TY - JOUR
T1 - Human perivascular stem cell-derived extracellular vesicles mediate bone repair
AU - Xu, Jiajia
AU - Wang, Yiyun
AU - Hsu, Ching Yun
AU - Gao, Yongxing
AU - Meyers, Carolyn Ann
AU - Chang, Leslie
AU - Zhang, Leititia
AU - Broderick, Kristen
AU - Ding, Catherine
AU - Peault, Bruno
AU - Witwer, Kenneth
AU - James, Aaron Watkins
N1 - Funding Information:
AWJ was supported by the NIH/NIAMS (R01 AR070773, K08 AR068316), NIH/NIDCR (R21 DE027922), Department of Defense (W81XWH-18-1-0121, W81XWH-18-1-0336, W81XWH-18– 10613), American Cancer Society (Research Scholar Grant, RSG-18-027-01-CSM), the Orthopaedic Research and Education Foundation with funding provided by the Musculoskeletal Transplant Foundation, the Maryland Stem Cell Research Foundation, and the Musculoskeletal Transplant Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health or Department of Defense. We thank the JHU microscopy facility and the Deep Sequencing and Microarray Core for their technical and analytical assistance.
Funding Information:
Human subjects: Human lipoaspirate was obtained under IRB approval at JHU with a waiver of informed consent (Approval No. IRB00119905 and IRB00137530). 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).
Publisher Copyright:
© Xu et al.
PY - 2019/9
Y1 - 2019/9
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.48191
DO - 10.7554/eLife.48191
M3 - Article
C2 - 31482845
AN - SCOPUS:85072848515
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e48191
ER -