Action at a Distance: Systemically Administered Adult Stem/Progenitor Cells (MSCs) Reduce Inflammatory Damage to theCornea Without Engraftment and Primarily by Secretion ofTNF-a Stimulated Gene/Protein 6
Gavin W. Roddy, Joo Youn Oh, Ryang Hwa Lee, Thomas J. Bartosh, Joni Ylostalo, Katie Coble, Robert H. Rosa, Jr, Darwin J. Prockop
Institute for Regenerative Medicine, Texas A&M Health Science Center
Stem Cells and Regenerative Medicine
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 3 107 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-a 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.