Intra-articular administration of xenogeneic neonatal Mesenchymal Stromal Cells early after meniscal injury down-regulates metalloproteinase gene expression in synovium and prevents cartilage degradation in a rabbit model of osteoarthritis

Saulnier, N.; Viguier, É.; Perrier‐Groult, Emeline; Chenu, Chantal; Pillet, Elodie; Roger, Thierry; Maddens, Stéphane; Boulocher, C.

doi:10.1016/j.joca.2014.09.007

Cited by 77 publications

(70 citation statements)

References 34 publications

(34 reference statements)

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“…However, in our study we observed lymphoplasmacytic infiltration and inflammation in both cohorts. Our findings are consistent with other studies showing immune responses related to xenogeneic transplantation [] and nonautologous transplantation of isolated cells [, ]. It appears there is no consensus on the biological effects of heterologous cell transplantation in rabbits.…”

Section: Discussionsupporting

confidence: 92%

“…Histologic evaluation of tissues did reveal a higher incidence of cellular infiltration in knees receiving AMSC therapy. The latter response has been observed in previous animal models of OA and/or MSC studies [], but it did not translate into evidence of major structural damage to cartilage or other intrasynovial tissues, as evident from the OARSI scoring for articular cartilage or synoviopathy.…”

Section: Discussionmentioning

confidence: 61%

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Safety Studies for Use of Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells in a Rabbit Model for Osteoarthritis to Support a Phase I Clinical Trial

Riester

Denbeigh

Yang

et al. 2016

Stem Cells Translational Medicine

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Adipose‐derived mesenchymal stem cells (AMSCs) offer potential as a therapeutic option for clinical applications in musculoskeletal regenerative medicine because of their immunomodulatory functions and capacity for trilineage differentiation. In preparation for a phase I clinical trial using AMSCs to treat patients with osteoarthritis, we carried out preclinical studies to assess the safety of human AMSCs within the intra‐articular joint space. Culture‐expanded human AMSCs grown in human platelet‐lysate were delivered via intra‐articular injections into normal healthy rabbit knees and knees at risk for the development of osteoarthritis after bilateral medial anterior hemimeniscectomy. Treatment outcomes and safety were evaluated by assessing the general health, function, and behavior of the animals. Joint tissues were analyzed by x‐ray, magnetic resonance imaging, and histopathology. Intra‐articular AMSC therapy was well tolerated in this study. We did not observe adverse systemic reactions, nor did we find evidence of damage to intra‐articular joint tissues. Thus, the data generated in this study show a favorable safety profile for AMSCs within the joint space in support of a phase I clinical trial evaluating the clinical utility of AMSCs to treat osteoarthritis. Stem Cells Translational Medicine 2017;6:910–922

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 61%

Safety Studies for Use of Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells in a Rabbit Model for Osteoarthritis to Support a Phase I Clinical Trial

Riester

Denbeigh

Yang

et al. 2016

Stem Cells Translational Medicine

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“…On the other hand, the expression of anti‐Calcitonin Gene‐Related Peptide in the C5 dorsal horn of the OA animals was also significantly decreased, indicating a suppressive effect on the central sensitization component of pain. Saulnier et al confirmed the reduced expression of metalloproteinases (1, 3, and 13) after MSC injection, but describe that MSC‐conditioned medium can also convey these anti‐inflammatory effects on OA synoviocytes. In sum, MSC treatments are known to induce potent anti‐inflammatory, tissue‐restoring, and analgesic effects that could explain the clinical findings described in recent trials as well as in the present phase I/II study.…”

Section: Discussionmentioning

confidence: 99%

Umbilical Cord-Derived Mesenchymal Stromal Cells (MSCs) for Knee Osteoarthritis: Repeated MSC Dosing Is Superior to a Single MSC Dose and to Hyaluronic Acid in a Controlled Randomized Phase I/II Trial

Matas

Orrego

Amenábar

et al. 2018

Stem Cells Translational Medicine

264

270

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Knee osteoarthritis (OA) is a leading cause of pain and disability. Although conventional treatments show modest benefits, pilot and phase I/II trials with bone marrow (BM) and adipose‐derived (AD) mesenchymal stromal cells (MSCs) point to the feasibility, safety, and occurrence of clinical and structural improvement in focal or diffuse disease. This study aimed to assess the safety and efficacy of the intra‐articular injection of single or repeated umbilical cord‐derived (UC) MSCs in knee OA. UC‐MSCs were cultured in an International Organization for Standardization 9001:2015 certified Good Manufacturing Practice‐type Laboratory. Patients with symptomatic knee OA were randomized to receive hyaluronic acid at baseline and 6 months (HA, n = 8), single‐dose (20 × 106) UC‐MSC at baseline (MSC‐1, n = 9), or repeated UC‐MSC doses at baseline and 6 months (20 × 106 × 2; MSC‐2, n = 9). Clinical scores and magnetic resonance images (MRIs) were assessed throughout the 12 months follow‐up. No severe adverse events were reported. Only MSC‐treated patients experienced significant pain and function improvements from baseline (p = .001). At 12 months, Western Ontario and Mc Master Universities Arthritis Index (WOMAC‐A; pain subscale) reached significantly lower levels of pain in the MSC‐2‐treated group (1.1 ± 1.3) as compared with the HA group (4.3 ± 3.5; p = .04). Pain Visual Analog scale was significantly lower in the MSC‐2 group versus the HA group (2.4 ± 2.1 vs. 22.1 ± 9.8, p = .03) at 12 months. For total WOMAC, MSC‐2 had lower scores than HA at 12 months (4.2 ± 3.9 vs. 15.2 ± 11, p = .05). No differences in MRI scores were detected. In a phase I/II trial (NCT02580695), repeated UC‐MSC treatment is safe and superior to active comparator in knee OA at 1‐year follow‐up. Stem Cells Translational Medicine 2019;8:215&224

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“…MSCs generate a local immunosuppressive microenvironment by secreting cytokines (19). In addition to immunomodulatory functions, MSCs secrete trophic and soluble factors that reduce synovial inflammation, exert anti-catabolic effects, and recruit endogenous MSCs in the joint environment (20–23). Taken together, these pleiotropic actions justify an evaluation of the extent to which the local administration of MSCs compares to NSAIDs in managing postoperative joint pain in dogs (24).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Effect of a Single Intra-articular Injection of Allogeneic Neonatal Mesenchymal Stromal Cells Compared to Oral Non-Steroidal Anti-inflammatory Treatment on the Postoperative Musculoskeletal Status and Gait of Dogs over a 6-Month Period after Tibial Plateau Leveling Osteotomy: A Pilot Study

Taroni

Cabon

Febre³

et al. 2017

Front. Vet. Sci.

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ObjectiveCompare the clinical and pressure walkway gait evolution of dogs after a tibial plateau leveling osteotomy (TPLO) for a cranial cruciate ligament rupture (CrCLR) and treatment with either a 1-month course of non-steroidal anti-inflammatory drugs (NSAIDs) or a single postoperative intra-articular (IA) injection of allogeneic neonatal mesenchymal stromal cells (MSCs).Study designProspective, double-blinded, randomized, controlled, monocentric clinical study.AnimalsSixteen client-owned dogs.Materials and methodsDogs with unilateral CrCLR confirmed by arthroscopy were included. Allogeneic neonatal canine MSCs were obtained from fetal adnexa retrieved after C-section performed on healthy pregnant bitches. The dogs were randomly allocated to either the “MSCs group,” receiving an IA injection of MSCs after TPLO, followed by placebo for 1 month, or the “NSAIDs group,” receiving IA equivalent volume of MSCs vehicle after TPLO, followed by oral NSAID for 1 month. One of the three blinded evaluators assessed the dogs in each group before and after surgery (1, 3, and 6 months). Clinical score and gait and bone healing process were assessed. The data were statistically compared between the two groups for pre- and postoperative evaluations.ResultsFourteen dogs (nine in the MSCs group, five in the NSAIDs group) completed the present study. No significant difference was observed between the groups preoperatively. No local or systemic adverse effect was observed after MSCs injection at any time point considered. At 1 month after surgery, bone healing scores were significantly higher in the MSCs group. At 1, 3, and 6 months after surgery, no significant difference was observed between the two groups for clinical scores and gait evaluation.ConclusionA single IA injection of allogeneic neonatal MSCs could be a safe and valuable postoperative alternative to NSAIDs for dogs requiring TPLO surgery, particularly for dogs intolerant to this class of drugs.

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Intra-articular administration of xenogeneic neonatal Mesenchymal Stromal Cells early after meniscal injury down-regulates metalloproteinase gene expression in synovium and prevents cartilage degradation in a rabbit model of osteoarthritis

Cited by 77 publications

References 34 publications

Safety Studies for Use of Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells in a Rabbit Model for Osteoarthritis to Support a Phase I Clinical Trial

Safety Studies for Use of Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells in a Rabbit Model for Osteoarthritis to Support a Phase I Clinical Trial

Umbilical Cord-Derived Mesenchymal Stromal Cells (MSCs) for Knee Osteoarthritis: Repeated MSC Dosing Is Superior to a Single MSC Dose and to Hyaluronic Acid in a Controlled Randomized Phase I/II Trial

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