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Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling.
Stem Cells 2016; 34(3):601-13SC

Abstract

Mesenchymal stem cells (MSC) are known to facilitate healing of ischemic tissue related diseases through proangiogenic secretory proteins. Recent studies further show that MSC derived exosomes function as paracrine effectors of angiogenesis, however, the identity of which components of the exosome proteome responsible for this effect remains elusive. To address this we used high-resolution isoelectric focusing coupled liquid chromatography tandem mass spectrometry, an unbiased high throughput proteomics approach to comprehensively characterize the proteinaceous contents of MSCs and MSC derived exosomes. We probed the proteome of MSCs and MSC derived exosomes from cells cultured under expansion conditions and under ischemic tissue simulated conditions to elucidate key angiogenic paracrine effectors present and potentially differentially expressed in these conditions. In total, 6,342 proteins were identified in MSCs and 1,927 proteins in MSC derived exosomes, representing to our knowledge the first time these proteomes have been probed comprehensively. Multilayered analyses identified several putative paracrine effectors of angiogenesis present in MSC exosomes and increased in expression in MSCs exposed to ischemic tissue-simulated conditions; these include platelet derived growth factor, epidermal growth factor, fibroblast growth factor, and most notably nuclear factor-kappaB (NFkB) signaling pathway proteins. NFkB signaling was identified as a key mediator of MSC exosome induced angiogenesis in endothelial cells by functional in vitro validation using a specific inhibitor. Collectively, the results of our proteomic analysis show that MSC derived exosomes contain a robust profile of angiogenic paracrine effectors, which have potential for the treatment of ischemic tissue-related diseases.

Authors+Show Affiliations

Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA.Cancer Proteomics, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA.Cancer Proteomics, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA.Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA.Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA.Surgical and Radiological Sciences, Department of Veterinary Medicine, University of California Davis, Davis, California, USA.Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA.Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA.Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA.Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA.Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA.Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA.Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA.Department of Molecular and Cellular Biology, University of California Davis, Davis, California, USA.Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.Department of Surgery, University of Washington, Seattle, Washington, USA.Department of Surgery, University of Washington, Seattle, Washington, USA.Cancer Proteomics, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

26782178

Citation

Anderson, Johnathon D., et al. "Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis Via Nuclear Factor-KappaB Signaling." Stem Cells (Dayton, Ohio), vol. 34, no. 3, 2016, pp. 601-13.
Anderson JD, Johansson HJ, Graham CS, et al. Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling. Stem Cells. 2016;34(3):601-13.
Anderson, J. D., Johansson, H. J., Graham, C. S., Vesterlund, M., Pham, M. T., Bramlett, C. S., ... Nolta, J. A. (2016). Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling. Stem Cells (Dayton, Ohio), 34(3), pp. 601-13. doi:10.1002/stem.2298.
Anderson JD, et al. Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis Via Nuclear Factor-KappaB Signaling. Stem Cells. 2016;34(3):601-13. PubMed PMID: 26782178.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling. AU - Anderson,Johnathon D, AU - Johansson,Henrik J, AU - Graham,Calvin S, AU - Vesterlund,Mattias, AU - Pham,Missy T, AU - Bramlett,Charles S, AU - Montgomery,Elizabeth N, AU - Mellema,Matt S, AU - Bardini,Renee L, AU - Contreras,Zelenia, AU - Hoon,Madeline, AU - Bauer,Gerhard, AU - Fink,Kyle D, AU - Fury,Brian, AU - Hendrix,Kyle J, AU - Chedin,Frederic, AU - El-Andaloussi,Samir, AU - Hwang,Billie, AU - Mulligan,Michael S, AU - Lehtiö,Janne, AU - Nolta,Jan A, Y1 - 2016/02/19/ PY - 2015/05/07/received PY - 2015/10/05/revised PY - 2015/10/22/accepted PY - 2016/1/20/entrez PY - 2016/1/20/pubmed PY - 2016/12/15/medline KW - Exosomes KW - High-resolution isoelectric focusing KW - Liquid chromatography tandem mass spectrometry KW - Mesenchymal stem cells KW - Nuclear factor kappaB KW - Peripheral arterial disease KW - Proteomics SP - 601 EP - 13 JF - Stem cells (Dayton, Ohio) JO - Stem Cells VL - 34 IS - 3 N2 - Mesenchymal stem cells (MSC) are known to facilitate healing of ischemic tissue related diseases through proangiogenic secretory proteins. Recent studies further show that MSC derived exosomes function as paracrine effectors of angiogenesis, however, the identity of which components of the exosome proteome responsible for this effect remains elusive. To address this we used high-resolution isoelectric focusing coupled liquid chromatography tandem mass spectrometry, an unbiased high throughput proteomics approach to comprehensively characterize the proteinaceous contents of MSCs and MSC derived exosomes. We probed the proteome of MSCs and MSC derived exosomes from cells cultured under expansion conditions and under ischemic tissue simulated conditions to elucidate key angiogenic paracrine effectors present and potentially differentially expressed in these conditions. In total, 6,342 proteins were identified in MSCs and 1,927 proteins in MSC derived exosomes, representing to our knowledge the first time these proteomes have been probed comprehensively. Multilayered analyses identified several putative paracrine effectors of angiogenesis present in MSC exosomes and increased in expression in MSCs exposed to ischemic tissue-simulated conditions; these include platelet derived growth factor, epidermal growth factor, fibroblast growth factor, and most notably nuclear factor-kappaB (NFkB) signaling pathway proteins. NFkB signaling was identified as a key mediator of MSC exosome induced angiogenesis in endothelial cells by functional in vitro validation using a specific inhibitor. Collectively, the results of our proteomic analysis show that MSC derived exosomes contain a robust profile of angiogenic paracrine effectors, which have potential for the treatment of ischemic tissue-related diseases. SN - 1549-4918 UR - https://www.unboundmedicine.com/medline/citation/26782178/Comprehensive_Proteomic_Analysis_of_Mesenchymal_Stem_Cell_Exosomes_Reveals_Modulation_of_Angiogenesis_via_Nuclear_Factor_KappaB_Signaling_ L2 - https://doi.org/10.1002/stem.2298 DB - PRIME DP - Unbound Medicine ER -