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Higher ratios of chondrocyte to mesenchymal stem cells elevate the therapeutic effects of extracellular vesicles harvested from chondrocyte/mesenchymal stem cell co-culture on osteoarthritis in a rat model

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Abstract

Extracellular vesicles (EVs) may have a key therapeutic role and offer an innovative treatment for osteoarthritis (OA). Studies have shown that ratio of MSC/chondrocyte could affect their therapeutic outcomes. Here, we investigate the chondrogenic potential and therapeutic effect of EVs derived from MSCs and chondrocytes in the naïve, chondrogenically primed, and co-culture states to treat OA. EVs are isolated from naïve MSCs (M-EV), chondrogenically primed MSCs (cpM-EV), chondrocytes (C-EV), and co-cultures of chondrocytes plus MSCs at ratios of 1:1 (C/M-EV), 2:1 (2C/M-EV), and 4:1 (4C/M-EV). We characterized the isolated EVs in terms of surface markers, morphology, size, and zeta potential, and evaluated their chondrogenic potential in vitro by qRT-PCR and histological analyses. Next, these EVs were intra-articularly injected into osteoarthritic cartilage of a rat model and assessed by radiography, gait parameters, and histological and immunohistochemical analyses. EVs obtained from chondrocytes co-cultured with MSCs resulted in improved matrix production and functional differentiation. Our research showed that close proximity between the two cell types was essential for this response, and improved chondrogenesis and matrix formation were the outcomes of this interaction in vitro. Furthermore, in the in vivo rat OA model induced by a monoiodoacetate (MIA), we observed recovery from OA by increasing ratio of the C/M-derived EV group compared to the other groups. Our findings show that the increasing chondrocyte ratio to MSC leads to high chondrogenic induction and the therapeutic effect of harvested EVs for cartilage repair.

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All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding authors.

Abbreviations

AC:

Articular cartilage

ACAN:

Aggrecan

Cho:

Chondrocyte

Col II:

Collagen type II

Col X:

Collagen type X

cpM:

Chondrogenically primed MSCs

DLS:

Dynamic light scattering

DMEM:

Dulbecco’s modified Eagle’s medium

ECM:

The extracellular matrix

EVs:

Extracellular vesicles

FBS:

Fetal bovine serum

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase (endogenous control gene)

H&E:

Hematoxylin and eosin

HRP:

Horseradish peroxidase

IHC:

Immunohistochemistry

IP:

Intraperitoneal

IOD:

Integrated optical density

MIA:

Monoiodoacetate

MISEV:

The first Minimal Information for Studies of Extracellular Vesicles

MSCs:

Mesenchymal stem cells

NBF:

Neutral buffered formalin

OA:

Osteoarthritis

qRT-PCR:

Quantitative real-time polymerase chain reaction

SEM:

Scanning electron microscopy

TGF-β3:

Transforming growth factor-β3

UC:

Ultracentrifugation

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Acknowledgements

Dr. Sara Farahi and Dr. Nahid Nasiri are gratefully acknowledged for their assistance with real-time PCR and the in vivo experiments. We also appreciate Dr. Abazar Esmaeili for his help and guidance.

Funding

This study was financially supported by the Iran National Science Foundation (INSF), award number 96008901.

Author information

Authors and Affiliations

  1. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Maryam Hosseinzadeh, Amir Kamali, Mohamadreza Baghaban Eslaminejad & Samaneh Hosseini

  2. Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Samaneh Hosseini

Authors
  1. Maryam Hosseinzadeh
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  2. Amir Kamali
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  3. Mohamadreza Baghaban Eslaminejad
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  4. Samaneh Hosseini
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Contributions

M.H., S.H., and M.B.E. conceived and designed the experiments. M.H. carried out the experiments, wrote the manuscript, analyzed the data, and prepared Figs. 2, 3, and 4. S.H. reviewed and edited the manuscript, acquired funding, and prepared Fig. 1. A.K. performed the histological analysis and prepared Figs. 5 and 6. M.B.E. and S.H. coordinated the study and provided technical assistance. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Mohamadreza Baghaban Eslaminejad or Samaneh Hosseini.

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Ethics approval

All procedures were approved by the Animal Care and Ethics Committee at Royan Institute, Tehran, Iran (IR.ACECR.ROYAN.REC.1398.245).

Consent for publication

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Hosseinzadeh, M., Kamali, A., Baghaban Eslaminejad, M. et al. Higher ratios of chondrocyte to mesenchymal stem cells elevate the therapeutic effects of extracellular vesicles harvested from chondrocyte/mesenchymal stem cell co-culture on osteoarthritis in a rat model. Cell Tissue Res 394, 145–162 (2023). https://doi.org/10.1007/s00441-023-03819-w

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