Induction of immunomodulatory monocytes by human mesenchymal stem cell-derived hepatocyte growth factor through ERK1/2.
Monocytes are a population of leukocytes that terminally differentiate into macrophages and DCs. Whereas these differentiated progeny have inflammatory and resident--which are more immunomodulatory--phenotypes, less has been reported on the plasticity of monocytes themselves. We found that MSCs, a population of somatic stem cells, can rapidly induce human and murine monocytes through secretion of HGF to acquire an immunomodulatory phenotype to suppress T cell effector function. MSCs are multilineage postnatal progenitor cells with strong immunomodulatory effects toward T lymphocytes, NK lymphocytes, and DCs, but less is known regarding their interactions with monocytes. We found that CD14(+) human monocytes express c-Met, the receptor for HGF, and both depletion of HGF-treated CD14(+) monocytes and knockdown of HGF secretion in MSCs abrogate the suppression of anti-CD3/28-activated T cell proliferation. HGF-treated monocytes remain undifferentiated and can alter activated T cell cytokine expression from a Th1 toward Th2 profile. Moreover, monocytes cocultured with MSCs or treated with HGF alone can produce high levels of IL-10, a potent immunomodulatory cytokine. Injection of HGF to WT mice also results in an increase in IL-10(+)-expressing monocytes from the spleen, a known reservoir for circulating monocytes. Mechanistically, HGFs modulate IL-10 production in monocytes through the ERK1/2 pathway. Our data demonstrate further the pleomorphic nature of MSC immunomodulation, as well as highlight the important role of immunomodulatory monocytes in altering T cell effector function.
Regenerative Medicine and.
Pei-Min
PM
Chen
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan; School of Medical Laboratory Science and Biotechnology and.
Ko-Jiunn
KJ
Liu
Regenerative Medicine and.
Pei-Ju
PJ
Hsu
Regenerative Medicine and.
Chung-Fan
CF
Wei
Department of Public Health, College of Medicine, Taipei Medical University, Taipei, Taiwan;
Chyi-Huey
CH
Bai
Gerontology Research Groups, Institute of Cellular and System Medicine, and.
Ling-Jun
LJ
Ho
Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan; and.
Huey-Kang
HK
Sytwu
Regenerative Medicine and Department of Obstetrics/Gynecology, Cathay General Hospital Shiji, Taipei, Taiwan blyen@nhri.org.tw.
B Linju
BL
Yen
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005260:Female; D017228:Hepatocyte Growth Factor / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D019859:Proto-Oncogene Proteins c-met / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
C066855:HGF protein, human; C553307:HGF protein, mouse; C508609:IL10 protein, human; D016753:Interleukin-10; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
CD14+ cells; CD4+ T cells; Th1/2 cytokine