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      TGF-β1-containing exosomes derived from bone marrow mesenchymal stem cells promote proliferation, migration and fibrotic activity in rotator cuff tenocytes

      research-article
      a , b , a , b , b , a ,
      Regenerative Therapy
      Japanese Society for Regenerative Medicine
      BMSC, Exosomes, TGF-β1, Rotator cuff tear, Proliferation, Migration, Fibrotic activity, BMSC, Bone mesenchymal stem cells, TGF-β1, Transforming growth factors β1, TGF-βR I/II, Transforming growth factors β1 receptor type I/II, qPCR, Quantitative reverse-transcription polymerase chain reaction, FBS, Fetal bovine serum, DMEM, Dulbecco's modified Eagle's medium, SDS-PAGE, Sodium dodecyl sulfate polyacrylamide gel electrophoresis, Col I, Collagen I, Col III, Collagen III, α-SMA, α-smooth muscle actin, Scx, Scleraxis, Tnc, Tenascin C, PVDF, Polyvinylidene fluoride, CCK8, Cell counting kit-8, Smad7, Mothers against decapentaplegic homolog 7

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          Abstract

          Objective

          This study aimed to investigate effects of TGF-β1-containing exosomes derived from bone marrow mesenchymal stem cells (BMSC) on cell function of rotator cuff tenocytes and its implication to rotator cuff tear.

          Methods

          The primary BMSC and rotator cuff tenocytes were extracted and cultured. Identification of BMSC were performed by observing cell morphology and measurement of surface biomarkers by flow cytometry. BMSC-derived exosomes were extracted and identified by using electron microscopy, nanoparticle-tracking analysis (NTA) and western blotting. Cell proliferation and cell cycle were measured by CCK-8 assay and flow cytometry assay, respectively. Transwell assay was used for detection of tenocytes migration. The fibrotic activity of tenocytes was determined via qPCR and western blotting assays.

          Results

          BMSC and BMSC-derived exosomes were successfully extracted. Treatment of BMSC-derived exosomes or TGF-β1 promoted cell proliferation, migration and increased cell ratio of (S + G2/M) phases in tenocytes, as well as enhanced the expression levels of fibrotic activity associated proteins. However, inhibition of TGF-β1 by transfection of sh-TGF-β1 or treatment of TGFβR I/II inhibitor partially reversed the impact of BMSC-derived exosomes on tenocytes function.

          Conclusion

          Taken together, TGF-β1-containing exosomes derived from BMSC promoted proliferation, migration and fibrotic activity in rotator cuff tenocytes, providing a new direction for treatment of rotator cuff tendon healing.

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          Most cited references33

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          Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2.

          Exosomes are nanometer-sized vesicles, secreted by normal and neoplastic cells. The outcome following interaction between the cellular immune system and cancer-derived exosomes is not well understood. Interleukin-2 (IL-2) is a key factor supporting expansion and differentiation of CTL and natural killer (NK) cells but can also support regulatory T cells and their suppressive functions. Our study examined whether tumor-derived exosomes could modify lymphocyte IL-2 responses. Proliferation of healthy donor peripheral blood lymphocytes in response to IL-2 was inhibited by tumor exosomes. In unfractionated lymphocytes, this effect was seen in all cell subsets. Separating CD4(+) T cells, CD8(+) T cells, and NK cells revealed that CD8(+) T-cell proliferation was not inhibited in the absence of CD4(+) T cells and that NK cell proliferation was only slightly impaired. Other exosome effects included selective impairment of IL-2-mediated CD25 up-regulation, affecting all but the CD3(+)CD8(-) T-cell subset. IL-2-induced Foxp3 expression by CD4(+)CD25(+) cells was not inhibited by tumor exosomes, and the suppressive function of CD4(+)CD25(+) T cells was enhanced by exosomes. In contrast, exosomes directly inhibited NK cell killing function in a T-cell-independent manner. Analysis of tumor exosomes revealed membrane-associated transforming growth factor beta(1) (TGFbeta(1)), which contributed to the antiproliferative effects, shown by using neutralizing TGFbeta(1)-specific antibody. The data show an exosome-mediated mechanism of skewing IL-2 responsiveness in favor of regulatory T cells and away from cytotoxic cells. This coordinated "double hit" to cellular immunity strongly implicates the role of exosomes in tumor immune evasion.
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            Alteration of fatty acid oxidation by increased CPT1A on replicative senescence of placenta-derived mesenchymal stem cells

            Background Human placenta-derived mesenchymal stem cells (PD-MSCs) are powerful sources for cell therapy in regenerative medicine. However, a limited lifespan by senescence through mechanisms that are well unknown is the greatest obstacle. In the present study, we first demonstrated the characterization of replicative senescent PD-MSCs and their possible mitochondrial functional alterations. Methods Human PD-MSCs were cultured to senescent cells for a long period of time. The cells of before passage number 8 were early cells and after passage number 14 were late cells. Also, immortalized cells of PD-MSCs (overexpressed hTERT gene into PD-MSCs) after passage number 14 were positive control of non-senescent cells. The characterization and mitochondria analysis of PD-MSCs were explored with long-term cultivation. Results Long-term cultivation of PD-MSCs exhibited increases of senescent markers such as SA-β-gal and p21 including apoptotic factor, and decreases of proliferation, differentiation potential, and survival factor. Mitochondrial dysfunction was also observed in membrane potential and metabolic flexibility with enlarged mitochondrial mass. Interestingly, we founded that fatty acid oxidation (FAO) is an important metabolism in PD-MSCs, and carnitine palmitoyltransferase1A (CPT1A) overexpressed in senescent PD-MSCs. The inhibition of CPT1A induced a change of energy metabolism and reversed senescence of PD-MSCs. Conclusions These findings suggest that alteration of FAO by increased CPT1A plays an important role in mitochondrial dysfunction and senescence of PD-MSCs during long-term cultivation.
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              Mesenchymal stem cell-derived exosomes ameliorate intervertebral disc degeneration via anti-oxidant and anti-inflammatory effects

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                Author and article information

                Contributors
                Journal
                Regen Ther
                Regen Ther
                Regenerative Therapy
                Japanese Society for Regenerative Medicine
                2352-3204
                21 July 2020
                December 2020
                21 July 2020
                : 15
                : 70-76
                Affiliations
                [a ]Department of Orthopedics, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, PR China
                [b ]Affiliated Hospital of Chengde Medical College, Chengde 067000, PR China
                Author notes
                []Corresponding author. Department of Orthopedics, Beijing Friendship Hospital, Capital Medical University, No.95, Yongan Road, Beijing 100050, PR China. guoaii7612@ 123456163.com
                Article
                S2352-3204(20)30054-7
                10.1016/j.reth.2020.07.001
                7770343
                8a753b0c-88f7-4f94-b91f-ba296c7aa3e4
                © 2020 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                Original Article

                bmsc,exosomes,tgf-β1,rotator cuff tear,proliferation,migration,fibrotic activity,bmsc, bone mesenchymal stem cells,tgf-β1, transforming growth factors β1,tgf-βr i/ii, transforming growth factors β1 receptor type i/ii,qpcr, quantitative reverse-transcription polymerase chain reaction,fbs, fetal bovine serum,dmem, dulbecco's modified eagle's medium,sds-page, sodium dodecyl sulfate polyacrylamide gel electrophoresis,col i, collagen i,col iii, collagen iii,α-sma, α-smooth muscle actin,scx, scleraxis,tnc, tenascin c,pvdf, polyvinylidene fluoride,cck8, cell counting kit-8,smad7, mothers against decapentaplegic homolog 7

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