1. Cell Biology
  2. Stem Cells and Regenerative Medicine
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Human perivascular stem cell-derived extracellular vesicles mediate bone repair

  1. Jiajia Xu
  2. Yiyun Wang
  3. Ching-Yun Hsu
  4. Yongxing Gao
  5. Carolyn Ann Meyers
  6. Leslie Chang
  7. Leititia Zhang
  8. Kristen Broderick
  9. Catherine Ding
  10. Bruno Peault
  11. Kenneth Witwer
  12. Aaron Watkins James  Is a corresponding author
  1. Johns Hopkins University, United States
  2. University of California, Los Angeles, United States
Research Article
  • Cited 22
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Cite this article as: eLife 2019;8:e48191 doi: 10.7554/eLife.48191

Abstract

The vascular wall is a source of progenitor cells that are able to induce skeletal repair, primarily by paracrine mechanisms. Here, the paracrine role of extracellular vesicles (EVs) in bone healing was investigated. First, purified human perivascular stem cells (PSCs) were observed to induce mitogenic, pro-migratory, and pro-osteogenic effects on osteoprogenitor cells while in non-contact co-culture via elaboration of EVs. PSC-derived EVs shared mitogenic, pro-migratory, and pro-osteogenic properties of their parent cell. PSC-EV effects were dependent on surface-associated tetraspanins, as demonstrated by EV trypsinization, or neutralizing antibodies for CD9 or CD81. Moreover, shRNA knockdown in recipient cells demonstrated requirement for the CD9/CD81 binding partners IGSF8 and PTGFRN for EV bioactivity. Finally, PSC-EVs stimulated bone repair, and did so via stimulation of skeletal cell proliferation, migration, and osteodifferentiation. In sum, PSC-EVs mediate the same tissue repair effects of perivascular stem cells, and represent an 'off-the-shelf' alternative for bone tissue regeneration.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE118961 and GSE130086.

The following data sets were generated

Article and author information

Author details

  1. Jiajia Xu

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6084-2029
  2. Yiyun Wang

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  3. Ching-Yun Hsu

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  4. Yongxing Gao

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  5. Carolyn Ann Meyers

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  6. Leslie Chang

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  7. Leititia Zhang

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  8. Kristen Broderick

    Department of Surgery, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  9. Catherine Ding

    Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  10. Bruno Peault

    Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    Bruno Peault, is the inventor of perivascular stem cell-related patents held by the UC Regents (Patent No. 20160271186).
  11. Kenneth Witwer

    Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  12. Aaron Watkins James

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    For correspondence
    awjames@jhmi.edu
    Competing interests
    Aaron Watkins James, is a scientific advisory board member for Novadip, LLC.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2002-622X

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR070773)

  • Aaron Watkins James

Department of Defense (W81XWH-18-10613)

  • Aaron Watkins James

National Institute of Dental and Craniofacial Research (R21 DE027922)

  • Aaron Watkins James

Department of Defense (W81XWH-18-1-0121)

  • Aaron Watkins James

American Cancer Society (Research Scholar Grant RSG-18-027-01-CSM)

  • Aaron Watkins James

Orthopaedic Research and Education Foundation with funding provided by the Musculoskeletal Transplant Foundation

  • Aaron Watkins James

Maryland Stem Cell Research Foundation

  • Aaron Watkins James

Musculoskeletal Transplant Foundation

  • Aaron Watkins James

National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08 AR068316)

  • Aaron Watkins James

Department of Defense (W81XWH-18-1-0336)

  • Aaron Watkins James

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed according to the approved protocol of the Animal Care and Use Committee (ACUC) at Johns Hopkins University (Approval No. MO16M226).

Human subjects: Human lipoaspirate was obtained under IRB approval at JHU with a waiver of informed consent (Approval No. IRB00119905 and IRB00137530).

Reviewing Editor

  1. Clifford J Rosen, Maine Medical Center Research Institute, United States

Publication history

  1. Received: May 3, 2019
  2. Accepted: September 3, 2019
  3. Accepted Manuscript published: September 4, 2019 (version 1)
  4. Version of Record published: September 27, 2019 (version 2)

Copyright

© 2019, Xu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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