Bone induction by <i>BMP‐2</i> transduced stem cells derived from human fat

Dragoo, Jason L.; Choi, Joon Young; Lieberman, Jay R.; Huang, Jerry I.; Zuk, Patricia A.; Zhang, Jeffery; Hedrick, Marc H.; Benhaim, Prosper

doi:10.1016/s0736-0266(02)00238-3

Cited by 330 publications

(202 citation statements)

References 23 publications

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“…[16][17][18] Similar to the results in NIH-3T3 and MC3T3-E1 cells, gene transfer of both AdBMP-2 and AdLMP-3 induced bone mineralization in hMSCs, as confirmed by the Von Kossa staining ( Figure 5). …”

Section: Control Adψ5supporting

confidence: 78%

Efficient bone formation by gene transfer of human LIM mineralization protein-3

et al. 2004

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LIM mineralization protein (LMP) is a novel positive regulator of the osteoblast differentiation program. In humans, three different LMP splice variants have been identified: LMP-1, LMP-2, and LMP-3. Gene transfer of human LMP-1 (hLMP-1) induces expression of genes involved in bone formation, including certain bone morphogenetic proteins (BMPs), promotes bone nodule formation in vitro, ectopic bone formation in vivo, and is therapeutic in animal models of posterior thoracic and lumbar spine fusion. To examine the osteoinductive properties of the LMP-3 in vitro and in vivo, we have generated plasmid and adenoviral vectors expressing codon-optimized hLMP-3. Here we demonstrate that gene transfer of hLMP-3 induces expression of the bonespecific genes osteocalcin, osteopontin, and bone sialoprotein and induced bone mineralization in preosteoblastic and fibroblastic cells. We also demonstrate that hLMP-3 is able to induce bone mineralization and the expression of the bonespecific genes, BMP-2, OSX, RunX2, and alkaline phosphatase in human mesenchymal stem cells in a dose-dependent manner. Finally, we demonstrate that direct gene transfer of hLMP-3 into murine skeletal muscle results in ectopic bone formation more efficiently than BMP-2. These results demonstrate that hLMP-3 gene transfer can be used to promote bone formation in cell culture and in vivo as or more efficiently than BMP-2, thus establishing feasibility and efficacy of direct gene delivery of hLMP-3 to produce bone in vivo. These results suggest that gene transfer of hLMP-3 could be developed as a bone-inductive therapeutic agent for clinical applications.

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Section: Control Adψ5supporting

confidence: 78%

Efficient bone formation by gene transfer of human LIM mineralization protein-3

et al. 2004

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“…Human adipose-derived stem cells (hASCs) have been shown to possess multilineage potential to differentiate into bone, cartilage, fat, muscle, endothelial and neural cells (Zuk et al, 2001;De Ugarte et al, 2003;Dudas et al, 2006;Dragoo et al, 2003;Planat-Benard et al, 2004;Choi et al, 2006). We here analyse the differentiation capacity of hASCs cultured in two different osteogenic-inductive media.…”

Section: Introductionmentioning

confidence: 99%

Osteogenic differentiation of human adipose-derived stem cells: comparison of two different inductive media

Girolamo

Sartori

Albisetti

et al. 2007

J Tissue Eng Regen Med

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Human mesenchymal stem cells (MSCs) have the potential to differentiate into cells of connective tissue lineages, including bone, cartilage, fat, muscle and also neurons. In our study we have examined the phenotypic profile of human adipose tissue-derived stem cells (hASCs) and compared different osteogenic-inductive media to assess hASC differentiation. Cells were enzymatically isolated from adipose tissues derived by liposuction from several adult human donors, purified and then expanded in culture. We obtained an abundant yield of hASCs with a constant proliferative trend, a doubling time of about 68 h and a mild variable clonogenic capacity. At passage 4, hASCs expressed MSC-related cell surface antigens (CD13, CD105, CD54, CD90, CD44), and subsequently hASCs were induced to differentiate into the osteogenic lineage for at least 3 weeks of culture in two distinct media, OM1 and OM2, differing in dexamethasone and ascorbic acid concentrations. Osteogenic differentiation of OM1-and OM2-cultured cells was assessed by evaluating cell morphology, osteopontin expression, alkaline phosphatase activity and calcium deposition. OM2 medium showed a higher osteogenic potential than OM1, as assessed by increased levels of calcium deposition, alkaline phospatase activity and osteopontin expression in comparison with OM1-differentiated cells. We conclude that hASCs efficiently differentiate into osteogenic lineage, particularly when cultured in inductive medium supplemented with 10 nM dexamethasone and 150 µM ascorbic acid.

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“…A single supraphysiological dose of BMP does not induce the complex pattern of growth factor and cytokine production required for optimal fracture repair. Ex vivo expansion of mesenchymal stromal cells transduced to express BMPs (8,9) have been shown to promote fracture healing in experimental animal models (10). However, the clinical benefits of these complex and costly strategies are unclear.…”

mentioning

confidence: 99%

TNF-α promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells

Glass

Chan

Freidin³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

340

295

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With an aging population, skeletal fractures are increasing in incidence, including the typical closed and the less common open fractures in normal bone, as well as fragility fractures in patients with osteoporosis. For the older age group, there is an urgent unmet need to induce predictable bone formation as well as improve implant fixation in situations such as hip joint replacement. Using a murine model of slow-healing fractures, we have previously shown that coverage of the fracture with muscle accelerated fracture healing and increased union strength. Here, we show that cells from muscle harvested after 3 d of exposure to an adjacent fracture differentiate into osteoblasts and form bone nodules in vitro. The osteogenic potential of these cells exceeds that of adipose and skinderived stromal cells and is equivalent to bone marrow stromal cells. Supernatants from human fractured tibial bone fragments promote osteogenesis and migration of muscle-derived stromal cells (MDSC) in vitro. The main factor responsible for this is TNF-α, which promotes first MDSC migration, then osteogenic differentiation at low concentrations. However, TNF-α is inhibitory at high concentrations. In our murine model, addition of TNF-α at 1 ng/mL at the fracture site accelerated healing. These data indicate that manipulating the local inflammatory environment to recruit, then differentiate adjacent MDSC, may be a simple yet effective way to enhance bone formation and accelerate fracture repair. Our findings are based on a combination of human specimens and an in vivo murine model and may, therefore, translate to clinical care.

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Bone induction by BMP‐2 transduced stem cells derived from human fat

Cited by 330 publications

References 23 publications

Efficient bone formation by gene transfer of human LIM mineralization protein-3

Efficient bone formation by gene transfer of human LIM mineralization protein-3

Osteogenic differentiation of human adipose-derived stem cells: comparison of two different inductive media

TNF-α promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells

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