Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling

Author:

Anderson Johnathon D.1,Johansson Henrik J.2,Graham Calvin S.1,Vesterlund Mattias2,Pham Missy T.1,Bramlett Charles S.1,Montgomery Elizabeth N.1,Mellema Matt S.3,Bardini Renee L.1,Contreras Zelenia1,Hoon Madeline1,Bauer Gerhard1,Fink Kyle D.1,Fury Brian1,Hendrix Kyle J.1,Chedin Frederic4,EL-Andaloussi Samir56,Hwang Billie7,Mulligan Michael S.7,Lehtiö Janne2,Nolta Jan A.1

Affiliation:

1. Stem Cell Program, Department of Internal Medicine, University of California Davis, Davis, California, USA

2. Cancer Proteomics, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

3. Surgical and Radiological Sciences, Department of Veterinary Medicine, University of California Davis, Davis, California, USA

4. Department of Molecular and Cellular Biology, University of California Davis, Davis, California, USA

5. Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

6. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom

7. Department of Surgery, University of Washington, Seattle, Washington, USA

Abstract

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.

Funder

NIH Transformative

NSF GROW

NIH

NIH T32

NSF GRFP

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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