Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients
01 May 2011-International Journal of Rheumatic Diseases (Int J Rheum Dis)-Vol. 14, Iss: 2, pp 211-215
TL;DR: This data indicates that suppression of pro‐inflammatory cytokines and metalloproteinases in MSC patients with Osteoarthritis is a major cause of disease progression and the use of MSCs for treatment is warranted.
Abstract: Background: Osteoarthritis (OA) is a cartilage degenerative process, involving the immune system, producing local inflammatory reactions, with production of pro-inflammatory cytokines and metalloproteinases. No treatment is still available to improve or reverse the process. Stem cell therapy opened new horizons for treatment of many incurable diseases. Mesenchymal stem cells (MSCs) due to their multi-lineage potential, immunosuppressive activities, limited immunogenicity and relative ease of growth in culture, have attracted attentions for clinical use. Aim: The aim of this study was to examine whether MSC transplantation could reverse the OA process in the knee joint. The project was approved by the Tehran University of Medical Sciences Research Committee and Ethical Committee. Patients and Methods: Four patients with knee osteoarthritis were selected for the study. They were aged 55, 57, 65 and 54 years, and had moderate to severe knee OA. After their signed written consent, 30 mL of bone marrow were taken and cultured for MSC growth. After having enough MSCs in culture (4‐5 weeks) and taking in consideration all safety measures, cells were injected in one knee of each patient. Results: The walking time for the pain to appear improved for three patients and remained unchanged for one. The number of stairs they could climb and the pain on visual analog scale improved for all of them. On physical examination, the improvement was mainly for crepitus. It was minor for the improvement of the range of motion. Conclusion: Results were encouraging, but not excellent. Improvement of the technique may improve the
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TL;DR: Allogeneic MSC treatments, categorized as a drug by regulatory agencies, have been widely pursued, but new studies demonstrate the efficacy of autologous MSC therapies, even for individuals affected by a disease state.
Abstract: Mesenchymal stem cells (MSCs) are partially defined by their ability to differentiate into tissues including bone, cartilage and adipose in vitro, but it is their trophic, paracrine and immunomodulatory functions that may have the greatest therapeutic impact in vivo. Unlike pharmaceutical treatments that deliver a single agent at a specific dose, MSCs are site regulated and secrete bioactive factors and signals at variable concentrations in response to local microenvironmental cues. Significant progress has been made in understanding the biochemical and metabolic mechanisms and feedback associated with MSC response. The anti-inflammatory and immunomodulatory capacity of MSC may be paramount in the restoration of localized or systemic conditions for normal healing and tissue regeneration. Allogeneic MSC treatments, categorized as a drug by regulatory agencies, have been widely pursued, but new studies demonstrate the efficacy of autologous MSC therapies, even for individuals affected by a disease state. Safety and regulatory concerns surrounding allogeneic cell preparations make autologous and minimally manipulated cell therapies an attractive option for many regenerative, anti-inflammatory and autoimmune applications.
990 citations
TL;DR: Current, widely used clinical repair techniques for resurfacing articular cartilage defects and a developmental pipeline of acellular and cellular regenerative products and techniques that could revolutionize joint care over the next decade by promoting the development of functional articular Cartilage are described.
Abstract: Chondral and osteochondral lesions due to injury or other pathology commonly result in the development of osteoarthritis, eventually leading to progressive total joint destruction. Although current progress suggests that biologic agents can delay the advancement of deterioration, such drugs are incapable of promoting tissue restoration. The limited ability of articular cartilage to regenerate renders joint arthroplasty an unavoidable surgical intervention. This Review describes current, widely used clinical repair techniques for resurfacing articular cartilage defects; short-term and long-term clinical outcomes of these techniques are discussed. Also reviewed is a developmental pipeline of acellular and cellular regenerative products and techniques that could revolutionize joint care over the next decade by promoting the development of functional articular cartilage. Acellular products typically consist of collagen or hyaluronic-acid-based materials, whereas cellular techniques use either primary cells or stem cells, with or without scaffolds. Central to these efforts is the prominent role that tissue engineering has in translating biological technology into clinical products; therefore, concomitant regulatory processes are also discussed.
867 citations
TL;DR: The preclinical and clinical studies of MSCs from different adult tissues are summarized, the current hurdles to their use are discussed, and the future development of pluripotent stem cell-derived M SCs are proposed as an approach to immunomodulation therapy.
Abstract: The unique immunomodulatory properties of mesenchymal stem cells (MSCs) make them an invaluable cell type for the repair of tissue/ organ damage caused by chronic inflammation or autoimmune disorders. Although they hold great promise in the treatment of immune disorders such as graft versus host disease (GvHD) and allergic disorders, there remain many challenges to overcome before their widespread clinical application. An understanding of the biological properties of MSCs will clarify the mechanisms of MSC-based transplantation for immunomodulation. In this review, we summarize the preclinical and clinical studies of MSCs from different adult tissues, discuss the current hurdles to their use and propose the future development of pluripotent stem cell-derived MSCs as an approach to immunomodulation therapy.
797 citations
TL;DR: Results showed that intra‐articular injection of 1.0 × 108 AD MSCs into the osteoarthritic knee improved function and pain of the knee joint without causing adverse events, and reduced cartilage defects by regeneration of hyaline‐like articular cartilage.
Abstract: Mesenchymal stem cells (MSCs) are known to have a potential for articular cartilage regeneration. However, most studies focused on focal cartilage defect through surgical implantation. For the treatment of generalized cartilage loss in osteoarthritis, an alternative delivery strategy would be more appropriate. The purpose of this study was to assess the safety and efficacy of intra-articular injection of autologous adipose tissue derived MSCs (AD-MSCs) for knee osteoarthritis. We enrolled 18 patients with osteoarthritis of the knee and injected AD MSCs into the knee. The phase I study consists of three dose-escalation cohorts; the low-dose (1.0 × 10(7) cells), mid-dose (5.0 × 10(7)), and high-dose (1.0 × 10(8)) group with three patients each. The phase II included nine patients receiving the high-dose. The primary outcomes were the safety and the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) at 6 months. Secondary outcomes included clinical, radiological, arthroscopic, and histological evaluations. There was no treatment-related adverse event. The WOMAC score improved at 6 months after injection in the high-dose group. The size of cartilage defect decreased while the volume of cartilage increased in the medial femoral and tibial condyles of the high-dose group. Arthroscopy showed that the size of cartilage defect decreased in the medial femoral and medial tibial condyles of the high-dose group. Histology demonstrated thick, hyaline-like cartilage regeneration. These results showed that intra-articular injection of 1.0 × 10(8) AD MSCs into the osteoarthritic knee improved function and pain of the knee joint without causing adverse events, and reduced cartilage defects by regeneration of hyaline-like articular cartilage.
727 citations
TL;DR: Assessment of the feasibility and safety of osteoarthritis treatment with mesenchymal stromal cells in humans found the intervention is simple, does not require hospitalization or surgery, provides pain relief, and significantly improves cartilage quality.
Abstract: Background Osteoarthritis is the most prevalent joint disease and a frequent cause of joint pain, functional loss, and disability. Osteoarthritis often becomes chronic, and conventional treatments have demonstrated only modest clinical benefits without lesion reversal. Cell-based therapies have shown encouraging results in both animal studies and a few human case reports. We designed a pilot study to assess the feasibility and safety of osteoarthritis treatment with mesenchymal stromal cells (MSCs) in humans and to obtain early efficacy information for this treatment. Methods Twelve patients with chronic knee pain unresponsive to conservative treatments and radiologic evidence of osteoarthritis were treated with autologous expanded bone marrow MSCs by intra-articular injection (40×10 cells). Clinical outcomes were followed for 1 year and included evaluations of pain, disability, and quality of life. Articular cartilage quality was assessed by quantitative magnetic resonance imaging T2 mapping. Results Feasibility and safety were confirmed, and strong indications of clinical efficacy were identified. Patients exhibited rapid and progressive improvement of algofunctional indices that approached 65% to 78% by 1 year. This outcome compares favorably with the results of conventional treatments. Additionally, quantification of cartilage quality by T2 relaxation measurements demonstrated a highly significant decrease of poor cartilage areas (on average, 27%), with improvement of cartilage quality in 11 of the 12 patients. Conclusions MSC therapy may be a valid alternative treatment for chronic knee osteoarthritis. The intervention is simple, does not require hospitalization or surgery, provides pain relief, and significantly improves cartilage quality.
399 citations
Cites background from "Mesenchymal stem cell therapy for k..."
...Autologous MSCs have also been administered by intra-articular injection in two case series with satisfactory results (30, 31)....
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...Our results supersede those of previous case reports, where results were described as ‘‘satisfactory’’ (31) or ‘‘encouraging’’ (30)....
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References
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TL;DR: Several studies which tested the use of MSCs in models of infarct (injured heart), stroke (brain), or meniscus regeneration models are reviewed within the context of M SC‐mediated trophic effects in tissue repair.
Abstract: Adult marrow-derived Mesenchymal Stem Cells (MSCs) are capable of dividing and their progeny are further capable of differentiating into one of several mesenchymal phenotypes such as osteoblasts, chondrocytes, myocytes, marrow stromal cells, tendon-ligament fibroblasts, and adipocytes. In addition, these MSCs secrete a variety of cytokines and growth factors that have both paracrine and autocrine activities. These secreted bioactive factors suppress the local immune system, inhibit fibrosis (scar formation) and apoptosis, enhance angiogenesis, and stimulate mitosis and differentiation of tissue-intrinsic reparative or stem cells. These effects, which are referred to as trophic effects, are distinct from the direct differentiation of MSCs into repair tissue. Several studies which tested the use of MSCs in models of infarct (injured heart), stroke (brain), or meniscus regeneration models are reviewed within the context of MSC-mediated trophic effects in tissue repair.
2,743 citations
TL;DR: Adult marrow stromal cells can be induced to overcome their mesenchymal commitment and may constitute an abundant and accessible cellular reservoir for the treatment of a variety of neurologic diseases.
Abstract: Bone marrow stromal cells exhibit multiple traits of a stem cell population. They can be greatly expanded in vitro and induced to differentiate into multiple mesenchymal cell types. However, differentiation to non-mesenchymal fates has not been demonstrated. Here, adult rat stromal cells were expanded as undifferentiated cells in culture for more than 20 passages, indicating their proliferative capacity. A simple treatment protocol induced the stromal cells to exhibit a neuronal phenotype, expressing neuron-specific enolase, NeuN, neurofilament-M, and tau. With an optimal differentiation protocol, almost 80% of the cells expressed NSE and NF-M. The refractile cell bodies extended long processes terminating in typical growth cones and filopodia. The differentiating cells expressed nestin, characteristic of neuronal precursor stem cells, at 5 hr, but the trait was undetectable at 6 days. In contrast, expression of trkA, the nerve growth factor receptor, persisted from 5 hr through 6 days. Clonal cell lines, established from single cells, proliferated, yielding both undifferentiated and neuronal cells. Human marrow stromal cells subjected to this protocol also differentiated into neurons. Consequently, adult marrow stromal cells can be induced to overcome their mesenchymal commitment and may constitute an abundant and accessible cellular reservoir for the treatment of a variety of neurologic diseases.
2,600 citations
TL;DR: Undifferentiated and differentiated MSC do not elicit alloreactive lymphocyte proliferative responses and modulate immune responses, and the findings support that MSC can be transplantable between HLA-incompatible individuals.
1,650 citations
TL;DR: It is concluded that stromal precursors are the cells responsible for the transfer of the microenvironmont typical of the given homopoiotic tissue.
Abstract: SUMMARYStromsil precursors ran bo detected in populations of homopoietic cells by their ability to form fibroblast colonies (clones) in monolayer cultures. The stable colony-forming efficiency is reached when the initial density of explanted bone marrow or spleen cells is not less than 104 cells/cm2
1,401 citations
TL;DR: The data suggest that the immunoregulatory properties of MSCs effectively interfere with the autoimmune attack in the course of EAE inducing an in vivo state of T-cell unresponsiveness occurring within secondary lymphoid organs.
1,398 citations