title: Flagellin preconditioning enhances the efficacy of mesenchymal stem cells in an irradiation-induced proctitis model.
abstract: The success of mesenchymal stem cell transplantation for proctitis depends not only on cell donors but also on host microenvironmental factors, which play a major role in conditioning mesenchymal stem cell immunosuppressive action and repair. This study sought to determine if flagellin, a TLR5 ligand, can enhance the mesenchymal stem cell treatment efficacy in radiation-induced proctitis. With the use of a colorectal model of 27 Gy irradiation in rats, we investigated and compared the effects on immune capacity and remodeling at 28 d after irradiation of the following: 1) systemic mesenchymal stem cell (5 × 10(6)) administration at d 7 after irradiation, 2) administration of flagellin at d 3 and systemic mesenchymal stem cell administration at d 7, and 3) in vitro preconditioning of mesenchymal stem cells with flagellin, 24 h before their administration on d 7. The mucosal CD8(+) T cell population was normalized after treatment with flagellin-preconditioned mesenchymal stem cells or flagellin plus mesenchymal stem cells, whereas mesenchymal stem cells alone did not alter the radiation-induced elevation of CD8(+) T cell frequency. Mesenchymal stem cell treatment returned the irradiation-elevated frequency of CD25(+) cells in the mucosa-to-control levels, whereas both flagellin-preconditioned mesenchymal stem cell and flagellin-plus-mesenchymal stem cell treatment each significantly increased not only CD25(+) cell frequency but also forkhead box p3 and IL-2Rα expression. Specifically, IL-10 was overexpressed after flagellin-preconditioned mesenchymal stem cell treatment. Analysis of collagen expression showed that the collagen type 1/collagen type 3 ratio, an indicator of wound-healing maturation, was low in the irradiated and mesenchymal stem cell-treated groups and returned to the normal level only after the flagellin-preconditioned mesenchymal stem cell treatment. This was associated with a reduction in myofibroblast accumulation. In a proctitis model, flagellin-preconditioned mesenchymal stem cells improved colonic immune capacity and enhanced tissue remodeling.
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France christine.linard@irsn.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Linard
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Strup-Perrot
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France.
authors.forename: Jean-Victor
authors.initials: JV
authors.lastname: Lacave-Lapalun
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Benderitter
mesh_terms: D000818:Animals; D003106:Colon / Q000276:immunology / Q000528:radiation effects; D005408:Flagellin / Q000378:metabolism*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D011349:Proctitis / Q000209:etiology / Q000378:metabolism / Q000628:therapy*; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000378:metabolism / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000276:immunology / Q000528:radiation effects
chemical_list: D005408:Flagellin
keywords: MSC; Th cells; colon; macrophage; myofibroblast