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Cited by 5Extracellular vesicles in diseaseTendon Structure and TreatmentKnee injuries and reconstruction techniques

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Bone marrow stromal and anterior cruciate ligament remnant cell co‐culture‐derived extracellular vesicles promote cell activity in both cell types

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Lin, Sung‐Yen, Wu, Shun Cheng, Liu, Zi‐Miao, Chou, Paul Pei‐Hsi, Zhao, Chunfeng, Ho, Mei‐Ling, Lu, Cheng‐Chang·2024·Journal of Cellular and Molecular Medicine
DOI 10.1111/jcmm.70049PMC PMC11366498
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Abstract

The significance of anterior cruciate ligament (ACL) remnants during reconstruction remains unclear. Co-culturing ACL remnant cells and bone marrow stromal cells (BMSCs) may reduce apoptosis and enhance hamstring tendon activity. This study investigated whether extracellular vesicles (EVs), which facilitate cell-cell interactions, act as the active components, improving graft maturation in this co-culture. The effects of EVs on cell viability, proliferation, migration and gene expression in the rabbit ACL remnant cells and BMSCs were assessed using control (BMSC-only culture), co-culture (ACL remnant cells and BMSCs, CM) and co-culture without EVs (CM ∆ EVs) media. EVs were isolated from control (BMSC-EV) and co-culture (CM-EV) media and characterized. CM significantly enhanced the proliferation, migration and expression of transforming growth factor (TGF-β)-, vascular endothelial growth factor (VEGF)-, collagen synthesis- and tenogenesis-related genes. However, CM-induced effects were reversed by the CM ∆ EVs treatment. CM-EV treatment exhibited higher potential to enhance proliferation, migration and gene expression in the ACL remnant cells and BMSCs than BMSC-EV and non-EV treatments. In conclusion, EVs, secreted under the coexistence of ACL remnant cells and BMSCs, primarily increase the cell viability, proliferation, migration and gene expression of collagen synthesis-, TGF-β-, VEGF- and tenogenesis-related genes in both cell types.

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FIGURE 1 Experimental design of the study. ACL, anterior cruciate ligament; BMSC, bone marrow stromal cell; CM, co‐culture medium; EV, extracellular vesicle.
FIGURE 1 Experimental design of the study. ACL, anterior cruciate ligament; BMSC, bone marrow stromal cell; CM, co‐culture medium; EV, extracellular vesicle.CC BY · PubMed Central
FIGURE 2 Cell proliferation, migration and expression of collagen I and III‐, TGF‐β‐, VEGF‐ and tenogenic‐related genes in ACL remnant cells following treatment with BMSC‐only culture medium (control), ACL remnant cell/BMSC co‐culture medium (CM) and co‐culture medium without extracellular vesicles (CM ∆ EVs). Migration is evaluated via transwell and scratch migration assays. In the transwell assay, cells that traverse the transwell membrane are stained in purple with crystal violet, and their migration ratio is determined. In the scratch assay, results are presented as the percentage of initial scratch closure. *p < 0.05; **p < 0.01.
FIGURE 2 Cell proliferation, migration and expression of collagen I and III‐, TGF‐β‐, VEGF‐ and tenogenic‐related genes in ACL remnant cells following treatment with BMSC‐only culture medium (control), ACL remnant cell/BMSC co‐culture medium (CM) and co‐culture medium without extracellular vesicles (CM ∆ EVs). Migration is evaluated via transwell and scratch migration assays. In the transwell assay, cells that traverse the transwell membrane are stained in purple with crystal violet, and their migration ratio is determined. In the scratch assay, results are presented as the percentage of initial scratch closure. *p < 0.05; **p < 0.01.CC BY · PubMed Central
FIGURE 3 Cell proliferation, migration and expression of collagen I and III‐, TGF‐β‐, VEGF‐ and tenogenic‐related genes in BMSCs following treatment with BMSC‐only culture medium (control), ACL remnant cell/BMSC co‐culture medium (CM) and co‐culture medium without extracellular vesicles (CM ∆ EVs). Migration is evaluated via transwell and scratch migration assays. In the transwell assay, cells that traverse the transwell membrane are stained in purple with crystal violet, and their migration ratio is determined. In the scratch assay, results are presented as the percentage of initial scratch closure. *p < 0.05; **p < 0.01.
FIGURE 3 Cell proliferation, migration and expression of collagen I and III‐, TGF‐β‐, VEGF‐ and tenogenic‐related genes in BMSCs following treatment with BMSC‐only culture medium (control), ACL remnant cell/BMSC co‐culture medium (CM) and co‐culture medium without extracellular vesicles (CM ∆ EVs). Migration is evaluated via transwell and scratch migration assays. In the transwell assay, cells that traverse the transwell membrane are stained in purple with crystal violet, and their migration ratio is determined. In the scratch assay, results are presented as the percentage of initial scratch closure. *p < 0.05; **p < 0.01.CC BY · PubMed Central
FIGURE 4 (A) Particle size distribution, expression levels of biomarkers and transmission electron microscopic images of EVs derived from BMSC‐only culture (BMSC‐EV) and ACL remnant cell/BMSC co‐culture medium (CM‐EV). (B) Immunofluorescence pictures show the CM‐EV uptake and internalization by the ACL remnant cells and BMSCs.
FIGURE 4 (A) Particle size distribution, expression levels of biomarkers and transmission electron microscopic images of EVs derived from BMSC‐only culture (BMSC‐EV) and ACL remnant cell/BMSC co‐culture medium (CM‐EV). (B) Immunofluorescence pictures show the CM‐EV uptake and internalization by the ACL remnant cells and BMSCs.CC BY · PubMed Central
FIGURE 5 Cell viability, proliferation, migration and expression of collagen I and III‐, TGF‐β‐, VEGF‐ and tenogenic‐related genes in ACL remnant cells following treatment with EVs derived from BMSC‐only culture medium (BMSC‐EV), ACL remnant cell/BMSC co‐culture medium (CM‐EV) and non‐EV medium (control) group. Migration is evaluated via transwell and scratch migration assays. In the transwell assay, cells that traverse the transwell membrane are stained in purple with crystal violet, and their migration ratio is determined. In the scratch assay, results are presented as the percentage of initial scratch closure. *p < 0.05; **p < 0.01.
FIGURE 5 Cell viability, proliferation, migration and expression of collagen I and III‐, TGF‐β‐, VEGF‐ and tenogenic‐related genes in ACL remnant cells following treatment with EVs derived from BMSC‐only culture medium (BMSC‐EV), ACL remnant cell/BMSC co‐culture medium (CM‐EV) and non‐EV medium (control) group. Migration is evaluated via transwell and scratch migration assays. In the transwell assay, cells that traverse the transwell membrane are stained in purple with crystal violet, and their migration ratio is determined. In the scratch assay, results are presented as the percentage of initial scratch closure. *p < 0.05; **p < 0.01.CC BY · PubMed Central
FIGURE 6 Cell viability, proliferation, migration and expression of collagen I and III‐, TGF‐β‐, VEGF‐ and tenogenic‐related genes in BMSCs following treatment with EV derived from BMSC‐only culture medium (BMSC‐EV), ACL remnant cell/BMSC co‐culture medium (CM‐EV) and non‐EV medium (control) groups. Migration is evaluated via transwell and scratch migration assays. In the transwell assay, cells that traverse the transwell membrane are stained in purple with crystal violet, and their migration ratio is determined. In the scratch assay, results are presented as the percentage of initial scratch closure. *p < 0.05; **p < 0.01.
FIGURE 6 Cell viability, proliferation, migration and expression of collagen I and III‐, TGF‐β‐, VEGF‐ and tenogenic‐related genes in BMSCs following treatment with EV derived from BMSC‐only culture medium (BMSC‐EV), ACL remnant cell/BMSC co‐culture medium (CM‐EV) and non‐EV medium (control) groups. Migration is evaluated via transwell and scratch migration assays. In the transwell assay, cells that traverse the transwell membrane are stained in purple with crystal violet, and their migration ratio is determined. In the scratch assay, results are presented as the percentage of initial scratch closure. *p < 0.05; **p < 0.01.CC BY · PubMed Central

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Citations

Cites

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Metadata

Authors
Lin, S., Wu, S. C., Liu, Z., Chou, P. P., Zhao, C., Ho, M., & Lu, C.
Affiliations
  • Kaohsiung Medical University (TW)
  • Asia University (TW)
  • Kaohsiung Medical University Chung-Ho Memorial Hospital (TW)
  • Mayo Clinic (US)
Corresponding author
Lu, Cheng‐Chang
ORCID
Venue
Journal of Cellular and Molecular Medicine
Publisher
Wiley
Published
2024-09
Volume
28
Issue
17
Pages
e70049-e70049
ISSN
  • 1582-1838 (ISSN-L)
  • 1582-4934
DOI
10.1111/jcmm.70049
PMC
PMC11366498
OpenAlex
W4402141916
Cited by
5
References
4
Citations by year
2026: 3 · 2025: 1 · 2024: 1
FWCI
0.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Cellular and Molecular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Tendon Structure and Treatment
  • Health Sciences › Medicine › Surgery › Knee injuries and reconstruction techniques
Keywords
extracellular vesicles, mesenchymal stem cells, co-culture, anterior cruciate ligament reconstruction, graft maturation, tenogenesis, collagen synthesis, TGF-beta, vascular endothelial growth factor, cell proliferation, cell migration, apoptosis, intercellular communication
MeSH terms
Extracellular Vesicles, Animals, Cell Communication, Cell Movement, Cell Survival, Cells, Cultured, Gene Expression Regulation, Male, Rabbits, Anterior Cruciate Ligament, Transforming Growth Factor beta, Coculture Techniques, Vascular Endothelial Growth Factor A, Cell Proliferation, Mesenchymal Stem Cells

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