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  • Fluocinolone Acetonide is a Potent Synergistic Factor of TGF-β3-Associated Chondrogenesis of Bone Marrow-Derived Mesenchymal Stem Cells for Articular Surface Regeneration € 

    Abstract

    Articular cartilage repair remains a challenging problem. Based on a high-throughput screening and functional analysis, we found that fluocinolone acetonide (FA) in combination with transforming growth factor beta 3 (TGF-β3) strongly potentiated chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). In an in vivo cartilage defect model in knee joints of immunocompromised mice, transplantation of FA/TGF-β3-treated hBMSCs could completely repair the articular surface. Analysis of the intracellular pathways revealed that FA enhanced TGF-β3-induced phosphorylation of Smad2 and Smad3. Additionally, we performed a pathway array and found that FA activates mTORC1/AKT pathway. Chemical inhibition of mTORC1 with rapamycin substantially suppressed FA effect, and inhibition of AKT completely repressed chondrogenesis of hBMSCs. Inhibition of glucocorticoid receptor with mifepristone also suppressed FA effect, suggesting that FA involves binding to glucocorticoid receptor. Comparative analysis with other glucocorticoids (triamcinolone acetonide (TA) and dexamethasone (DEX)) revealed the unique ability of FA to repair articular cartilage surgical defects. Analysis of intracellular pathways showed that mTORC1/AKT pathway and glucocorticoid receptor was highly activated with FA and TA, but to a less extent with DEX. Collectively, these results show a unique ability of FA to enhance TGF-β3-associated chondrogenesis, and suggest that the FA/TGF-β3 combination may be used as major inducer of chondrogenesis in vitro. Additionally, FA/TGF-β3 could be potentially applied in a clinical setting to increase the efficiency of regenerative approaches based on chondrogenic differentiation of stem cells. This article is protected by copyright. All rights reserved.

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  • Musculoskeletal biology and bioengineering: A new in vivo stem cell model for regenerative rheumatology

    With advances in stem cell techniques for the bioengineering and regeneration of musculoskeletal tissues comes added complexity in our understanding of stem cell biology. How will the recent discovery of a novel stem cell subset, termed osteochondroreticular stem cells, contribute to progression in the field?

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  • Future of Cell-Based Therapies in Orthopedic Sports Medicine

    Abstract

    Orthopedic Sports Medicine involves the treatment of complex injuries in both the acute and chronic setting. Massive tears of soft tissue, large hard tissue breaks, or malalignments or catastrophic collapse of both soft and hard tissue structures require clever surgical intervention both as open or arthroscopic procedures. Small tears or fractures or resistant chronic, nonhealing, and often painful conditions are a challenge to the orthopedic practitioner. My prediction for the future is that cell-based therapies will provide the key to these clinically challenging situations. Specifically, the use of either autologous or allogeneic mesenchymal stem cells (MSCs) can and will provide clinical solutions (Caplan 2009; Caplan and Correa 2011).

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  • Hydrostatic pressure promotes the proliferation and osteogenic/chondrogenic differentiation of mesenchymal stem cells: the roles of RhoA and Rac1

    Abstract

    Our previous studies have shown that hydrostatic pressure can serve as an active regulator for bone marrow mesenchymal stem cells (BMSCs). The current work further investigates the roles of cytoskeletal regulatory proteins Ras homolog gene family member A (RhoA) and Ras-related C3 botulinum toxin substrate 1 (Rac1) in hydrostatic pressure-related effects on BMSCs. Flow cytometry assays showed that the hydrostatic pressure promoted cell cycle initiation in a RhoA- and Rac1-dependent manner. Furthermore, fluorescence assays confirmed that RhoA played a positive and Rac1 displayed a negative role in the hydrostatic pressure-induced F-actin stress fiber assembly. Western blots suggested that RhoA and Rac1 play central roles in the pressure-inhibited ERK phosphorylation, and Rac1 but not RhoA was involved in the pressure-promoted JNK phosphorylation. Finally, real-time polymerase chain reaction (PCR) experiments showed that pressure promoted the expression of osteogenic marker genes in BMSCs at an early stage of osteogenic differentiation through the up-regulation of RhoA activity. Additionally, the PCR results showed that pressure enhanced the expression of chondrogenic marker genes in BMSCs during chondrogenic differentiation via the up-regulation of Rac1 activity. Collectively, our results suggested that RhoA and Rac1 are critical to the pressure-induced proliferation and differentiation, the stress fiber assembly, and MAPK activation in BMSCs.

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  • The Role of Stem Cells and Tissue Engineering in Orthopaedic Sports Medicine: Current Evidence and Future Directions

    Abstract

    The use of stem cell therapies for the treatment of orthopaedic injuries continues to advance. The purpose of this review was to provide an update of the current role and future directions of stem cell strategies in sports medicine. The application of cell-based treatments in the sports medicine arena has expanded in recent years. Promising preclinical results have led to translation of these novel therapies into the clinical setting. Early well-designed comparative clinical studies have also shown positive outcomes. Despite significant advances in this arena, there remains a need for additional high-powered and well-designed clinical trials to confirm the safety and efficacy of treatment.

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  • Mesenchymal Stem Cell Implantation in Osteoarthritic Knees Is Fibrin Glue Effective as a Scaffold?

    Abstract

    Background: The cell-based tissue engineering approach that uses mesenchymal stem cells (MSCs) has addressed the issue of articular cartilage repair in osteoarthritic (OA) knees. However, to improve outcomes, an advanced surgical procedure with tissue-engineered scaffolds may be needed to treat patients with large cartilage lesions.

    Purpose: To investigate the clinical and second-look arthroscopic outcomes of the implantation of MSCs loaded in fibrin glue as a scaffold in patients with OA knees and to compare these outcomes with those of MSC implantation without a scaffold.

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  • TGF-b1, GDF-5, and BMP-2 Stimulation Induces Chondrogenesis in Expanded Human Articular Chondrocytes and Marrow-Derived Stromal Cells

    Abstract

    Replacement of degenerated cartilage with cell-based cartilage products may offer a long-term solution to halt arthritis\'   degenerative   progression. Chondrocytes   are   frequently   used   in   cell- based   FDA-approved   cartilage   products;   yet   human   marrow-derived   stromal   cells   (hMSCs)   show signicant   translational   potential, reducing   donor   site   morbidity   and   maintaining   their   undiffer- entiated   phenotype   with   expansion.   This   study   sought   to   investigate   the   effects   of   transforming growth   factor     b1   (TGF-b1),   growth/differentiation   factor   5   (GDF-5),   and   bone   morphogenetic protein   2   (BMP-2)   during   postexpansion   chondrogenesis   in   human   articular   chondrocytes   (hACs) and   to   compare   chondrogenesis   in   passaged   hACs   with   that   of   passaged   hMSCs.   Through   serial expansion,   chondrocytes   dedifferentiated,   decreasing   expression   of   chondrogenic   genes   while increasing   expression   of   broblastic   genes.   However,   following   expansion,   10   ng/mL   TGF-b1,   100 ng/mL   GDF-5,   or   100   ng/mL   BMP-2   supplementation   during   three-dimensional   aggregate   culture each   upregulated   one   or   more   markers   of   chondrogenic   gene   expression   in   both   hACs   and hMSCs.   Additionally,   in   both   cell   types,   the   combination   of   TGF-b1,   GDF-5,   and   BMP-2   induced the   greatest   upregulation   of   chondrogenic   genes,   that   is,   Col2A1,   Col2A1/Col1A1   ratio,   SOX9, and   ACAN,   and   synthesis   of   cartilage-specic   matrix,   that   is,   glycosaminoglycans   (GAGs)   and ratio   of   collagen   II/I.   Finally,   TGF-b1,   GDF-5,   and   BMP-2   stimulation   yielded   mechanically   robust cartilage   rich   in   collagen   II   and   GAGs   in   both   cell   types,   following   4   weeks   maturation.   This study   illustrates   notable   success   in   using   the   self-assembling   method   to   generate   robust, scaffold-free   neocartilage   constructs   using   expanded   hACs   and   hMSCs. STEM     CELLS 2015;33:762-773

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  • Advanced cell therapies for articular cartilage regeneration

    Advanced cell-based therapies are promising approaches for stimulating full regeneration of cartilage lesions. In addition to a few commercially available medicinal pro-ducts, several clinical and preclinical studies are ongoing worldwide. In preclinical settings, high-quality cartilage tissue has been produced using combination strategies involving stem or progenitor cells, biomaterials, and bio-molecules to generate a construct for implantation at the lesion site. Cell numbers and mechanical stimulation of the constructs are not commonly considered, but are important parameters to be evaluated in forthcoming clinical studies. We review current clinical and preclinical studies for advanced therapy cartilage regeneration and evaluate the progress of the field.

    Advanced cell-based therapies are promising approaches for stimulating full regeneration of cartilage lesions. In addition to a few commercially available medicinal products, several clinical and preclinical studies are ongoing worldwide. In preclinical settings, high-quality cartilage tissue has been produced using combination strategies involving stem or progenitor cells, biomaterials, and bio-molecules to generate a construct for implantation at the lesion site. Cell numbers and mechanical stimulation of the constructs are not commonly considered, but are important parameters to be evaluated in forthcoming clinical studies. We review current clinical and preclinical studies for advanced therapy cartilage regeneration and evaluate the progress of the field.

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  • Histochemical and Functional Improvement of Adipose-Derived Stem Cell-Based Tissue-Engineered Cartilage by Hyperbaric Oxygen/Air Treatment in a Rabbit Articular Defect Model

    Cartilage is exposed to compression forces during joint loading. Therefore, exogenous stimuli are frequently used in cartilage tissue engineering strategies to enhance chondrocyte differentiation and extracellular matrix (ECM) secretion. In this study, human adipose-derived stem cells were seeded on a gelatin/polycaprolactone scaffold to evaluate the histochemical and functional improvement of tissue-engineered cartilage after hyperbaric oxygen/air treatment in a rabbit articular defect model. Behavior tests showed beneficial effects on weight-bearing and rear leg-supporting capacities after treatment of tissue-engineered cartilage with 2.5 ATA oxygen or air. Moreover, positron emission tomography images and immunohistochemistry staining demonstrated hydroxyapatite formation and increased ECM synthesis, respectively, at the tissue-engineered cartilage graft site after high pressure oxygen/air treatment. Based on these results, we concluded that hyperbaric oxygen and air treatment can improve the quality of tissue-engineered cartilage in vivo by increasing the synthesis of ECM.

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  • Platelet-rich Plasma as an Effective Treatment for Proximal Hamstring Injuries

    Abstract

    Proximal hamstring injuries can be disabling, and several traditional conservative treatments, including physiotherapy and nonsteroidal anti-inflammatory drugs, have been inconsistent. Corticosteroid injections have demonstrated success but can adversely affect local tissues. Platelet-rich plasma (PRP) has emerged as a safe, effective treatment for several orthopedic pathologies. The authors propose a PRP injection at the muscle origin as a novel treatment for proximal hamstring injuries.

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  • Platelet-rich Plasma Modulates the Secretion of Inflammatory/Angiogenic Proteins by Inflamed Tenocytes

    Abstract

    BACKGROUND: Platelet-rich plasma therapies for tendinopathy appear to provide moderate pain reduction. However, the biological mechanisms behind the observed clinical effects remain poorly characterized. QUESTIONS

    PURPOSES: The purpose of this study was to explore whether platelet-rich plasma modifies the inflammatory/angiogenic status of already inflamed tenocytes by examining (1) gene expression; (2) modulation of chemokine and interleukin secretion; and (3) differences between healthy and tendinopathic tenocytes.

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  • Platelet-rich plasma to treat ankle cartilage pathology - from translational potential to clinical evidence: a systematic review

    Abstract

    Platelet-rich Plasma (PRP) is a fascinating biological treatment showing promising results for the management of cartilage disorders. However, despite the step forwards in this research area and the increasing use of PRP in clinical practice, its use remains still controversial and especially its application as injective treatment for ankle cartilage pathology have been scarcely investigated.

    The aim of this paper is to describe the translational evidence for the use of PRP in cartilage treatment and to systematically review all the available evidence regarding the clinical application of PRP for ankle cartilage disorders, in order to understand what is the current state of the art for this specific clinical indication, underlining both limits and potential of this biological strategy.

    A systematic review of the clinical literature was performed on the use of PRP to treat ankle cartilage disorders and 7 papers were identified. PRP has been used in two different ways: 5 of the available papers focus on its use as an augmentation procedure to various surgical techniques for cartilage regeneration, while only two studies report its conservative application through intra-articular injections. Based on the limited number of clinical studies available on this topic, this systematic review showed the lack of major adverse events related to PRP and overall good results for the treatment of ankle cartilage pathology, thus confirming the translational potential of this biological treatment suggested by several preclinical studies. Further high quality clinical trials in the ankle are still needed to clarify proper indications and best applicative modalities.

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  • Plantar fasciitis: Outcome evaluation of plantar fasciitis treated with PRP against steroid injection

    Abstract

    Plantar fasciitis is the most common cause of heel pain which seems difficult to treat in its most chronic and severe forms. Earlier treatments, including orthoses, non steroidal anti-inflammatory drugs, and steroid injections are paucity of supportive clinical evidence but carry the potential for serious

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  • Mesenchymal stromal cells and rheumatic diseases: new tools from pathogenesis to regenerative therapies

    Abstract

    In recent years, mesenchymal stromal cells (MSCs) have been largely investigated and tested as a new therapeutic tool for several clinical applications, including the treatment of different rheumatic diseases. MSCs are responsible for the normal turnover and maintenance of adult mesenchymal tissues as the result of their multipotent differentiation abilities and their secretion of a variety of cytokines and growth factors. Although initially derived from bone marrow, MSCs are present in many different tissues such as many peri-articular tissues. MSCs may exert immune-modulatory properties, modulating different immune cells in both in

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  • New and Emerging Strategies in Platelet-Rich Plasma Application in Musculoskeletal Regenerative Procedures: General Overview on Still Open Questions and Outlook

    Abstract

    Despite its pervasive use, the clinical efficacy of platelet-rich plasma (PRP) therapy and the different mechanisms of action have yet to be established. This overview of the literature is focused on the role of PRP in bone, tendon, cartilage, and ligament tissue regeneration considering basic science literature deriving from in vitro and in vivo studies. Although this work provides evidence that numerous preclinical studies published within the last 10 years showed promising results concerning the application of PRP, many key questions remain unanswered and controversial results have arisen. Additional preclinical studies are needed to define the dosing, timing, and frequency of PRP injections, different techniques for delivery and location of delivery, optimal physiologic conditions for injections, and the concomitant use of recombinant proteins, cytokines, additional growth factors, biological scaffolds, and stems cells to develop optimal treatment protocols that can effectively treat various musculoskeletal conditions.

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  • Systemic and local administration of allogeneic bone marrow derived mesenchymal stem cells promotes fracture healing in rats

    Abstract

    Mesenchymal stem cells (MSCs) are immune-privileged and a cell source for tissue repair. Previous studies showed that there is systemic mobilization of osteoblastic precursors to the fracture site, we hypothesized that both systemic and local administration of allogeneic MSCs may promote fracture healing. Bone marrow derived MSCs and skin fibroblasts were isolated from the GFP-Sprague-Dawley rats, cultured and characterized. Closed transverse femoral fracture with internal fixation was established in 48 adult male Sprague-Dawley rats, whom were randomly assigned into 4 groups receiving: PBS injection; MSCs systemic injection; Fibroblasts systemic injection and MSCs fracture site injection. 2x106 cells were injected at 4 days after fracture. All animals were terminated at 5 weeks after fracture; examinations included weekly radiograph; Micro-CT; mechanical testing; histology, immunohistochemistry and double immunofluorescence. The callus size of MSCs injection groups were significant larger among all the groups. Radiographs and 3D-reconstruction images showed that the fracture gaps united in the MSCs injected groups, while gaps were still seen in the fibroblast and PBS injection groups. The mechanical properties were significantly higher in the MSCs injection groups than those in the fibroblast and PBS groups, but no difference was found between the MSCs local and systemic injection groups. Immunohistochemistry and double immunofluorescence demonstrated that GFP-positive MSCs were present in the callus in the MSCs injection groups at 5 weeks after fracture, and some have differentiated into osteoblasts. Quantitative analysis revealed the number of GFP-positive cells in the callus in the MSCs systemic injection group was significantly lower than that of the MSCs local injection group. The proportion of GFP-osteoblasts in GFP-positive cells in the MSCs systemic injection group was significantly lower than that of the MSCs local injection group. These findings provide critical insight for developing MSC-based therapies and systemic injection of allogeneic MSCs may be a novel treatment method for promoting fracture repair.

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  • Regenerative treatment in osteochondral lesions of the talus: autologous chondrocyte implantation versus one-step bone marrow derived cells transplantation

    Abstract

    Purpose

    Osteochondral lesions of the talus (OLT) usually require surgical treatment. Regenerative techniques for hyaline cartilage restoration, like autologous chondrocytes implantation (ACI) or bone marrow derived cells transplantation (BMDCT), should be preferred. The aim of this work is comparing two clusters with OLT, treated with ACI or BMDCT.

    Methods

    Eighty patients were treated with regenerative techniques, 40 with ACI and 40 with BMDCT. The two groups were homogenous regarding age, lesion size and depth, previous surgeries, etiology of the lesion, subchondral bone graft, final follow-up and pre-operative AOFAS score. The two procedures were performed arthroscopically. The scaffold was a hyaluronic acid membrane in all the cases, loaded with previously cultured chondrocytes (ACI) or with bone marrow concentrated cells, harvested in the same surgical session (BMDCT). All the patients were clinically and radiologically evaluated, using MRI Mocart score and T2 mapping sequence.

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  • Differentiation of directly co-cultured bone marrow mesenchymal stem cells and ligament fibroblasts into ligament cells after induced by transforming growth factor β1 and basic fibroblast growth factor

    Abstract

    OBJECTIVE: To investigate the effect of transforming growth factor β1 (TGF-β1) and basic fibroblast growth factor 1 (bFGF-1) on the cellular activities, proliferation, and expressions of ligament-specific mRNA and proteins in bone marrow mesenchymal stem cells (BMSCs) and ligament fibroblasts (LFs) after directly co-cultured.

    METHODS: BMSCs from 3-month-old Sprague Dawley rats were isolated and cultured using intensity gradient centrifugation. LFs were isolated using collagenase. The cells at passage 3 were divided into 6 groups: non-induced BMSCs group (group A), non-induced LFs group (group B), non-induced co-cultured BMSCs and LFs group (group C), induced BMSCs group (group D), induced LFs group (group E), and induced co-cultured BMSCs and LFs group (group F). The cellular activities and proliferation were examined by inverted contrast microscope and MTT; the concentrations of collagen type I and type III were determined by ELISA; and mRNA expressions of collagen types I and III, fibronectin, tenascin C, and matrix metalloproteinase 2 (MMP-2) were measured by real-time fluorescent quantitative PCR.

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  • Scaffold-Based Cartilage Treatments: With or Without Cells? A Systematic Review of Preclinical and Clinical Evidence

    Purpose

    Regenerative scaffold-based procedures are emerging as a potential therapeutic option for the treatment of chondral and osteochondral lesions. In general, we can summarize most of the recent developments to reach clinical application into 2 major trends: the use of different cell sources or the application of biomaterials as a cell-free approach. The aim of this systematic review was to analyze both preclinical and clinical studies on these new trends to understand how the available evidence supports the use of cell sources or justifies the cell-free approach for the scaffold-based treatment of cartilage lesions.

    Methods

    The research was performed using the PubMed database by looking at studies published in the English language referring to chondral or osteochondral defect repair with scaffold-based procedures until the end of 2013. The following strings were used: (\"cartilage\"[MeSH] AND \"tissue scaffolds\"[MeSH]).

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  • Modulation of Hyaluronan Synthesis by the Interaction between Mesenchymal Stem Cells and Osteoarthritic Chondrocytes

    Abstract

    Bone marrow mesenchymal stem cells (BM-MSCs) are considered a good source for cellular therapy in cartilage repair. But, their potential to repair the extracellular matrix, in an osteoarthritic environment, is still controversial. In osteoarthritis (OA), anti-inflammatory action and extracellular matrix production are important steps for cartilage healing. This study examined the interaction of BM-MSC and OA-chondrocyte on the production of hyaluronan and inflammatory cytokines in a Transwell system. We compared cocultured BM-MSCs and OA-chondrocytes with the individually cultured controls (monocultures). There was a decrease in BM-MSCs cell count in coculture with OA-chondrocytes when compared to BM-MSCs alone. In monoculture, BM-MSCs produced higher amounts of hyaluronan than OA-chondrocytes and coculture of BM-MSCs with OA-chondrocytes increased hyaluronan production per cell. Hyaluronan synthase-1 mRNA expression was upregulated in BM-MSCs after coculture with OA-chondrocytes, whereas hyaluronidase-1 was downregulated. After coculture, lower IL-6 levels were detected in BM-MSCs compared with OA-chondrocytes. These results indicate that, in response to coculture with OA-chondrocytes, BM-MSCs change their behavior by increasing production of hyaluronan and decreasing inflammatory cytokines. Our results indicate that BM-MSCs per se could be a potential tool for OA regenerative therapy, exerting short-term effects on the local microenvironment even when cell:cell contact is not occurring.

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