Lung Resident Mesenchymal Stem Cells Isolated from Human Lung Allografts Inhibit T Cell Proliferation via a Soluble Mediator

Abstract

Development of allograft rejection continues to be the major determinant of morbidity and mortality post-lung transplantation. We have recently demonstrated that a population of donor-derived mesenchymal stem cells are present in human lung allografts and can be isolated and expanded ex vivo. In this study, we investigated the impact of lung resident mesenchymal stem cells (LR-MSCs), derived from allografts of human lung transplant recipients, on T cell activation in vitro. Similar to bone marrow derived MSCs, LR-MSCs did not express MHC II nor the co-stimulatory molecules CD80 or CD86. In vitro, LR-MSCs profoundly suppressed the proliferative capacity of T cells in response to a mitogenic or an allogeneic stimulus. The immunosuppressive function of LR-MSCs was also noted in absence of direct cell contact, indicating that LR-MSCs mediated their effect predominantly via a soluble mediator. LR-MSCs isolated from lung transplant recipients demonstrated PGE2 secretion at baseline (385 ± 375 pg/ml) which increased in response to IL-1β (1149 ± 1081 pg/ml). Addition of prostaglandin synthesis inhibitors (indomethacin and NS-398) substantially abrogated LR-MSC-mediated immunosuppression, indicating that PGE2 may be one of the major soluble mediators impacting T cell activity. This is the first report to demonstrate that human tissue-derived MSCs isolated from an allogeneic environment, have the potential to mediate immunological responses in vitro.

Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

“…34,35 MSCs, including LR-MSCs, demonstrate an in vitro potential to inhibit T-cell function via secretion of soluble mediators, such as prostaglandin E 2 . 16,36 However, MSCs potentiate fibrotic differentiation of other mesenchymal cells by secreting profibrotic mediators, such as TGF-␤1. 37 Thus, although MSCs can likely modulate an inflammatory microenvironment, they can also promote fibrogenesis by secreting profibrotic mediators 37 or differentiating to myofibroblasts.…”

“…15,16 Surface marker expression for cells used in the present study was determined using flow cytometry. LR-MSCs were negative for CD45 and positive for CD73, CD105, CD90, and CD44.…”

Mesenchymal stem cell like (MSCl) cells generated from human embryonic stem cells support pluripotent cell growth

“…Moreover, MSCs show multipotent stem 41 cell characteristics [2] and special immunological features [3]. MSCs 42 can also be obtained from various tissues including peripheral blood, 43 umbilical cord, placenta, vein wall, muscle, adipose and connective 44 tissues [4].…”

Relevance of the mevalonate biosynthetic pathway in the regulation of bone marrow mesenchymal stromal cell-mediated effects on T-cell proliferation and B-cell survival

“…These data, would support the idea that IL10 gives a relevant contribution to the inhibiting activity present in BMSC-PBMC cocultures, besides the reported role of PGE2 in BMSC-and/or fibroblast-like-mediated immunosuppression. 9,14,36 It has been recently reported that BMSC can support Bcell survival by delivering anti-apoptotic and pro-differentiating signals. 19 We found that fluvastatin can significantly inhibit the pro-survival signal delivered by BMSC to B cells in the presence of dexamethasone, although this signal is marginally inhibited in the absence of corticosteroids.…”