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TGF-β1-modified MSC-derived exosomal miR-135b attenuates cartilage injury via promoting M2 synovial macrophage polarization by targeting MAPK6

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Abstract

Osteoarthritis (OA) is the most common joint disease with an unsatisfactory therapy outcome and characterized by the degradation of articular cartilage and synovial inflammation. Here, we isolated bone marrow mesenchymal stem cells (BMSCs) from rat’s bone marrow and BMSC-derived exosome (BMSCs-Exo) from BMSCs successfully. MiR-135b was proved to be highly expressed in TGF-β1-stimulated BMSC-derived exosomes (BMSCs-ExoTGF-β1). Then, our results demonstrated that BMSCs-ExoTGF-β1 reduced OA-induced upregulation of pro-inflammatory factors in rat’s serum and damage in cartilage tissues, which was then reversed by miR-135b decreasing. Subsequently, we found that the OA-resulted M1 polarization of synovial macrophages (SMs) was repressed by BMSCs-ExoTGF-β1, this effect of BMSCs-ExoTGF-β1 was limited by miR-135b decreasing. We also proved that M2 polarization of SMs can be induced by miR-135b mimics. Furthermore, we found that the promotory effect of miR-135b and BMSCs-ExoTGF-β1 on M2 SMs polarization was reversed by increasing of MAPK6. Overall, our data showed that BMSCs-ExoTGF-β1 attenuated cartilage damage in OA rats through carrying highly expressed miR-135b. Mechanistically, miR-135b promoted M2 polarization of SMs through targeting MAPK6, thus improving cartilage damage. Our study provided a novel regulatory mechanism of BMSCs-Exo in OA development and revealed a new potential treatment target of OA.

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Abbreviations

BMSCs:

Bone marrow-derived MSCs

BMSC-Exo:

BMSCs-derived exosome

BMSC-ExoPBS :

PBS-stimulated BMSC-derived exosome

BMSC-ExoTGF - β1 :

TGF-β1-treated BMSC-derived exosome

INC-BMSC-ExoTGF - β1 :

Inhibitor NC together with TGF-β1-treated BMSC-derived exosome

MiR-135bI-BMSC-ExoTGF - β1 :

MiR-135b inhibitor together with TGF-β1-stimulated BMSC-derived exosome

MSCs:

Mesenchymal stem cells

NTA:

Nanoparticle tracking analysis

OA:

Osteoarthritis

SMs:

Synovial macrophages

TEM:

Transmission electron microscope

TGF-β1:

Transforming growth factor β1

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Funding

This study was supported by Anhui Province Natural Science Youth Funding Projects (grant no. 1908085QH318).

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Authors and Affiliations

  1. Department of Sports Trauma & Arthroscopy, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, Anhui, 230022, People’s Republic of China

    Rui Wang & Bin Xu

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  1. Rui Wang
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  2. Bin Xu
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Correspondence to Bin Xu.

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This study was approved by the Animal Research Committee of First Affiliated Hospital of Anhui Medical University.

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441_2020_3319_MOESM1_ESM.tif

Supplementary file1: Supplementary figure 1. BMSCs identification. (a-k) Flow cytometry was performed to verify the expression of BMSCs markers (CD11b, CD34 and CD45 Low; CD29, CD44 and CD90 High). (l) The shape of BMSCs was identified using light microscope. (m) The ability of BMSCs differentiation into osteogenic lineage was ensured using alizarin red staining. (n) The ability of BMSCs differentiation into adipogenic lineage was confirmed using Oil red O staining. (TIF 1.76 MB)

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Wang, R., Xu, B. TGF-β1-modified MSC-derived exosomal miR-135b attenuates cartilage injury via promoting M2 synovial macrophage polarization by targeting MAPK6. Cell Tissue Res 384, 113–127 (2021). https://doi.org/10.1007/s00441-020-03319-1

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  • DOI: https://doi.org/10.1007/s00441-020-03319-1

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