title: Mesenchymal stem cells express serine protease inhibitor to evade the host immune response.
abstract: Clinical trials using mesenchymal stem cells (MSCs) have been initiated worldwide. An improved understanding of the mechanisms by which allogeneic MSCs evade host immune responses is paramount to regulating their survival after administration. This study has focused on the novel role of serine protease inhibitor (SPI) in the escape of MSCs from host immunosurveillance through the inhibition of granzyme B (GrB). Our data indicate bone marrow-derived murine MSCs express SPI6 constitutively. MSCs from mice deficient for SPI6 (SPI6(-/-)) exhibited a 4-fold higher death rate by primed allogeneic cytotoxic T cells than did wild-type MSCs. A GrB inhibitor rescued SPI6(-/-) MSCs from cytotoxic T-cell killing. Transduction of wild-type MSCs with MigR1-SPI6 also protected MSCs from cytotoxic T cell-mediated death in vitro. In addition, SPI6(-/-) MSCs displayed a shorter lifespan than wild-type MSCs when injected into an allogeneic host. We conclude that SPI6 protects MSCs from GrB-mediated killing and plays a pivotal role in their survival in vivo. Our data could serve as a basis for future SPI-based strategies to regulate the survival and function of MSCs after administration and to enhance the efficacy of MSC-based therapy for diseases.
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Najib
authors.initials: N
authors.lastname: El Haddad
authors.forename: Dean
authors.initials: D
authors.lastname: Heathcote
authors.forename: Robert
authors.initials: R
authors.lastname: Moore
authors.forename: Sunmi
authors.initials: S
authors.lastname: Yang
authors.forename: Jamil
authors.initials: J
authors.lastname: Azzi
authors.forename: Bechara
authors.initials: B
authors.lastname: Mfarrej
authors.forename: Mark
authors.initials: M
authors.lastname: Atkinson
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Jeng-Shin
authors.initials: JS
authors.lastname: Lee
authors.forename: Philip G
authors.initials: PG
authors.lastname: Ashton-Rickardt
authors.forename: Reza
authors.initials: R
authors.lastname: Abdi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D053804:Granzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D057131:Immune Evasion / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000235:genetics* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases; C106610:Serpinb9 protein, mouse