Multipotent human mesenchymal stromal cells mediate expansion of myeloid-derived suppressor cells via hepatocyte growth factor/c-met and STAT3.
Mesenchymal stromal cells (MSCs) are multilineage progenitors with immunomodulatory properties, including expansion of immunomodulatory leukocytes such as regulatory T lymphocytes (Tregs) and tolerogenic dendritic cells. We report that human MSCs can expand CD14(-)CD11b(+)CD33(+) human myeloid-derived suppressor cells (MDSCs). MSC-expanded MDSCs suppress allogeneic lymphocyte proliferation, express arginase-1 and inducible nitric oxide synthase, and increase the number of Tregs. This expansion occurs through the secretion of hepatocyte growth factor (HGF), with effects replicated by adding HGF singly and abrogated by HGF knockdown in MSCs. In wild-type mice, the liver, which secretes high levels of HGF, contains high numbers of Gr-1(+)CD11b(+) MDSCs, and injection of HGF into mice significantly increases the number of MDSCs. Expansion of MDSCs by MSC-secreted HGF involves c-Met (its receptor) and downstream phosphorylation of STAT3, a key factor in MDSC expansion. Our data further support the strong immunomodulatory nature of MSCs and demonstrate the role of HGF, a mitogenic molecule, in the expansion of MDSCs.
Regenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan ; Department of Obstetrics/Gynecology, Cathay General Hospital Shiji, No. 2 Lane 59 Chien-chen Road, Shiji, New Taipei City 221, Taiwan.
B Linju
BL
Yen
Men-Luh
ML
Yen
Pei-Ju
PJ
Hsu
Ko-Jiunn
KJ
Liu
Chia-Jen
CJ
Wang
Chyi-Huey
CH
Bai
Huey-Kang
HK
Sytwu
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D010920:Placenta / Q000166:cytology; D011247:Pregnancy; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
D015703:Antigens, CD; C066855:HGF protein, human; C553307:HGF protein, mouse; D050796:STAT3 Transcription Factor; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met