title: Substance P enhances mesenchymal stem cells-mediated immune modulation.
abstract: Since clinical application of MSCs requires long-term ex vivo culture inducing senescence in MSCs and reducing the therapeutic activity of transplanted MSCs, numerous efforts have been attempted to sustain the active state of MSCs. Substance P (SP) is a neuropeptide that functions to activate the cellular physiological responses of MSCs, including proliferation, migration, and secretion of specific cytokines. In this study, we explored the potential of SP to restore the weakened immune modulating activity of MSCs resulting from long-term culture by measuring T cell activity and interleukin-2 (IL-2) secretion of CD4(+) Jurkat leukemic T cells and primary CD4(+) T cells. As the number of cell passages increased, the immunosuppressive function of MSCs based on T cell activity decreased. This weakened activity of MSCs could be restored by SP treatment and nullified by co-treatment of an NK1 receptor blocker. Higher levels of transforming growth factor beta 1 (TGF-β1) secretion were noted in the medium of SP-treated late passage MSC cultures, but IL-10 levels did not change. SP-treated MSC-conditioned medium decreased T cell activity and IL-2/Interferon gamma (IFN-g) secretion in T cells even in the activation by lipopolysaccharide (LPS) or CD3/CD28 antibodies, both of which were successfully blocked by inhibiting the TGF beta signaling pathway. This stimulatory effect of SP on late passage MSCs was also confirmed in direct cell-cell contact co-culture of MSCs and CD4(+) Jurkat T cells. Collectively, our study suggests that SP pretreatment to MSCs may recover the immunosuppressive function of late passage MSCs by potentiating their ability to secrete TGF-β1, which can enhance the therapeutic activity of ex vivo expanded MSCs in long-term culture.
authors.affiliation: Department of Genetic Engineering, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seochun-dong, Kiheung-ku, Yong In 441-706, South Korea. Electronic address: yinji8825@hotmail.com.
authors.forename: Yinji
authors.initials: Y
authors.lastname: Jin
authors.affiliation: College of Medicine/East-West Medical Research Institute, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-702, South Korea. Electronic address: hshong@khu.ac.kr.
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Hong
authors.affiliation: Department of Genetic Engineering, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seochun-dong, Kiheung-ku, Yong In 441-706, South Korea. Electronic address: ysson@khu.ac.kr.
authors.forename: Youngsook
authors.initials: Y
authors.lastname: Son
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D013373:Substance P / Q000494:pharmacology*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D007376:Interleukin-2; D008070:Lipopolysaccharides; D053773:Transforming Growth Factor beta1; D013373:Substance P; D007371:Interferon-gamma
keywords: Immune modulation; Mesenchymal stem cells; Substance P; T cells; TGF-β1