Transplantation of autologous synovial mesenchymal stem cells promotes meniscus regeneration in aged primates

Kondo, Shimpei; Muneta, Takeshi; Nakagawa, Yusuke; Koga, Hideyuki; Watanabe, Toshifumi; Tsuji, Kunikazu; Sotome, Shinichi; Okawa, Atsushi; Kiuchi, Shinji; Onο, Hideo; Mizuno, Mitsuru; Sekiya, Ichiro

doi:10.1002/jor.23211

Cited by 67 publications

(59 citation statements)

References 29 publications

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“…In our current study we used BMP7 due to its availability in our laboratory. We previously examined the dose effect of BMP7 on in vitro cartilage formation of synovial MSCs and 1 μg/ml BMP7 formed the largest cartilage pellets, therefore, 1μg/ml BMP7 was used in this study as well as in other such studies [7, 27, 41, 42]. …”

Section: Discussionmentioning

confidence: 99%

TNFα promotes proliferation of human synovial MSCs while maintaining chondrogenic potential

et al. 2017

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Synovial mesenchymal stem cells (MSCs) are a candidate cell source for cartilage and meniscus regeneration. If we can proliferate synovial MSCs more effectively, we can expand clinical applications to patients with large cartilage and meniscus lesions. TNFα is a pleiotropic cytokine that can affect the growth and differentiation of cells in the body. The purpose of this study was to examine the effect of TNFα on proliferation, chondrogenesis, and other properties of human synovial MSCs. Passage 1 human synovial MSCs from 2 donors were cultured with 2.5 x 10−12~10−7 g/ml, 10 fold dilution series of TNFα for 14 days, then the cell number and colony number was counted. The effect of the optimum dose of TNFα on proliferation was also examined in synovial MSCs from 6 donors. Chondrogenic potential of synovial MSCs pretreated with TNFα was evaluated in 6 donors. The expressions of 12 surface antigens were also examined in 3 donors.2.5 ng/ml and higher concentration of TNFα significantly increased cell number/dish and cell number/colony in both donors. The effect of 25 ng/ml TNFα was confirmed in all 6 donors. There was no significant difference in the weight, or amount of glycosaminoglycan and DNA of the cartilage pellets between the MSCs untreated and MSCs pretreated with 25 ng/ml TNFα. TNFα decreased expression rate of CD 105 and 140b in all 3 donors. TNFα promoted proliferation of synovial MSCs with increase of cell number/ colony. Pretreatment with TNFα did not affect chondrogenesis of synovial MSCs. However, TNFα affected some properties of synovial MSCs.

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Section: Discussionmentioning

confidence: 99%

TNFα promotes proliferation of human synovial MSCs while maintaining chondrogenic potential

et al. 2017

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“…When chondrogenic differentiation was induced with BMP-2, TGF-β and dexamethasone in 3D pellet culture, synovial-derived MSCs consistently produce larger cartilaginous pellets than bone marrow MSCs from the same patients (Shirasawa et al, 2006). Intra-articular injection of SM-MSCs in rat, rabbit, porcine and primate meniscal defect and injury models have shown that SM-MSCs can promote meniscus regeneration and provide protection of medial femoral articular cartilage (Hatsushika et al, 2013, 2014; Ozeki et al, 2015; Kondo et al, 2016). In early clinical trials SM-MSCs have shown promise for treatment of articular cartilage defects, producing hyaline cartilage repair tissue (Sekiya et al, 2015).…”

Section: Tissue Reservoirs Of Mscsmentioning

confidence: 99%

Adipose, Bone Marrow and Synovial Joint-Derived Mesenchymal Stem Cells for Cartilage Repair

et al. 2016

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Current cell-based repair strategies have proven unsuccessful for treating cartilage defects and osteoarthritic lesions, consequently advances in innovative therapeutics are required and mesenchymal stem cell-based (MSC) therapies are an expanding area of investigation. MSCs are capable of differentiating into multiple cell lineages and exerting paracrine effects. Due to their easy isolation, expansion, and low immunogenicity, MSCs are an attractive option for regenerative medicine for joint repair. Recent studies have identified several MSC tissue reservoirs including in adipose tissue, bone marrow, cartilage, periosteum, and muscle. MSCs isolated from these discrete tissue niches exhibit distinct biological activities, and have enhanced regenerative potentials for different tissue types. Each MSC type has advantages and disadvantages for cartilage repair and their use in a clinical setting is a balance between expediency and effectiveness. In this review we explore the challenges associated with cartilage repair and regeneration using MSC-based cell therapies and provide an overview of phenotype, biological activities, and functional properties for each MSC population. This paper also specifically explores the therapeutic potential of each type of MSC, particularly focusing on which cells are capable of producing stratified hyaline-like articular cartilage regeneration. Finally we highlight areas for future investigation. Given that patients present with a variety of problems it is unlikely that cartilage regeneration will be a simple “one size fits all,” but more likely an array of solutions that need to be applied systematically to achieve regeneration of a biomechanically competent repair tissue.

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“…Prior studies have reported promising results in meniscal regeneration utilizing meniscus ECM preparations in allograft [16,20,70], hydrogel [43,44], and soluble [46] forms; MSCs derived from the bone marrow [71–73], synovium [29], and meniscus [23,31]; and evaluation in animal models ranging from subcutaneous implantation [43,45] to intra-articular injections in rats [29,31,72] up to primates [74]; but none have studied the combination of MSCs and meniscus ECM hydrogel at their relevant site of action. We demonstrate the use of decellularized bovine meniscus hydrogel for intra-articular delivery of human mesenchymal stem cells in an orthotopic nude rat model of meniscal injury.…”

Section: Discussionmentioning

confidence: 99%

Stem cell delivery in tissue-specific hydrogel enabled meniscal repair in an orthotopic rat model

et al. 2017

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Interest in non-invasive injectable therapies has rapidly risen due to their excellent safety profile and ease of use in clinical settings. Injectable hydrogels can be derived from the extracellular matrix (ECM) of specific tissues to provide a biomimetic environment for cell delivery and enable seamless regeneration of tissue defects. We investigated the in situ delivery of human mesenchymal stem cells (hMSCs) in decellularized meniscus ECM hydrogel to a meniscal defect in a nude rat model. First, decellularized meniscus ECM hydrogel retained tissue-specific proteoglycans and collagens, and significantly upregulated expression of fibrochondrogenic markers by hMSCs versus collagen hydrogel alone in vitro. The meniscus ECM hydrogel in turn supported delivery of hMSCs for integrative repair of a full-thickness defect model in meniscal explants after in vitro culture and in vivo subcutaneous implantation. When applied to an orthotopic model of meniscal injury in nude rat, hMSCs in meniscus ECM hydrogel were retained out to eight weeks post-injection, contributing to tissue regeneration and protection from joint space narrowing, pathologic mineralization, and osteoarthritis development, as evidenced by macroscopic and microscopic image analysis. Based on these findings, we propose the use of tissue-specific meniscus ECM-derived hydrogel for the delivery of therapeutic hMSCs to treat meniscal injury.

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Transplantation of autologous synovial mesenchymal stem cells promotes meniscus regeneration in aged primates

Cited by 67 publications

References 29 publications

TNFα promotes proliferation of human synovial MSCs while maintaining chondrogenic potential

TNFα promotes proliferation of human synovial MSCs while maintaining chondrogenic potential

Adipose, Bone Marrow and Synovial Joint-Derived Mesenchymal Stem Cells for Cartilage Repair

Stem cell delivery in tissue-specific hydrogel enabled meniscal repair in an orthotopic rat model

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