Fibroblast Growth Factor-2 Primes Human Mesenchymal Stem Cells for Enhanced Chondrogenesis

Handorf, Andrew M.; Li, Wan‐Ju

doi:10.1371/journal.pone.0022887

Cited by 105 publications

(77 citation statements)

References 38 publications

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“…Many efforts have been made to study the molecular signals involved in FGF-2 induced proliferation of chondrocytes [43][44][45], with the hope of preventing the formation of fibrous cartilage tissue caused by FGF-2 treatment [ 46,47]. Our data uncover a positive role of FGF-1 in proliferation of hPCs, at least in co-culture with MSCs.…”

Section: Discussionmentioning

confidence: 66%

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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Section: Discussionmentioning

confidence: 66%

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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“…[ 43,44 ] On the other hand, FGF-2 can be used to maintain hBM-MSCs in PEG gels in a nonosteogenic differentiated state. Moreover, while it has been shown that FGF-2 not only suppresses dedifferentiation of hBM-MSCs but also enhances their chondrogenic potential [45][46][47][48] in Figure 3 c that 14 d after culture in FGF-2 hBM-MSCs can still be adipogenically and osteogenically differentiated indicating the maintenance of their multipotency.…”

Section: D Msc Monocultures Can Be Osteogenically Differentiated In mentioning

confidence: 88%

Dual Role of Mesenchymal Stem Cells Allows for Microvascularized Bone Tissue‐Like Environments in PEG Hydrogels

Blache

Metzger

Vallmajó-Martín

et al. 2015

Adv Healthcare Materials

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In vitro engineered tissues which recapitulate functional and morphological properties of bone marrow and bone tissue will be desirable to study bone regeneration under fully controlled conditions. Among the key players in the initial phase of bone regeneration are mesenchymal stem cells (MSCs) and endothelial cells (ECs) that are in close contact in many tissues. Additionally, the generation of tissue constructs for in vivo transplantations has included the use of ECs since insufficient vascularization is one of the bottlenecks in (bone) tissue engineering. Here, 3D cocultures of human bone marrow derived MSCs (hBM-MSCs) and human umbilical vein endothelial cells (HUVECs) in synthetic biomimetic poly(ethylene glycol) (PEG)-based matrices are directed toward vascularized bone mimicking tissue constructs. In this environment, bone morphogenetic protein-2 (BMP-2) or fibroblast growth factor-2 (FGF-2) promotes the formation of vascular networks. However, while osteogenic differentiation is achieved with BMP-2, the treatment with FGF-2 suppressed osteogenic differentiation. Thus, this study shows that cocultures of hBM-MSCs and HUVECs in biological inert PEG matrices can be directed toward bone and bone marrow-like 3D tissue constructs.

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“…A recent study demonstrated that FGF7 promotes preadipocyte proliferation [32]. In addition, FGF2 also induces cell growth and chondrogenic and osteoblast differentiation in bone marrow-derived mesenchymal cells [33,34]. However, the role of FGFs in adipogenic differentiation of hMSCs, especially FGF7 and FGF14, remains elusive.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of human bone marrow-derived mesenchymal stem cells during adipogenesis

Yan

et al. 2015

Folia Histochem Cytobiol.

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Introduction. Adipogenesis comprises multiple processes by which mesenchymal stem cells differentiate into adipocytes. To increase our knowledge of the mechanism underlying adipogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs), we performed full-genome gene expression microarray and gene ontology analyses of induced differentiation of hMSCs. Material and methods. Adipogenic differentiation of hMSCs was induced by an adipogenic medium, and total RNA was extracted from undifferentiated hMSCs (day 0) and differentiated adipocytes (day 14). Then microarray hybridization of RNA samples was performed. The GeneChip Operating Software was used to analyze the hybridization data to identify differentially expressed genes, which were performed Gene Ontology categorization and pathway analysis. Pathway-act-network and genes-act-network were built according to the Kyoto Encyclopedia of Genes and Genomes database. Some differentially expressed genes were subjected to qRT-PCR to verify the microarray data. Results. We detected a total of 3,821 differentially expressed genes, of which 753 were upregulated and 3,068 downregulated. These genes were well represented in a variety of functional categories, including collagen fibril organization, brown fat cell differentiation, cell division, and S phase of mitotic cell cycle. Subsequently, pathway analysis was conducted, and significant pathways (from top 50) were selected for pathway-act-network analysis, which indicated that the mitogen-activated protein kinase (MAPK) pathway and cell cycle were of high degrees (> 10). Gene-act-network analysis showed that insulin-like growth factor 1 receptor (IGF1R), histone deacetylase 1 (HDAC1), HDAC2, MAPK13, MAPK8, phosphoinositide-3-kinase regulatory subunit 1 (PI3KR1), and PI3KR2 also had high degrees (> 18). Conclusions. Collectively, these data provide novel information and could serve as a basis for future study to clarify the mechanisms underlying adipocyte differentiation of hMSCs.

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Fibroblast Growth Factor-2 Primes Human Mesenchymal Stem Cells for Enhanced Chondrogenesis

Cited by 105 publications

References 38 publications

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

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

Dual Role of Mesenchymal Stem Cells Allows for Microvascularized Bone Tissue‐Like Environments in PEG Hydrogels

Gene expression profiling of human bone marrow-derived mesenchymal stem cells during adipogenesis

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