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      Injective mesenchymal stem cell-based treatments for knee osteoarthritis: from mechanisms of action to current clinical evidences

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          Abstract

          Purpose

          Osteoarthritis (OA) represents a relevant social and economic burden worldwide. “Mesenchymal stem cells” or, as recently proposed, “medicinal signaling cells” (MSCs) have been recently introduced as injective treatments for OA with the aim of restoring joint homeostasis. The aim of this review is to provide the reader with the tools necessary to interpret the currently available clinical data, focusing on the MSC mechanisms of action which might help to clarify what we should expect from this treatment.

          Methods

          Clinical studies reporting MSC injections for the treatment of knee OA, either freshly isolated or culture-expanded cells, have been included and commented in relation to the supposed therapeutic effect that MSCs might exert giving their supposed mode of actions.

          Results

          The majority of the studies reports significant improvements in terms of pain and knee function compared to baseline values, up to 24 months of follow-up. Although these data support the expected therapeutic effect of this therapy giving the features of these cells, only 14% of the studies present a control group and more than one-third of them report the results on less than ten patients.

          Conclusions

          Despite the constant presence of positive and satisfactory results in the studies analyzed, the complexity of MSC metabolism and related therapeutic effects as well as the weakness of most of the studies do not allow withdrawing definitive conclusions about the superiority of one tissue source over another, as well as about the best cell dose and the long-term durability of the effects of these procedures. Given the high potential value of these therapies in the treatment of OA, further studies accurately designed, carefully defining the type of patients to be included and pursuing minimal standard requirements in terms of follow-up, number of patients, and types of measurements should be conducted to finally assess the efficacy of MSC-based injective treatments.

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          Most cited references45

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          Concise review: the surface markers and identity of human mesenchymal stem cells.

          The concept of mesenchymal stem cells (MSCs) is becoming increasingly obscure due to the recent findings of heterogeneous populations with different levels of stemness within MSCs isolated by traditional plastic adherence. MSCs were originally identified in bone marrow and later detected in many other tissues. Currently, no cloning based on single surface marker is capable of isolating cells that satisfy the minimal criteria of MSCs from various tissue environments. Markers that associate with the stemness of MSCs await to be elucidated. A number of candidate MSC surface markers or markers possibly related to their stemness have been brought forward so far, including Stro-1, SSEA-4, CD271, and CD146, yet there is a large difference in their expression in various sources of MSCs. The exact identity of MSCs in vivo is not yet clear, although reports have suggested they may have a fibroblastic or pericytic origin. In this review, we revisit the reported expression of surface molecules in MSCs from various sources, aiming to assess their potential as MSC markers and define the critical panel for future investigation. We also discuss the relationship of MSCs to fibroblasts and pericytes in an attempt to shed light on their identity in vivo. © 2014 AlphaMed Press.
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            Adipose Mesenchymal Stromal Cell-Based Therapy for Severe Osteoarthritis of the Knee: A Phase I Dose-Escalation Trial.

            : Osteoarthritis (OA) is the most widespread musculoskeletal disorder in adults. It leads to cartilage damage associated with subchondral bone changes and synovial inflammation, causing pain and disability. The present study aimed at evaluating the safety of a dose-escalation protocol of intra-articular injected adipose-derived stromal cells (ASCs) in patients with knee OA, as well as clinical efficacy as secondary endpoint. A bicentric, uncontrolled, open phase I clinical trial was conducted in France and Germany with regulatory agency approval for ASC expansion procedure in both countries. From April 2012 to December 2013, 18 consecutive patients with symptomatic and severe knee OA were treated with a single intra-articular injection of autologous ASCs. The study design consisted of three consecutive cohorts (six patients each) with dose escalation: low dose (2 × 10(6) cells), medium dose (10 × 10(6)), and high dose (50 × 10(6)). The primary outcome parameter was safety evaluated by recording adverse events throughout the trial, and secondary parameters were pain and function subscales of the Western Ontario and McMaster Universities Arthritis Index. After 6 months of follow-up, the procedure was found to be safe, and no serious adverse events were reported. Four patients experienced transient knee joint pain and swelling after local injection. Interestingly, patients treated with low-dose ASCs experienced significant improvements in pain levels and function compared with baseline. Our data suggest that the intra-articular injection of ASCs is a safe therapeutic alternative to treat severe knee OA patients. A placebo-controlled double-blind phase IIb study is being initiated to assess clinical and structural efficacy.
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              Mesenchymal stem cells in joint disease and repair.

              Osteoarthritis (OA), a prevalent chronic condition with a striking impact on quality of life, represents an enormous societal burden that increases greatly as populations age. Yet no approved pharmacological intervention, biologic therapy or procedure prevents the progressive destruction of the OA joint. Mesenchymal stem cells (MSCs)-multipotent precursors of connective tissue cells that can be isolated from many adult tissues, including those of the diarthrodial joint-have emerged as a potential therapy. Endogenous MSCs contribute to maintenance of healthy tissues by acting as reservoirs of repair cells or as immunomodulatory sentinels to reduce inflammation. The onset of degenerative changes in the joint is associated with aberrant activity or depletion of these cell reservoirs, leading to loss of chondrogenic potential and preponderance of a fibrogenic phenotype. Local delivery of ex vivo cultures of MSCs has produced promising outcomes in preclinical models of joint disease. Mechanistically, paracrine signalling by MSCs might be more important than differentiation in stimulating repair responses; thus, paracrine factors must be assessed as measures of MSC therapeutic potency, to replace traditional assays based on cell-surface markers and differentiation. Several early-stage clinical trials, initiated or underway in 2013, are testing the delivery of MSCs as an intra-articular injection into the knee, but optimal dose and vehicle are yet to be established.
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                Author and article information

                Contributors
                silvia.lopa@grupposandonato.it
                alessandra.colombini@grupposandonato.it
                matteo.moretti@grupposandonato.it
                laura.degirolamo@grupposandonato.it
                Journal
                Knee Surg Sports Traumatol Arthrosc
                Knee Surg Sports Traumatol Arthrosc
                Knee Surgery, Sports Traumatology, Arthroscopy
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0942-2056
                1433-7347
                29 August 2018
                29 August 2018
                2019
                : 27
                : 6
                : 2003-2020
                Affiliations
                [1 ]GRID grid.417776.4, Cell and Tissue Engineering Laboratory, , IRCCS Istituto Ortopedico Galeazzi, ; Via R. Galeazzi 4, 20161 Milan, Italy
                [2 ]GRID grid.417776.4, Orthopaedic Biotechnology Lab, , IRCCS Istituto Ortopedico Galeazzi, ; Via R. Galeazzi 4, 20161 Milan, Italy
                [3 ]ISNI 0000 0004 0514 7845, GRID grid.469433.f, Regenerative Medicine Technologies Lab, , Ente Ospedaliero Cantonale, ; Via Tesserete 46, 6900 Lugano, Switzerland
                [4 ]GRID grid.483229.6, Swiss Institute for Regenerative Medicine, ; Lugano, Switzerland
                Author information
                http://orcid.org/0000-0002-9979-3092
                Article
                5118
                10.1007/s00167-018-5118-9
                6541568
                30159741
                9d302116-f50b-421a-8847-4f2ac7876cf2
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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.

                History
                : 21 March 2018
                : 14 August 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003196, Ministero della Salute;
                Award ID: Project Line 1, Progressive ID 28
                Award ID: Project Line 4 Progressive ID 98
                Award Recipient :
                Categories
                Knee
                Custom metadata
                © European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA) 2019

                Surgery
                osteoarthritis,inflammation,mesenchymal stem cells,intra-articular injection,articular cartilage,bone marrow concentrate,stromal vascular fraction,adipose tissue

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