Abstract
Exosomes of human mesenchymal stem cells (hMSC) are known to effectively increase the proliferation rate of chondrocytes and stimulate cartilage extracellular matrix. However, the therapeutic efficacy of the other signaling direction (i.e., the effect of chondrocyte-derived exosomes on hMSC) has not been extensively investigated. Therefore, the present study was designed to investigate exosome-mediated in vitro bidirectional signalings between progenitor hMSC and mature chondrocytes in cartilage tissues with various culture medial formulations. The exosomes isolated from bovine chondrocytes (BC) and hMSC (50 µg/ mL of exosomes per 3000 cells) were treated to hMSC and BC, respectively. Both cells were cultured in media formulations with 10% FBS, 10% exosome free-FBS, and 0.5% FBS. A variety of cellular responses by exosome treatments including proliferation, chondrogenic differentiation, cartilage extracellular matrix (ECM) deposition were evaluated using WST-1 assay, RT-PCR, and alcian blue staining for glycosaminoglycan (GAG) content. The results demonstrated that bidirectional exosome treatments increased proliferation of both BC and hMSC, and similar bidirectional influences including chondrogenic differentiation, glycosaminoglycan (GAG) ECM deposition were also up-regulated in both cell populations. Moreover, exosome-mediated in vitro activation between two cell populations could be regulated by media formulations. Therefore, exosomes could play important signaling roles in communication between two major cell populations in cartilage tissues.
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Carballo, C. B., Y. Nakagawa, I. Sekiya, and S. A. Rodeo (2017) Basic science of articular cartilage. Clin. Sports Med. 36: 413–425.
Temenoff, J. S. and A. G. Mikos (2000) Review: tissue engineering for regeneration of articular cartilage. Biomaterials. 21: 431–440.
Kim, K., J. Lam, S. Lu, P. P. Spicer, A. Lueckgen, Y. Tabata, M. E. Wong, J. A. Jansen, A. G. Mikos, and F. K. Kasper (2013) Osteochondral tissue regeneration using a bilayered composite hydrogel with modulating dual growth factor release kinetics in a rabbit model. J. Controlled Release. 168: 166–178.
Coates, E. E., C. N. Riggin, and J. P. Fisher (2012) Matrix molecule influence on chondrocyte phenotype and proteoglycan 4 expression by alginate-embedded zonal chondrocytes and mesenchymal stem cells. J. Orthop. Res. 30: 1886–1897.
Li, G., J. Yin, J. Gao, T. S. Cheng, N. J. Pavlos, C. Zhang, and M. H. Zheng (2013) Subchondral bone in osteoarthritis: insight into risk factors and microstructural changes. Arthritis Res. Ther. 15: 223.
Krishnan, Y. and A. J. Grodzinsky (2018) Cartilage diseases. Matrix Biol. 71–72: 51–69.
Richter, D. L., R. C. Schenck Jr., D. C. Wascher, and G. Treme (2016) Knee articular cartilage repair and restoration techniques: A review of the literature. Sports Health. 8: 153–160.
Toh, W. S., C. B. Foldager, M. Pei, and J. H. Hui (2014) Advances in mesenchymal stem cell-based strategies for cartilage repair and regeneration. Stem Cell Rev. 10: 686–696.
Zheng, X. F., S. B. Lu, W. G. Zhang, S. Y. Liu, J. X. Huang, and Q. Y. Guo (2011) Mesenchymal stem cells on a decellularized cartilage matrix for cartilage tissue engineering. Biotechnol. Bioprocess Eng. 16: 593–602.
Cho, H., D. Kim, and K. Kim (2018) Engineered co-culture strategies using stem cells for facilitated chondrogenic differentiation and cartilage repair. Biotechnol. Bioprocess Eng. 23: 261–270.
Wong, K. L., K. B. Lee, B. C. Tai, P. Law, E. H. Lee, and J. H. Hui (2013) Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years’ follow-up. Arthroscopy. 29: 2020–2028.
Mortada, I. and R. Mortada (2018) Epigenetic changes in mesenchymal stem cells differentiation. Eur. J. Med. Genet. 61: 114–118.
Li, X., L. Duan, Y. Liang, W. Zhu, J. Xiong, and D. Wang (2016) Human umbilical cord blood-derived mesenchymal stem cells contribute to chondrogenesis in coculture with chondrocytes. BioMed. Res. Int. 2016: 3827057.
Meretoja, V. V., R. L. Dahlin, S. Wright, F. K. Kasper, and A. G. Mikos (2014) Articular chondrocyte redifferentiation in 3D co-cultures with mesenchymal stem cells. Tissue Eng. Part C Methods. 20: 514–523.
Kubosch, E. J., E. Heidt, A. Bernstein, K. Bottiger, and H. Schmal (2016) The trans-well coculture of human synovial mesenchymal stem cells with chondrocytes leads to self-organization, chondrogenic differentiation, and secretion of TGFbeta. Stem Cell Res. Ther. 7: 64.
Park, K. M., Y. M. Shin, K. Kim, and H. Shin (2018) Tissue engineering and regenerative medicine 2017: A year in review. Tissue Eng. Part B Rev. 24: 327–344.
Thery, C., L. Zitvogel, and S. Amigorena (2002) Exosomes: composition, biogenesis and function. Nat. Rev. Immunol. 2: 569–579.
EL Andaloussi, S., I. Mager, X. O. Breakefield, and M. J. Wood (2013) Extracellular vesicles: biology and emerging therapeutic opportunities. Nat. Rev. Drug Discovery. 12: 347–357.
Simons, M. and G. Raposo (2009) Exosomes—vesicular carriers for intercellular communication. Curr. Opin. Cell Biol. 21: 575–581.
Zhang, S., S. J. Chuah, R. C. Lai, J. H. P. Hui, S. K. Lim, and W. S. Toh (2018) MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials. 156: 16–27.
Wang, R., B. Xu, and H. Xu (2018) TGF-beta1 promoted chondrocyte proliferation by regulating Sp1 through MSC-exosomes derived miR-135b. Cell Cycle. 17: 2756–2765.
Tofino-Vian, M., M. I. Guillen, M. D. Perez Del Caz, A. Silvestre, and M. J. Alcaraz (2018) Microvesicles from human adipose tissue-derived mesenchymal stem cells as a new protective strategy in osteoarthritic chondrocytes. Cell. Physiol. Biochem. 47: 11–25.
Wang, Y., D. Yu, Z. Liu, F. Zhou, J. Dai, B. Wu, J. Zhou, B. C. Heng, X. H. Zou, H. Ouyang, and H. Liu (2017) Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Res. Ther. 8: 189.
Vonk, L. A., S. F. J. van Dooremalen, N. Liv, J. Klumperman, P. J. Coffer, D. B. F. Saris, and M. J. Lorenowicz (2018) Mesenchymal stromal/stem cell-derived extracellular vesicles promote human cartilage regeneration in vitro. Theranostics. 8: 906–920.
Lee, Y., S. El Andaloussi, and M. J. Wood (2012) Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum. Mol. Genet. 21: R125–134.
Subra, C., K. Laulagnier, B. Perret, and M. Record (2007) Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie. 89: 205–212.
Zhang, S., K. Y. W. Teo, S. J. Chuah, R. C. Lai, S. K. Lim, and W. S. Toh (2019) MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis. Biomaterials. 200: 35–47.
Jiang, X., J. Liu, Q. Liu, Z. Lu, L. Zheng, J. Zhao, and X. Zhang (2018) Therapy for cartilage defects: functional ectopic cartilage constructed by cartilage-simulating collagen, chondroitin sulfate and hyaluronic acid (CCH) hybrid hydrogel with allogeneic chondrocytes. Biomater. Sci. 6: 1616–1626.
Heinegard, D. and T. Saxne (2011) The role of the cartilage matrix in osteoarthritis. Nat. Rev. Rheumatol. 7: 50–56.
DeLise, A. M., L. Fischer, and R. S. Tuan (2000) Cellular interactions and signaling in cartilage development. Osteoarthr. Cartilage. 8: 309–334.
Tao, S. C., T. Yuan, Y. L. Zhang, W. J. Yin, S. C. Guo, and C. Q. Zhang (2017) Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics. 7: 180–195.
Mao, G., Z. Zhang, S. Hu, Z. Zhang, Z. Chang, Z. Huang, W. Liao, and Y. Kang (2018) Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A. Stem Cell Res. Ther. 9: 247.
Vainieri, M. L., D. Wahl, M. Alini, G. J. V. M. van Osch, and S. Grad (2018) Mechanically stimulated osteochondral organ culture for evaluation of biomaterials in cartilage repair studies. Acta Biomater. 81: 256–266.
Cho, H., A. Lee, and K. Kim (2018) The effect of serum types on Chondrogenic differentiation of adipose-derived stem cells. Biomater. Res. 22: 6.
Acknowledgement
This research work was supported by (1) Nano-Material Technology Development Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (No. 2017M3A7B8061942), (2) NRF grant funded by the Korea government (MSIP) (NRF-2017R1C1B1003665).
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Kim, Y.G., Park, U., Park, B.J. et al. Exosome-mediated Bidirectional Signaling between Mesenchymal Stem Cells and Chondrocytes for Enhanced Chondrogenesis. Biotechnol Bioproc E 24, 734–744 (2019). https://doi.org/10.1007/s12257-019-0332-y
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DOI: https://doi.org/10.1007/s12257-019-0332-y