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

Abstract

Previous reports demonstrated that the deleterious effects of chemical injury to the cornea were ameliorated by local or systemic administration of adult stem/progenitor cells from bone marrow referred to as mesenchymal stem or stromal cells (MSCs). However, the mechanisms for the beneficial effects of MSCs on the injured cornea were not clarified. Herein, we demonstrated that human MSCs (hMSCs) were effective in reducing corneal opacity and inflammation without engraftment after either intraperitoneal (i.p.) or intravenous (i.v.) administration following chemical injury to the rat cornea. A quantitative assay for human mRNA for glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) demonstrated that less than 10 hMSCs were present in the corneas of rats 1‐day and 3 days after i.v. or i.p. administration of 1 × 107 hMSCs. In vitro experiments using a transwell coculture system demonstrated that chemical injury to corneal epithelial cells activated hMSCs to secrete the multipotent anti‐inflammatory protein TNF‐α stimulated gene/protein 6 (TSG‐6). In vivo, the effects of i.v. injection of hMSCs were largely abrogated by knockdown of TSG‐6. Also, the effects of hMSCs were essentially duplicated by either i.v. or topical administration of TSG‐6. Therefore, the results demonstrated that systemically administered hMSCs reduce inflammatory damage to the cornea without engraftment and primarily by secretion of the anti‐inflammatory protein TSG‐6 in response to injury signals from the cornea. STEM CELLS 2011;29:1572–1579

How stem cells speak with host immune cells in inflammatory brain diseases

“…Two recent reports have confirmed this TSG-6-dependent, but engraftmentindependent, action at a distance of grafted MSCs, in mice with both EAE (Fisher-Shoval et al, 2012) and ethanol-induced corneal inflammation (Roddy et al, 2011) (Table 3).…”

“…Data in Table 1 are in part summarized in (Chamberlain et al, 2008;Hall et al, 2006;Martino and Pluchino 2006;Pluchino et al, 2009b;Rojewski et al, 2008;Uccelli et al, 2008;Yuan et al, 2011). (Cusimano et al, 2012;Jaderstad et al, 2010) aracrine IDO-kynurenine MSCs (h) T cells, DCs T cell apoptosis, inhibition of antigen presentation (Lanz et al, 2010;Matysiak et al, 2008Matysiak et al, , 2011Meisel et al, 2004;Plumas et al, 2005 Bonnamain et al, 2012;Chabannes et al, 2007;Moll et al, 2011) Paracrine VEGF NPCs Microglia/macrophages Inhibition of microglial activation, proliferation and phagocytosis (Horie et al, 2011;Kim et al, 2009a;Mosher et al, 2012) Paracrine LIF NPCs Th17 cells Inhibition of Th17 cell differentiation (Cao et al, 2011;Horie et al, 2011;Kim et al, 2009a;Mosher et al, 2012) Paracrine Galectins MSCs/NPCs T cells Inhibition of T cell proliferation (Gieseke et al, 2010;Sioud 2011;Yamane et al, 2010Yamane et al, , 2011 Endocrine/Paracrine TSG-6 MSCs Macrophages Inhibition of macrophage activation, proliferation and phagocytosis (Fisher-Shoval et al, 2012;Lee et al, 2009;Roddy et al, 2011) EVs miR transfer MSCs/NPCs Multiple Post-transcriptional regulation (Bruno et al, 2009;Chen et al, 2010;…”

Human cytomegalovirus infection of human adipose-derived stromal/stem cells restricts differentiation along the adipogenic lineage

“…TSG-6 is a 35-kDa protein that is secreted in response to TNF-a or IL-1b and is natural modulator of inflammation. 27,28 We, and others, have shown that hMSCs suppresses excessive sterile inflammation thereby ameliorating lung injury, 5 myocardial infarction, 29 corneal injury 30 or peritonitis, 26 in part due to hMSCs activation and secretion of TSG-6. Recently, Lee et al, 7 have proposed TSG-6 mRNA levels as a biomarker to predict in vivo efficacy in suppressing inflammation of different donor-derived hMSCs prior to use.…”

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

“…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.…”