

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye

“…injections of the cells at days −7 and −3. We carried out quantitative RT-PCR assays at day 0 for human-specific GAPDH as previously described (4,5), and detected less than 10 hMSCs in the tissues, an observation consistent with previous studies (4,5). Therefore, the beneficial effects of hMSC pretreatment in corneal allografts were not attributed to direct immunosuppression by hMSCs, and suggest induction of immune tolerance by hMSCs.…”

“…Recently, observations by our group and others identified TSG-6 as being responsible for the beneficial effects of MSCs in the treatment of disease models of the heart (4), cornea (5,19,32), brain (33), lung (34), and pancreas (35). TSG-6 exerts its antiinflammatory actions through multiple mechanisms, one of which is the modulation of myeloid cells into a tolerogenic phenotype.…”

“…infusion, most MSCs reside transiently within the lung and disappear rapidly with a t 1/2 of approximately 24 h in mice (4,5). Therefore, direct suppressive effects of MSCs on the immune system are short-lived, and do not explain the long-term therapeutic effects observed with MSCs in clinical and animal studies.…”

Mesenchymal Stem Cell Therapy Promotes Corneal Allograft Survival in Rats by Local and Systemic Immunomodulation

“…We chose to administer the MSCs before transplantation (day À7) as previous studies have shown enhanced efficacy when applied pretransplantation in preclinical models of cardiac (34) and kidney (35) transplantation. To date, a number of groups have investigated the ability of MSCs to repair chemically damaged corneas (20,(36)(37)(38) but relatively few have reported on the effects of MSCs on corneal allograft survival (22,39). To our knowledge, we show here for the first time that MSCs derived from a thirdparty strain are effective in prolonging corneal allograft survival.…”

“…Recently, treatment of experimental corneal injuries in rabbits and limbal stem cell deficiencies in rats with MSCs has been reported (20,21); however, very little is known about the role of MSCs in the prevention of corneal allograft rejection. One recent study did report the therapeutic benefit of human MSC infusion in a fully allogeneic mouse model of cornea transplantation (22). The authors demonstrated that human MSCs can suppress the early surgery-induced inflammatory response leading to the prolongation of corneal allograft survival, an effect mediated, at least in part, by the increased production of tumor necrosis factor alpha (TNF-a) stimulated gene/protein 6.…”