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      Amelioration of ligamentum flavum hypertrophy using umbilical cord mesenchymal stromal cell-derived extracellular vesicles

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          Abstract

          Ligamentum flavum (LF) hypertrophy (LFH) has been recognised as one of the key contributors to lumbar spinal stenosis. Currently, no effective methods are available to ameliorate this hypertrophy. In this study, human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hUCMSC-EVs) were introduced for the first time as promising vehicles for drug delivery to treat LFH. The downregulation of miR-146a-5p and miR-221-3p expressions in human LF tissues negatively correlated with increased LF thickness. The hUCMSC-EVs enriched with these two miRNAs significantly suppressed LFH in vivo and notably ameliorated the progression of transforming growth factor β1(TGF-β1)-induced fibrosis in vitro after delivering these two miRNAs to mouse LF cells. The results further demonstrated that miR-146a-5p and miR-221-3p directly bonded to the 3′-UTR regions of SMAD4 mRNA, thereby inhibiting the TGF-β/SMAD4 signalling pathway. Therefore, this translational study determined the effectiveness of a hUCMSC-EVs-based approach for the treatment of LFH and revealed the critical target of miR-146a-5p and miR-221-3p. Our findings provide new insights into promising therapeutics using a hUCMSC-EVs-based delivery system for patients with lumbar spinal stenosis.

          Highlights

          • •

            The downregulation of miR-146a-5p and miR-221-3p expressions were negatively correlated with the development of LFH.

          • •

            MiR-146a-5p and miR-221-3p enriched in hUCMSC-EVs prevent the fibrosis of LF by targeting SMAD4.

          • •

            hUCMSC-EVs are effective as bioactive vehicles to ameliorate the progression of LFH.

          • •

            hUCMSC-EVs-based delivery system is a promising therapy for the patients with lumbar spinal stenosis.

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          Most cited references57

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          The biology, function, and biomedical applications of exosomes

          Raghu Kalluri, Valerie LeBleu (2020)
          The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.
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            Shedding light on the cell biology of extracellular vesicles

            Guillaume van Niel, Gisela D'Angelo, Graça Raposo (2018)
            Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively. They are present in biological fluids and are involved in multiple physiological and pathological processes. Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material. Knowledge of the cellular processes that govern extracellular vesicle biology is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis. However, in this expanding field, much remains unknown regarding the origin, biogenesis, secretion, targeting and fate of these vesicles.
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              TGF-β: the master regulator of fibrosis.

              Xiao-ming Meng, David J Nikolic-Paterson, Hui-Yao Lan (2016)
              Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease (CKD). Inhibition of the TGF-β isoform, TGF-β1, or its downstream signalling pathways substantially limits renal fibrosis in a wide range of disease models whereas overexpression of TGF-β1 induces renal fibrosis. TGF-β1 can induce renal fibrosis via activation of both canonical (Smad-based) and non-canonical (non-Smad-based) signalling pathways, which result in activation of myofibroblasts, excessive production of extracellular matrix (ECM) and inhibition of ECM degradation. The role of Smad proteins in the regulation of fibrosis is complex, with competing profibrotic and antifibrotic actions (including in the regulation of mesenchymal transitioning), and with complex interplay between TGF-β/Smads and other signalling pathways. Studies over the past 5 years have identified additional mechanisms that regulate the action of TGF-β1/Smad signalling in fibrosis, including short and long noncoding RNA molecules and epigenetic modifications of DNA and histone proteins. Although direct targeting of TGF-β1 is unlikely to yield a viable antifibrotic therapy due to the involvement of TGF-β1 in other processes, greater understanding of the various pathways by which TGF-β1 controls fibrosis has identified alternative targets for the development of novel therapeutics to halt this most damaging process in CKD.
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                Author and article information

                Contributors
                Ya-Nan Pu
                Yong-Can Huang
                Yong-Xin Ren
                Journal
                Journal ID (nlm-ta): Bioact Mater
                Journal ID (iso-abbrev): Bioact Mater
                Title: Bioactive Materials
                Publisher: KeAi Publishing
                ISSN (Electronic): 2452-199X
                Publication date PMC-release: 08 April 2022
                Publication date Collection: January 2023
                Publication date (Electronic): 08 April 2022
                Volume: 19
                Pages: 139-154
                Affiliations
                [a ]Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China
                [b ]Department of Pathogen Biology and Immunology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China
                [c ]Department of Orthopaedics, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210024, China
                [d ]Outpatient & Emergency Management Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
                [e ]Shenzhen Engineering Laboratory of Orthopaedic Regenerative Technologies, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
                Author notes
                [∗ ]Corresponding author. Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China. renyongxin@ 123456njmu.edu.cn
                [∗∗ ]Corresponding author. Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China. hycpku@ 123456hotmail.com
                [∗∗∗ ]Corresponding author. Outpatient & Emergency Management Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China. pyn342626@ 123456163.com
                [1]

                These authors contributed equally to this work.

                Article
                Publisher Item ID: S2452-199X(22)00158-X
                DOI: 10.1016/j.bioactmat.2022.03.042
                PMC ID: 9014323
                PubMed ID: 35475028
                SO-VID: ee2906e7-9151-4d49-ba2a-05fafc079742
                Copyright © © 2022 The Authors
                License:

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

                History
                Date received : 27 January 2022
                Date revision received : 29 March 2022
                Date accepted : 30 March 2022
                Categories
                Subject: Article

                Keywords: ligamentum flavum hypertrophy,fibrosis,umbilical cord mesenchymal stromal cells,extracellular vesicle,mir-146a-5p,mir-221-3p,lf, ligamentum flavum,lfh, ligamentum flavum hypertrophy,hucmsc-evs, human umbilical cord mesenchymal stromal cell-derived extracellular vesicles,tgf-β1, transforming growth factor-β1,lss, lumbar spinal stenosis,ecm, extracellular matrix,smad, mothers against the decapentaplegic homolog,mri, magnetic resonance imaging
                Data availability:
                Keywords: ligamentum flavum hypertrophy, fibrosis, umbilical cord mesenchymal stromal cells, extracellular vesicle, mir-146a-5p, mir-221-3p, lf, ligamentum flavum, lfh, ligamentum flavum hypertrophy, hucmsc-evs, human umbilical cord mesenchymal stromal cell-derived extracellular vesicles, tgf-β1, transforming growth factor-β1, lss, lumbar spinal stenosis, ecm, extracellular matrix, smad, mothers against the decapentaplegic homolog, mri, magnetic resonance imaging

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