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      Immunomodulatory matrix-bound nanovesicles mitigate acute and chronic pristane-induced rheumatoid arthritis

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          Abstract

          Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and destruction of synovial joints affecting ~7.5 million people worldwide. Disease pathology is driven by an imbalance in the ratio of pro-inflammatory vs. anti-inflammatory immune cells, especially macrophages. Modulation of macrophage phenotype, specifically an M1 to M2, pro- to anti-inflammatory transition, can be induced by biologic scaffold materials composed of extracellular matrix (ECM). The ECM-based immunomodulatory effect is thought to be mediated in part through recently identified matrix-bound nanovesicles (MBV) embedded within ECM. Isolated MBV was delivered via intravenous (i.v.) or peri-articular (p.a.) injection to rats with pristane-induced arthritis (PIA). The results of MBV administration were compared to intraperitoneal (i.p.) administration of methotrexate (MTX), the clinical standard of care. Relative to the diseased animals, i.p. MTX, i.v. MBV, and p.a. MBV reduced arthritis scores in both acute and chronic pristane-induced arthritis, decreased synovial inflammation, decreased adverse joint remodeling, and reduced the ratio of synovial and splenic M1 to M2 macrophages ( p < 0.05). Both p.a. and i.v. MBV reduced the serum concentration of RA and PIA biomarkers CXCL10 and MCP-3 in the acute and chronic phases of disease ( p < 0.05). Flow-cytometry revealed the presence of a systemic CD43hi/His48lo/CD206+, immunoregulatory monocyte population unique to p.a. and i.v. MBV treatment associated with disease resolution. The results show that the therapeutic efficacy of MBV is equal to that of MTX for the management of acute and chronic pristane-induced arthritis and, further, this effect is associated with modulation of local synovial macrophages and systemic myeloid populations.

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          QuPath: Open source software for digital pathology image analysis

          QuPath is new bioimage analysis software designed to meet the growing need for a user-friendly, extensible, open-source solution for digital pathology and whole slide image analysis. In addition to offering a comprehensive panel of tumor identification and high-throughput biomarker evaluation tools, QuPath provides researchers with powerful batch-processing and scripting functionality, and an extensible platform with which to develop and share new algorithms to analyze complex tissue images. Furthermore, QuPath’s flexible design makes it suitable for a wide range of additional image analysis applications across biomedical research.
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            UMAP: Uniform Manifold Approximation and Projection

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              Rheumatoid arthritis

              Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that primarily affects the joints and is associated with autoantibodies that target various molecules including modified self-epitopes. The identification of novel autoantibodies has improved diagnostic accuracy, and newly developed classification criteria facilitate the recognition and study of the disease early in its course. New clinical assessment tools are able to better characterize disease activity states, which are correlated with progression of damage and disability, and permit improved follow-up. In addition, better understanding of the pathogenesis of RA through recognition of key cells and cytokines has led to the development of targeted disease-modifying antirheumatic drugs. Altogether, the improved understanding of the pathogenetic processes involved, rational use of established drugs and development of new drugs and reliable assessment tools have drastically altered the lives of individuals with RA over the past 2 decades. Current strategies strive for early referral, early diagnosis and early start of effective therapy aimed at remission or, at the least, low disease activity, with rapid adaptation of treatment if this target is not reached. This treat-to-target approach prevents progression of joint damage and optimizes physical functioning, work and social participation. In this Primer, we discuss the epidemiology, pathophysiology, diagnosis and management of RA.
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                Author and article information

                Contributors
                badysx@upmc.edu
                Journal
                NPJ Regen Med
                NPJ Regen Med
                NPJ Regenerative Medicine
                Nature Publishing Group UK (London )
                2057-3995
                2 February 2022
                2 February 2022
                2022
                : 7
                : 13
                Affiliations
                [1 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, McGowan Institute for Regenerative Medicine, , University of Pittsburgh, ; 450 Technology Drive, Suite 300, Pittsburgh, PA 15219 USA
                [2 ]GRID grid.461860.d, ISNI 0000 0004 0462 9068, Department of Surgery, School of Medicine, University of Pittsburgh, , University of Pittsburgh Medical Center Presbyterian Hospital, ; 200 Lothrop Street, Pittsburgh, PA 15213 USA
                [3 ]ECM Therapeutics, Inc., 118 Marshall Dr., Warrendale, PA 15086 USA
                [4 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Musculoskeletal Growth and Regeneration Laboratory, Department of Orthopaedic Surgery, , University of Pittsburgh, ; 450 Technology Drive, Suite 206, Pittsburgh, PA 15219 USA
                [5 ]GRID grid.214572.7, ISNI 0000 0004 1936 8294, Department of Orthopedics and Rehabilitation, , University of Iowa, ; 25 Grand Ave, Iowa City, IA 52246 USA
                [6 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Department of Bioengineering, , University of Pittsburgh, ; 3700 O’Hara Street, Pittsburgh, PA 15261 USA
                Author information
                http://orcid.org/0000-0001-8597-1874
                http://orcid.org/0000-0001-5636-0994
                http://orcid.org/0000-0003-3555-0689
                Article
                208
                10.1038/s41536-022-00208-9
                8810774
                35110573
                3691cbd2-0114-4985-912f-d5372118b91d
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 19 March 2021
                : 20 December 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/100006108, U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS);
                Award ID: TL1 TR001858
                Award Recipient :
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                © The Author(s) 2022

                autoimmunity,regenerative medicine,tissue engineering,preclinical research

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