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Intraarticular Administration of Dexamethasone after Mesenchymal Stem Cells Implantation Does Not Improve Significantly the Treatment of Preestablished Full-Thickness Chondral Defect in a Rabbit Model.

ABSTRACT: OBJECTIVE: The aim of this study was to evaluate the contribution to hyaline cartilage regeneration of dexamethasone intraarticular administration after autologous mesenchymal stem cells (MSCs) implantation into a preestablished knee full-thickness chondral defect. DESIGN: Full-thickness chondral defects of 4.5 × 4.5 mm(2) were surgically made in both medial femoral condyles of adult male New Zealand rabbits. Two weeks later, autologous ex vivo expanded bone marrow-derived MSCs were embedded in hyaluronic acid and implanted into the chondral defects. Immediately and every week after the intervention, dexamethasone 0.25 mg/kg was intraarticularly administered (MSC/dexa-treated group). Six weeks after MSC transplantation, the animals were euthanized and condyles were characterized molecularly according to aggrecan, collagen type II, and collagen type I gene expression (quantitative reverse transcriptase-polymerase chain reaction) and histologically (hematoxylin-eosin staining). Data of MSC/dexa-treated condyles were compared with untreated, dexa-treated, MSC-treated, or normal unlesioned condyles. RESULTS: The ratio between collagen type II expression versus collagen type I expression in MSC/dexa-treated condyles was higher than one, even though the group mean value was not statistically different from that of untreated defects. Histological changes were observed between MSC/dexa-treated and untreated defects mainly in surface regularity and in hyaline matrix abundance. However, International Cartilage Repair Society score analysis did not support robust differences between those groups. CONCLUSION: Intraarticular administration of dexamethasone after autologous MSC implantation into a preestablished full-thickness chondral defect does not contribute significantly to the regeneration of a tissue with molecular and histological characteristics identical to hyaline cartilage.

SUBMITTER: Espinosa M

PROVIDER: S-EPMC4297101 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Intraarticular Administration of Dexamethasone after Mesenchymal Stem Cells Implantation Does Not Improve Significantly the Treatment of Preestablished Full-Thickness Chondral Defect in a Rabbit Model.

Espinosa Maximiliano M Vaisman Alex A Nazal Nicolas N Figueroa David D Gallegos Marcela M Conget Paulette P

Cartilage 20130401 2

<h4>Objective</h4>The aim of this study was to evaluate the contribution to hyaline cartilage regeneration of dexamethasone intraarticular administration after autologous mesenchymal stem cells (MSCs) implantation into a preestablished knee full-thickness chondral defect.<h4>Design</h4>Full-thickness chondral defects of 4.5 × 4.5 mm(2) were surgically made in both medial femoral condyles of adult male New Zealand rabbits. Two weeks later, autologous ex vivo expanded bone marrow-derived MSCs were ...[more]

PMID: 26069657

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Project description:BackgroundMesenchymal stem cells (MSCs) are a promising cell source for cartilage regeneration. However, the function of MSC can vary according to cell culture conditions, donor age, and heterogeneity of the MSC population, resulting in unregulated MSC quality control. To overcome these limitations, we previously developed a fluorescent real-time thiol tracer (FreSHtracer) that monitors cellular levels of glutathione (GSH), which are known to be closely associated with stem cell function. In this study, we investigated whether using FreSHtracer could selectively separate high-functioning MSCs based on GSH levels and evaluated the chondrogenic potential of MSCs with high GSH levels to repair cartilage defects in vivo.MethodsFlow cytometry was conducted on FreSHtracer-loaded MSCs to select cells according to their GSH levels. To determine the function of FreSHtracer-isolated MSCs, mRNA expression, migration, and CFU assays were conducted. The MSCs underwent chondrogenic differentiation, followed by analysis of chondrogenic-related gene expression. For in vivo assessment, MSCs with different cellular GSH levels or cell culture densities were injected in a rabbit chondral defect model, followed by histological analysis of cartilage-regenerated defect sites.ResultsFreSHtracer successfully isolated MSCs according to GSH levels. MSCs with high cellular GSH levels showed enhanced MSC function, including stem cell marker mRNA expression, migration, CFU, and oxidant resistance. Regardless of the stem cell tissue source, FreSHtracer selectively isolated MSCs with high GSH levels and high functionality. The in vitro chondrogenic potential was the highest in pellets generated by MSCs with high GSH levels, with increased ECM formation and chondrogenic marker expression. Furthermore, the MSCs' function was dependent on cell culture conditions, with relatively higher cell culture densities resulting in higher GSH levels. In vivo, improved cartilage repair was achieved by articular injection of MSCs with high levels of cellular GSH and MSCs cultured under high-density conditions, as confirmed by Collagen type 2 IHC, Safranin-O staining and O'Driscoll scores showing that more hyaline cartilage was formed on the defects.ConclusionFreSHtracer selectively isolates highly functional MSCs that have enhanced in vitro chondrogenesis and in vivo hyaline cartilage regeneration, which can ultimately overcome the current limitations of MSC therapy.

Project description:BackgroundIndications for surgical meniscal repair are limited, and failure rates remain high. Thus, new ways to augment repair and stimulate meniscal regeneration are needed. Mesenchymal stem cells are multipotent cells present in mature individuals and accessible from peripheral connective tissue sites, including synovium. The purpose of this study was to quantitatively evaluate the effect of implantation of synovial tissue-derived mesenchymal stem cells on meniscal regeneration in a rabbit model of partial meniscectomy.MethodsSynovial mesenchymal stem cells were harvested from the knee of one New Zealand White rabbit, expanded in culture, and labeled with a fluorescent marker. A reproducible 1.5-mm cylindrical defect was created in the avascular portion of the anterior horn of the medial meniscus bilaterally in fifteen additional rabbits. Allogenic synovial mesenchymal stem cells suspended in phosphate-buffered saline solution were implanted into the right knees, and phosphate-buffered saline solution alone was placed in the left knees. Meniscal regeneration was evaluated histologically at four, twelve, and twenty-four weeks for (1) quantity and (2) quality (with use of an established three-component scoring system). A similar procedure was performed in four additional rabbits with use of green fluorescent protein-positive synovial mesenchymal stem cells for the purpose of tracking progeny following implantation.ResultsThe quantity of regenerated tissue in the group that had implantation of synovial mesenchymal stem cells was greater at all end points, reaching significance at four and twelve weeks (p < 0.05). Tissue quality scores were also superior in knees treated with mesenchymal stem cells compared with controls at all end points, achieving significance at twelve and twenty-four weeks (3.8 versus 2.8 at four weeks [p = 0.29], 5.7 versus 1.7 at twelve weeks [p = 0.008], and 6.0 versus 3.9 at twenty-four weeks [p = 0.021]). Implanted cells adhered to meniscal defects and were observed in the regenerated tissue, where they differentiated into type-I and II collagen-expressing cells, at up to twenty-four weeks.ConclusionsSynovial mesenchymal stem cells adhere to sites of meniscal injury, differentiate into cells resembling meniscal fibrochondrocytes, and enhance both quality and quantity of meniscal regeneration.

Dataset Information

Intraarticular Administration of Dexamethasone after Mesenchymal Stem Cells Implantation Does Not Improve Significantly the Treatment of Preestablished Full-Thickness Chondral Defect in a Rabbit Model.

Publications

Intraarticular Administration of Dexamethasone after Mesenchymal Stem Cells Implantation Does Not Improve Significantly the Treatment of Preestablished Full-Thickness Chondral Defect in a Rabbit Model.

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