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Matrix regeneration proteins in the hypoxia-triggered exosomes of shoulder tenocytes and adipose-derived mesenchymal stem cells

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Abstract

Regenerative functions of exosomes rely on their contents which are influenced by pathological stimuli, including hypoxia, in rotator cuff tendon injuries (RCTI). The hypoxic environment triggers tenocytes and adjacent adipose-derived mesenchymal stem cells (ADMSCs) to release regenerative mediators to the ECM via the exosomes which elicit autocrine/paracrine responses to protect the tendon matrix from injury. We investigated the exosomal protein contents from tenocytes and subcutaneous ADMSCs from the shoulder of Yucatan microswine cultured under hypoxic conditions (2% O2). The exosomal proteins were detected using high-resolution mass spectrometry nano-LC–MS/MS Tribrid system and were compiled using ‘Scaffold’ software. Hypoxic exosomes from tenocytes and ADMSCs carried 199 and 65 proteins, respectively. The key proteins identified by mass spectrometry and associated with ECM homeostasis from hypoxic ADMSCs included MMP2, COL6A, CTSD and TN-C and those from hypoxic tenocytes were THSB1, NSEP1, ITIH4 and TN-C. These findings were confirmed at the mRNA and protein level in the hypoxic ADMSCs and tenocytes. These proteins are involved in multiple signaling pathways of ECM repair/regeneration. This warrants further investigations for their translational significance in the management of RCTI.

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Acknowledgements

This work was supported by LB506 grant to DKA and LB606 Grant to MFD from the State of Nebraska. The research work of DKA is also supported by Grants R01HL120659 and R01HL144125 from the National Institutes of Health. The contents of this original research article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or the State of Nebraska.

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Authors and Affiliations

  1. Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA, 91766-1854, USA

    Finosh G. Thankam & Devendra K. Agrawal

  2. Departments of Clinical & Translational Science and Orthopedic Surgery, Creighton University School of Medicine, Omaha, NE, 68178, USA

    Isaiah Chandra, Connor Diaz, Matthew F. Dilisio, Jonathan Fleegel & R. Michael Gross

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  1. Finosh G. Thankam
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Thankam, F.G., Chandra, I., Diaz, C. et al. Matrix regeneration proteins in the hypoxia-triggered exosomes of shoulder tenocytes and adipose-derived mesenchymal stem cells. Mol Cell Biochem 465, 75–87 (2020). https://doi.org/10.1007/s11010-019-03669-7

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