title: Exosomes from Cardiomyocyte Progenitor Cells and Mesenchymal Stem Cells Stimulate Angiogenesis Via EMMPRIN.
abstract: To date, cellular transplantation therapy has not yet fulfilled its high expectations for cardiac repair. A major limiting factor is lack of long-term engraftment of the transplanted cells. Interestingly, transplanted cells can positively affect their environment via secreted paracrine factors, among which are extracellular vesicles, including exosomes: small bi-lipid-layered vesicles containing proteins, mRNAs, and miRNAs. An exosome-based therapy will therefore relay a plethora of effects, without some of the limiting factors of cell therapy. Since cardiomyocyte progenitor cells (CMPC) and mesenchymal stem cells (MSC) induce vessel formation and are frequently investigated for cardiac-related therapies, the pro-angiogenic properties of CMPC and MSC-derived exosome-like vesicles are investigated. Both cell types secrete exosome-like vesicles, which are efficiently taken up by endothelial cells. Endothelial cell migration and vessel formation are stimulated by these exosomes in in vitro models, mediated via ERK/Akt-signaling. Additionally, these exosomes stimulated blood vessel formation into matrigel plugs. Analysis of pro-angiogenic factors revealed high levels of extracellular matrix metalloproteinase inducer (EMMPRIN). Knockdown of EMMPRIN on CMPCs leads to a diminished pro-angiogenic effect, both in vitro and in vivo. Therefore, CMPC and MSC exosomes have powerful pro-angiogenic effects, and this effect is largely mediated via the presence of EMMPRIN on exosomes.
authors: Department of Cardiology, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.
authors: Krijn R
authors: KR
authors: Vrijsen
authors: Department of Molecular Cell Biology, Leiden University Medical Center, 2333ZA, The Netherlands.
authors: Janita A
authors: JA
authors: Maring
authors: Department of Cardiology, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.|UMC Utrecht Regenerative Medicine Center, University Medical Center, Utrecht, 3584CT, The Netherlands.
authors: Steven A J
authors: SA
authors: Chamuleau
authors: Department of Cardiology, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.
authors: Vera
authors: V
authors: Verhage
authors: Department of Cardiology, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.
authors: Emma A
authors: EA
authors: Mol
authors: Department of Cardiology, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.
authors: Janine C
authors: JC
authors: Deddens
authors: Department of Cardiology, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.|UMC Utrecht Regenerative Medicine Center, University Medical Center, Utrecht, 3584CT, The Netherlands.
authors: Corina H G
authors: CH
authors: Metz
authors: Department of Molecular Cell Biology, Leiden University Medical Center, 2333ZA, The Netherlands.
authors: Kirsten
authors: K
authors: Lodder
authors: Department of Cardiology, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.
authors: Esther C M
authors: EC
authors: van Eeuwijk
authors: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.
authors: Susan M
authors: SM
authors: van Dommelen
authors: Department of Cardiology, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.|UMC Utrecht Regenerative Medicine Center, University Medical Center, Utrecht, 3584CT, The Netherlands.|Netherlands Heart Institute (ICIN), Utrecht, 3584CX, The Netherlands.
authors: Pieter A
authors: PA
authors: Doevendans
authors: Department of Molecular Cell Biology, Leiden University Medical Center, 2333ZA, The Netherlands.
authors: Anke M
authors: AM
authors: Smits
authors: Department of Molecular Cell Biology, Leiden University Medical Center, 2333ZA, The Netherlands. m.j.goumans@lumc.nl.
authors: Marie-José
authors: MJ
authors: Goumans
authors: Department of Cardiology, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands. j.sluijter@umcutrecht.nl.|UMC Utrecht Regenerative Medicine Center, University Medical Center, Utrecht, 3584CT, The Netherlands. j.sluijter@umcutrecht.nl.|Netherlands Heart Institute (ICIN), Utrecht, 3584CX, The Netherlands. j.sluijter@umcutrecht.nl.
authors: Joost P G
authors: JP
authors: Sluijter
mesh_terms: D000818:Animals; D051926:Basigin / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D051926:Basigin; D051057:Proto-Oncogene Proteins c-akt
keywords: EMMPRIN; angiogenesis; cardiomyocyte progenitor cells; extracellular vesicles; mesenchymal stem cells