A New Vision of Mesenchymal Stromal Cells
Authors: Richard L Hurwitz
Journal: Molecular Therapy (2012)

Although corneal grafts can restore vision to damaged and opaque eyes, these grafts, like any other transplanted tissue, may be rejected by the host so that blindness returns. In this issue of Molecular Therapy, Oh et al. report that the infusion of human mesenchymal stromal cells (MSCs) prevents allogeneic corneal rejection in a murine model and—crucially—that these benefits may be mediated by a soluble, MSC-derived anti-inflammatory protein, tumor necrosis factor-α (TNF-α) stimulated gene/protein 6 (TSG-6).1Oh JY Lee RH Yu JM Ko JH Lee HJ Ko AY et al.Intravenous mesenchymal stem cells prevented rejection of allogeneic corneal transplants by aborting the early inflammatory response.Mol Ther. 2012; 20: 2143-2152Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar If similar effects can be produced in humans, injection of the recombinant protein may greatly increase the success and survival of corneal grafts. Infection, injury, or inborn errors of metabolism can all damage the cornea, the transparent tissue covering the pupil in the eye, producing an opaque scar that leaves the person functionally blind. Corneal transplants were among the first successful human tissue transplants and have been very effective in restoring vision to affected individuals. The unique environment of the eye supports a phenomenon termed anterior chamber acquired immune deviance that usually allows even mismatched corneal transplants to survive without rejection.2Zhang-Hoover J Stein-Streilein J Therapies based on principles of ocular immune privilege.Chem Immunol Allergy. 2007; 92: 317-327Crossref PubMed Scopus (24) Google Scholar,3Niederkorn JY The induction of anterior chamber-associated immune deviation.Chem Immunol Allergy. 2007; 92: 27-35Crossref PubMed Scopus (57) Google Scholar This same immune tolerance mechanism may help to explain why the ocular environment has allowed recent gene therapy advances for retinal degenerative diseases and ocular malignancies.4Brenner MK The eyes have it.Mol Ther. 2010; 18: 451-452Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar,5Herzog RW Seeing eye to eye with gene therapy.Mol Ther. 2012; 20: 687-688Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar,6Maguire AM Simonelli F Pierce EA Pugh Jr EN Mingozzi F Bennicelli J et al.Safety and efficacy of gene transfer for Leber's congenital amaurosis.N Engl J Med. 2008; 358: 2240-2248Crossref PubMed Scopus (1709) Google Scholar,7Chévez-Barrios P Chintagumpala M Mieler W Paysse E Boniuk M Kozinetz C et al.Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir.J Clin Oncol. 2005; 23: 7927-7935Crossref PubMed Scopus (132) Google Scholar,8Ildefonso CJ Kong L Leen A Chai SJ Petrochelli V Chintagumpala M et al.Absence of systemic immune response to adenovectors after intraocular administration to children with retinoblastoma.Mol Ther. 2010; 18: 1885-1890Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Because of this corneal immune privilege, low-risk corneal transplants have an 80% chance of being rejection-free after 5 years, even without the immunosuppressive therapy needed for most other human tissue grafts. Although outcomes are generally good, there is an increased risk of graft failure that may be as high as 50% over 5 years if inflammation is present at the time of transplant, if the endothelial layer is disrupted during surgery, or if there has been a previous rejection episode. Systemic immunosuppression has not been proven useful in preventing this complication, and although prolonged administration of topical steroids may help salvage corneal rejection, this therapy is commonly associated with cataract and glaucoma. More recent efforts have therefore focused on improving surgical techniques to enable salvaging of the endothelial cell layer of the host (if this layer is not diseased), allowing transplantation of only the anterior layer of the donor cornea. Technically this is a difficult procedure, and it remains uncertain whether graft survival is truly increased. The report by Oh et al.1Oh JY Lee RH Yu JM Ko JH Lee HJ Ko AY et al.Intravenous mesenchymal stem cells prevented rejection of allogeneic corneal transplants by aborting the early inflammatory response.Mol Ther. 2012; 20: 2143-2152Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar offers an alternative to the above approaches. Recent studies had already suggested that the administration of (allogeneic) MSCs can decrease the incidence of organ rejection in a variety of animal transplant models through mechanisms that were not elucidated.9English K French A Wood KJ Mesenchymal stromal cells: facilitators of successful transplantation.Cell Stem Cell. 2010; 7: 431-442Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar Oh et al. now show that the same approach can prevent the rejection of corneal grafts in a murine model. They show that MSC infusion suppressed early surgically induced inflammation and reduced the activation of antigen-presenting cells in the cornea and draining lymph nodes. The subsequent risk of immune rejection was decreased and allograft survival prolonged. Importantly, these benefits did not require the local presence of the MSCs, which did not infiltrate the transplanted cornea but instead appeared to remain in the lung vasculature. This paradox prompted the investigators to seek an indirect mechanism of immune modulation. Previous investigations had shown that MSCs secrete the soluble anti-inflammatory protein TSG-6 after tissue injury and that TSG-6 prevented subsequent inflammation.10Lee RH Pulin AA Seo MJ Kota DJ Ylostalo J Larson BL et al.Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6.Cell Stem Cell. 2009; 5: 54-63Abstract Full Text Full Text PDF PubMed Scopus (1383) Google Scholar,11Roddy GW Oh JY Lee RH Bartosh TJ Ylostalo J Coble K et al.Action at a distance: systemically administered adult stem/progenitor cells (MSCs) reduce inflammatory damage to the cornea without engraftment and primarily by secretion of TNF-α stimulated gene/protein 6.Stem Cells. 2011; 29: 1572-1579Crossref PubMed Scopus (202) Google Scholar This evidence prompted the authors to investigate the cytokine messages upregulated in human MSCs injected into mice in conjunction with corneal engraftment, and they found that TSG-6 messenger RNA was increased more than any of the other cytokines tested. TSG-6 is a 30-kDa secreted protein that contains a hyaluronan-binding domain and, as its name suggests, is expressed in response to the presence of TNF-α as well as interleukin-1 (ref. 12Lee TH Klampfer L Shows TB Vilcek J Transcriptional regulation of TSG6, a tumor necrosis factor- and interleukin-1-inducible primary response gene coding for a secreted hyaluronan-binding protein.J Biol Chem. 1993; 268: 6154-6160Abstract Full Text PDF PubMed Google Scholar). As a member of the hyaluronan-binding family, TSG-6 stabilizes the extracellular matrix through its association with proteoglycans and also presents hyaluronan to the hyaluronan receptor CD44,13Lesley J Gál I Mahoney DJ Cordell MR Rugg MS Hyman R et al.TSG-6 modulates the interaction between hyaluronan and cell surface CD44.J Biol Chem. 2004; 279: 25745-25754Crossref PubMed Scopus (140) Google Scholar a protein that is also important in the regulation of the immune system. Moreover, TSG-6 also forms a covalent complex with inter-alpha-inhibitor, which enhances the serine protease inhibitory activity of the latter and enables it to act as an important negative regulator of the protease network associated with inflammation.14Wisniewski HG Hua JC Poppers DM Naime D Vilcek J Cronstein BN TNF/IL-1-inducible protein TSG-6 potentiates plasmin inhibition by inter-alpha-inhibitor and exerts a strong anti-inflammatory effect in vivo.J Immunol. 1996; 156: 1609-1615PubMed Google Scholar When TSG-6 expression by MSCs was blocked using a specific small interfering RNA, administration of the mesenchymal cells could no longer prevent rejection of the graft. Perhaps most importantly for future therapeutic intervention, injection of recombinant TSG-6 protein prevented corneal rejection even in the absence of MSCs. Unlike human corneal grafts, the murine model described by Oh et al. was characterized by an extremely high rate of rejection.1Oh JY Lee RH Yu JM Ko JH Lee HJ Ko AY et al.Intravenous mesenchymal stem cells prevented rejection of allogeneic corneal transplants by aborting the early inflammatory response.Mol Ther. 2012; 20: 2143-2152Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Nonetheless, if even the relatively low number of human corneal rejections could be prevented or if the survival of the graft could be prolonged with a lower toxicity reagent, then this alone would be a substantial benefit to a significant number of patients. And if TSG-6 administration proves equally potent in reducing the risk of solid-organ or hematopoietic stem cell allotransplants in humans, then the impact of this approach would be very substantial indeed. In the meantime, the work provides a solid vision of a molecular framework for rejection and shows a mechanism by which this process can be prevented.