title: Human podoplanin-positive monocytes and platelets enhance lymphangiogenesis through the activation of the podoplanin/CLEC-2 axis.
abstract: Emerging studies suggested that murine podoplanin-positive monocytes (PPMs) are involved in lymphangiogenesis. The goal of this study was to demonstrate the therapeutic lymphangiogenesis of human PPMs by the interaction with platelets. Aggregation culture of human peripheral blood mononuclear cells (PBMCs) resulted in cellular aggregates termed hematospheres. During 5-day culture, PPMs expanded exponentially and expressed several lymphatic endothelial cell-specific markers including vascular endothelial growth factor receptor (VEGFR)-3 and well-established lymphangiogenic transcription factors. Next, we investigated the potential interaction of PPMs with platelets that had C-type lectin-like receptor-2 (CLEC-2), a receptor of podoplanin. In vitro coculture of PPMs and platelets stimulated PPMs to strongly express lymphatic endothelial markers and upregulate lymphangiogenic cytokines. Recombinant human CLEC-2 also stimulated PPMs through Akt and Erk signaling. Likewise, platelets in coculture with PPMs augmented secretion of a lymphangiogenic cytokine, interleukin (IL)-1-β, via podoplanin/CLEC-2 axis. The supernatant obtained from coculture was able to enhance the migration, viability, and proliferation of lymphatic endothelial cell. Local injection of hematospheres with platelets significantly increased lymphatic neovascularization and facilitated wound healing in the full-thickness skin wounds of nude mice. Cotreatment with PPMs and platelets augments lymphangiogenesis through podoplanin/CLEC-2 axis, which thus would be a promising novel strategy of cell therapy to treat human lymphatic vessel disease.
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Hur
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea; Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Jae Hee
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Bundang Hospital, Bundang, Republic of Korea.
authors.forename: Il-Young
authors.initials: IY
authors.lastname: Oh
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Choi
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea; Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Yun
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea; Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Joonoh
authors.initials: J
authors.lastname: Kim
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Choi
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea; Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Seung-Bum
authors.initials: SB
authors.lastname: Ko
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea; Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Jin-A
authors.initials: JA
authors.lastname: Kang
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea; Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Jeehoon
authors.initials: J
authors.lastname: Kang
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea; Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Hwan
authors.initials: H
authors.lastname: Lee
authors.affiliation: Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea; Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University Hospital, Seoul, Republic of Korea. Electronic address: hyosoo@snu.ac.kr.
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods*; D004195:Disease Models, Animal; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D042583:Lymphangiogenesis; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000293:injuries; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D000098853:Podoplanin
chemical_list: D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D040321:Vascular Endothelial Growth Factor Receptor-3; C104778:CLEC2B protein, human; C117468:PDPN protein, human; D000098853:Podoplanin; C581309:FLT4 protein, human
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