Adenoviral VEGF‐A gene transfer induces angiogenesis and promotes bone formation in healing osseous tissues

Tarkka, Tatu; Sipola, Annina; Jämsä, Timo; Soini, Ylermi; Ylä‐Herttuala, Seppo; Tuukkanen, Juha; Hautala, Timo

doi:10.1002/jgm.392

Cited by 127 publications

(97 citation statements)

References 41 publications

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“…1,2 Efforts to enhance fracture neovascularization by supplementing with recognized proangiogenic cytokines have yielded promising results. [3][4][5][6]39 However, the resident population of endothelial cells that is responsive to available levels of angiogenic growth factors may potentially limit the extent to which supplementation enhances tissue neovascularization. Situations which classically exhibit compromised endothelial function and angiogenesis are well recognized in contributing to the significant complications of delayed fracture healing and atrophic non-union.…”

Section: Introductionmentioning

confidence: 99%

Mobilization of endothelial precursor cells: Systemic vascular response to musculoskeletal trauma

Laing

Dillon

Condon

et al. 2006

Journal Orthopaedic Research

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Postnatal vasculogenesis, the process by which vascular committed bone marrow stem cells or endothelial precursor cells (EPC) migrate, differentiate, and incorporate into the nacent endothelium contributing to physiological and pathological neovascularization, has stimulated much interest. Its contribution to tumor nonvascularization, wound healing, and revascularization associated with skeletal and cardiac muscles ischaemia is established. We evaluated the mobilization of EPCs in response to musculoskeletal trauma. Blood from patients (n ¼ 15) following AO type 42a1 closed diaphyseal tibial fractures was analyzed for CD34 and AC133 cell surface marker expression. Immunomagnetically enriched CD34þ mononuclear cell (MNC CD34þ ) populations were cultured and examined for phenotypic and functional vascular endothelial differentiation. Circulating MNC CD34þ levels increased sevenfold by day 3 postinjury. Circulating MNC AC133þ increased 2.5-fold. Enriched MNC CD34þ populations from day 3 samples in culture exhibited cell cluster formation with sprouting spindles. These cells bound UEA-1 and incorporated fluorescent DiI-Ac-LDL intracellularily. Our findings suggest a systemic provascular response is initiated in response to musculoskeletal trauma. Its therapeutic manipulation may have implications for the potential enhancement of fracture healing. ß

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Section: Introductionmentioning

confidence: 99%

Mobilization of endothelial precursor cells: Systemic vascular response to musculoskeletal trauma

Laing

Dillon

Condon

et al. 2006

Journal Orthopaedic Research

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“…The function of cellular localization also plays an important role for the transfer of bone marrow cells to fracture callus (Devine et al, 2002). In vivo experiments demonstrated that the pluripotent bone marrow cells containing many fracture repair cellular elements need to be transferred to the fracture callus (Devine et al, 2002;Tarkka et al, 2003). In the plate fixation group, most of the enriched functions were similar to those of the nail fixation group.…”

Section: Discussionmentioning

confidence: 99%

Analysis of gene expression profiles in healing rat fractures treated with nail and plate fixation

Wang¹,

Li²,

Liu³

2014

Genet. Mol. Res.

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ABSTRACT.To compare fracture healing therapies, the gene expression profiles of rat fracture samples treated with nail and plate fixation were analyzed at 1 day, 3 days, 1 week, 2 weeks, 4 weeks, and 6 weeks after surgery. The gene expression profiles GSE1685, which include 19 samples, were downloaded from the Gene Expression Omnibus database. After preprocessing, the gene expression profiles were subjected to time series analysis using the Short Time-series Expression Miner software, and the significantly differentially expressed gene (DEG) sets were selected. Further, the distributions of those DEG sets on the corresponding chromosomes were identified using the functional classification tool. Finally, the DEGs were subjected to function and pathway enrichment analysis. DEG analysis indicated that the number of DEGs (854 genes) from nail fixation was significantly lower than that of DEGs (1029 genes) from plate fixation. The DEGs were mainly enriched in cell proliferation, cellular localization, and response to wounding functions. Several critical DEGs expressed during the fracture healing process were screened, and 2 common pathways were enriched for the DEGs in the nail fixation and plate fixation. These Gene expression profile comparisonDEGs and pathways may be potential targets or predictive markers during fracture healing.

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“…Extrinsic or host-driven vascularization can be stimulated through local administration of VEGF (Takeshita et al, 1994). As it is the main angiogenic growth factor in fracture healing, VEGF has been shown to enhance bone regeneration (Street et al, 2002;Tarkka et al, 2003). However, safety concerns exist over the use of high-dosed VEGF (Lee et al, 2000;Maes et al, 2010;Vajanto et al, 2002), which may lead to fibrosis and abnormal blood vessel formation and function.…”

Section: Reducing Hypoxia Through Extrinsic Angiogenesismentioning

confidence: 99%

Targeting the hypoxic response in bone tissue engineering: A balance between supply and consumption to improve bone regeneration

Stiers

Gastel

Carmeliet

2016

Molecular and Cellular Endocrinology

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a b s t r a c tBone tissue engineering is a promising therapeutic alternative for bone grafting of large skeletal defects. It generally comprises an ex vivo engineered combination of a carrier structure, stem/progenitor cells and growth factors. However, the success of these regenerative implants largely depends on how well implanted cells will adapt to the hostile and hypoxic host environment they encounter after implantation. In this review, we will discuss how hypoxia signalling may be used to improve bone regeneration in a tissue-engineered construct. First, hypoxia signalling induces angiogenesis which increases the survival of the implanted cells as well as stimulates bone formation. Second, hypoxia signalling has also angiogenesis-independent effects on mesenchymal cells in vitro, offering exciting new possibilities to improve tissue-engineered bone regeneration in vivo. In addition, studies in other fields have shown that benefits of modulating hypoxia signalling include enhanced cell survival, proliferation and differentiation, culminating in a more potent regenerative implant. Finally, the stimulation of endochondral bone formation as a physiological pathway to circumvent the harmful effects of hypoxia will be briefly touched upon. Thus, angiogenic dependent and independent processes may counteract the deleterious hypoxic effects and we will discuss several therapeutic strategies that may be combined to withstand the hypoxia upon implantation and improve bone regeneration.

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Adenoviral VEGF‐A gene transfer induces angiogenesis and promotes bone formation in healing osseous tissues

Abstract: Our data confirm the important role of VEGF in bone healing. We show for the first time that adenoviral VEGF-A gene transfer may modify bone defect healing in a rodent model.

Cited by 127 publications

References 41 publications

Mobilization of endothelial precursor cells: Systemic vascular response to musculoskeletal trauma

Mobilization of endothelial precursor cells: Systemic vascular response to musculoskeletal trauma

Analysis of gene expression profiles in healing rat fractures treated with nail and plate fixation

Targeting the hypoxic response in bone tissue engineering: A balance between supply and consumption to improve bone regeneration

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