title: Priming with ceramide-1 phosphate promotes the therapeutic effect of mesenchymal stem/stromal cells on pulmonary artery hypertension.
abstract: Some molecules enriched in damaged organs can contribute to tissue repair by stimulating the mobilization of stem cells. These so-called "priming" factors include bioactive lipids, complement components, and cationic peptides. However, their therapeutic significance remains to be determined. Here, we show that priming of mesenchymal stromal/stem cells (MSCs) with ceramide-1 phosphate (C1P), a bioactive lipid, enhances their therapeutic efficacy in pulmonary artery hypertension (PAH). Human bone marrow (BM)-derived MSCs treated with 100 or 200 μM C1P showed improved migration activity in Transwell assays compared with non-primed MSCs and concomitantly activated MAPK(p42/44) and AKT signaling cascades. Although C1P priming had little effect on cell surface marker phenotypes and the multipotency of MSCs, it potentiated their proliferative, colony-forming unit-fibroblast, and anti-inflammatory activities. In a monocrotaline-induced PAH animal model, a single administration of human MSCs primed with C1P significantly attenuated the PAH-related increase in right ventricular systolic pressure, right ventricular hypertrophy, and thickness of α-smooth muscle actin-positive cells around the vessel wall. Thus, this study shows that C1P priming increases the effects of MSC therapy by enhancing the migratory, self-renewal, and anti-inflammatory activity of MSCs and that MSC therapy optimized with priming protocols might be a promising option for the treatment of PAH patients.
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea; Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 88 Olympic-ro 43 gil, Songpa-gu, Seoul 05505, South Korea.
authors.forename: Jisun
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea; Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: YongHwan
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea; Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Jinbeom
authors.initials: J
authors.lastname: Heo
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea; Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Kang-Hyun
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea; Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Seungun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pulmonary and Critical Care Medicine and Clinical Research Center for Chronic Obstructive Airway Diseases, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Sei Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, South Korea; Clinical Proteomics Core Lab, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Kyunggon
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 88 Olympic-ro 43 gil, Songpa-gu, Seoul 05505, South Korea. Electronic address: igkim@plaza.snu.ac.kr.
authors.forename: In-Gyu
authors.initials: IG
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea; Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea. Electronic address: d0shin03@amc.seoul.kr.
authors.forename: Dong-Myung
authors.initials: DM
authors.lastname: Shin
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D002465:Cell Movement; D049109:Cell Proliferation; D002518:Ceramides / Q000737:chemistry*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000628:therapy*; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology; D020935:MAP Kinase Signaling System; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D016686:Monocrotaline / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells
chemical_list: D000893:Anti-Inflammatory Agents; D002518:Ceramides; C065576:ceramide 1-phosphate; D016686:Monocrotaline; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: Ceramide-1 phosphate; Mesenchymal stem cell; Priming; Pulmonary artery hypertension