Lessons from musculoskeletal stem cell research: The key to successful regenerative medicine development

McGonagle, Dennis; Bari, Cosimo De; Arnold, Peter; Jones, Elena

doi:10.1002/art.22440

Cited by 11 publications

(6 citation statements)

References 93 publications

(89 reference statements)

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“…It is currently envisaged that the limited number of joint repair procedures that utilize stem cells or autologous chondrocytes will greatly expand in the coming years with developments in regenerative medicine (McGonagle et al. 2007a).…”

Section: Synovial‐derived Osteoarthritismentioning

confidence: 99%

The anatomical basis for a novel classification of osteoarthritis and allied disorders

et al. 2010

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Osteoarthritis (OA) has historically been classified as 'primary' where no discernible cause was evident and 'secondary' where a triggering factor was apparent. Irrespective of the triggering events, late-stage OA is usually characterized by articular cartilage attrition and consequently the anatomical basis for disease has been viewed in terms of cartilage. However, the widespread application of magnetic resonance imaging in early OA has confirmed several different anatomical abnormalities within diseased joints. A key observation has been that several types of primary or idiopathic OA show ligament-related pathology at the time of clinical presentation, so these categories of disease are no longer idiopathic -at least from the anatomical perspective. There is also ample evidence for OA initiation in other structures including menisci and bones in addition to articular cartilage. Therefore, a new classification for OA is proposed, which is based on the anatomical sites of earliest discernible joint structural involvement. The major proposed subgroups within this classification are ligament-, cartilage-, bone-, meniscal-and synovial-related, in addition to disease that is mixed pattern or multifocal in origin. We show how such a structural classification for OA provides a useful reference framework for staging the magnitude of disease. For late-stage or end-stage ⁄ whole organ disease, the final common pathway of these different scenarios, joint replacement strategies are likely to remain the only viable option. However, for younger subjects in particular, near the time of clinical disease onset, this scheme has implications for therapy targeted to specific anatomical locations. Thus, in the same way that tumours can be classified and staged according to their tissue of origin and extent of involvement, OA can likewise be anatomically classified and staged. This has implications for therapeutic strategies including regenerative medicine therapy development.

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Section: Synovial‐derived Osteoarthritismentioning

confidence: 99%

The anatomical basis for a novel classification of osteoarthritis and allied disorders

et al. 2010

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“…Because of the limitation of autologous chondrocyte transplantation, cartilage tissue engineering currently explores the potential use of adult stem cells present in different tissues [1] as an alternative source of chondrocytes. Mesenchymal stem cells (MSCs) have the ability to differentiate in vitro after extensive expansion in monolayer culture [2] into a variety of adult tissues such as bone, fat, muscle and cartilage. The chondrogenic potential of stem cells from various tissues (umbilical cord blood, adipose tissue, synovial membranes, periosteum and muscle) has been investigated [1] and it appears that the most common and studied sources are bone marrow (BM) and adipose tissue (AT) for historical and easy access reasons.…”

Section: Introductionmentioning

confidence: 99%

Chondrogenic potential of bone marrow- and adipose tissue-derived adult human mesenchymal stem cells

Ronzière¹,

Perrier²,

Malléin-Gerin³

et al. 2010

Bio-Medical Materials and Engineering

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Regarding cartilage repair, tissue engineering is currently focusing on the use of adult mesenchymal stem cells (MSC) as an alternative to autologous chondrocytes. The potential of stem cells from various tissues to differentiate towards the chondrogenic phenotype has been investigated and it appears that the most common and studied sources are bone marrow (BM) and adipose tissue (AT) for historical and easy access reasons. In addition to three dimensional environment, the presence of member(s) of the transforming growth factor (TGF-β family and low oxygen tension have been reported to promote the in vitro differentiation of MSCs. Our work aimed at characterizing and comparing the degree of chondrogenic differentiation of MSCs isolated from BM and AT cultured in the same conditions. We also further aimed at and at determining whether hypoxia (2% oxygen) could affect the chondrogenic potential of AT-MSCs. Cells were first expanded in the presence of FGF-2, then harvested and centrifuged to allow formation of cell pellets, which were cultured in the presence of TGF-β3 and/or Bone Morphogenetic Protein-2 (BMP-2) and with 2 or 20% oxygen tension, for 24 days. Markers of the chondrocyte (COL2A1, AGC1, Sox9) and hypertrophic chondrocyte (COL10A1, MMP-13) were monitored by real-time PCR and/or by immunohistological staining. Our data show that BMP-2/TGF-β3 combination is the best culture condition to induce the chondrocyte phenotype in pellet cultures of BM and AT-MSCs. Particularly, a switch in the expression of the pre-chondrogenic type IIA form to the cartilagespecific type IIB form of COL2A1 was observed. A parallel increase in gene expression of COL10A1 and MMP-13 was also recorded. However when AT-MSCs were cultured in hypoxia, the expression of markers of hypertrophic chondrocytes decreased when BMP-2/TGF-β3 were present in the medium. Thus it seems that hypoxia participates to the control of AT-MSCs chondrogenesis. Altogether, these cellular model systems will help us to investigate further the potential of different adult stem cells for cartilage engineering.

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“…Besides immuno-suppressive effects, intra-articularly injected MSCs were also reported to inhibit thickening of the synovium and to protect against cartilage destruction in a mouse OA model [8]. However, with the cellular interactions between MSCs and native chondrocytes receiving less attention [9], the molecular mechanism of interactions between MSCs and native chondrocytes is poorly understood [10]. In order to maximize the benefits of stem cell therapy, these cellular interactions need to be clarified.…”

mentioning

confidence: 99%

Fibroblast Growth Factor-1 Is a Mesenchymal Stromal Cell-Secreted Factor Stimulating Proliferation of Osteoarthritic Chondrocytes in Co-Culture

Leijten

Blitterswijk

et al. 2013

Stem Cells and Development

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Previously, we showed that mesenchymal stromal cells (MSCs) in co-culture with primary chondrocytes secrete soluble factors that increase chondrocyte proliferation. The objective of this study is to identify these factors. Human primary chondrocytes (hPCs) isolated from late-stage osteoarthritis patients were co-cultured with human bone marrow-derived MSCs (hMSCs) in pellets. Genome-wide mRNA expression analysis and quantitative polymerase chain reactions (qPCR) were used to identify soluble factors that were specifically induced in co-cultures. Immunofluorescent staining combined with cell tracking and enzyme-linked immunosorbent assay (ELISA) were performed to validate up-regulation at the protein level and to identify the cellular origin of the increased proteins. Chemical blockers and neutralizing antibodies were used to elucidate the role of the identified candidate genes in co-cultures. A number of candidate factors were differentially regulated in co-cultures at the mRNA level. Of these, fibroblast growth factor-1 (FGF-1) mRNA and protein expression were markedly increased in co-cultures predominantly due to up-regulated expression in MSCs. Blocking of FGF signaling in co-culture pellets by specific FGF receptor inhibitors or FGF-1 neutralizing antibodies completely blocked hPCs proliferation. We demonstrate that MSCs increase FGF-1 secretion on co-culture with hPCs, which, in turn, is responsible for increased hPCs proliferation in pellet co-cultures. C artilage repair is among the key targets of regenerative medicine. Several stem cell-based therapies have been proposed to treat cartilage defects, rheumatic arthritis, osteoarthiris (OA), and other joint diseases. These therapeutic strategies include implantation or injection of mesenchymal stromal cells (MSCs) in the diseased joint or bone marrow stimulation techniques such as micro fracture. These procedures rely on cellular interactions between MSCs and native cells in the joint [1][2][3][4]. Recent studies showed that intra-articularly injected MSCs can reduce incidence and severity of arthritis in animal model by inducing immune tolerance [5]. Further investigations showed that MSCs are capable of inducing hyporesponsiveness of T-lymphocytes and of expressing antiinflammatory mediators in macrophages [6,7]. Besides immuno-suppressive effects, intra-articularly injected MSCs were also reported to inhibit thickening of the synovium and to protect against cartilage destruction in a mouse OA model [8]. However, with the cellular interactions between MSCs and native chondrocytes receiving less attention [9], the molecular mechanism of interactions between MSCs and native chondrocytes is poorly understood [10]. In order to maximize the benefits of stem cell therapy, these cellular interactions need to be clarified.Previous reports showed that cartilage matrix formation was increased in co-cultures of human primary chondrocytes (hPCs) with MSCs compared with monocultures [11,12]. Further investigations revealed that the inductive effects of MSCs on cartila...

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Lessons from musculoskeletal stem cell research: The key to successful regenerative medicine development

Cited by 11 publications

References 93 publications

The anatomical basis for a novel classification of osteoarthritis and allied disorders

The anatomical basis for a novel classification of osteoarthritis and allied disorders

Chondrogenic potential of bone marrow- and adipose tissue-derived adult human mesenchymal stem cells

Fibroblast Growth Factor-1 Is a Mesenchymal Stromal Cell-Secreted Factor Stimulating Proliferation of Osteoarthritic Chondrocytes in Co-Culture

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