RESUMO
The elements of peripheral nerve regeneration comprise a complex combination of nerve growth, muscle satellite cells proliferation and differentiation and vessel growth. There is also increasing evidence that growth factors may act at multiple levels in the regenerative response. One such factor affecting multiple cell processes is insulin-like growth factor (IGF-1). As a neurotrophic factor IGF-1 is known to promote nerve elongation and branching. As a myogenic factor, IGF-1 promotes satellite cell proliferation, differentiation and muscle hypertrophy. As an angiogenic factor, IGF-1 is known to promote angiogenesis in regenerating skeletal muscle by activating VEGF and VEGF receptors. Additionally, recent studies show that IGF-1 may also promote the activation of muscle stem cells during the regenerative process. This review will outline the pathways by which IGF-1 affects multiple layers of the regenerative response and how these pathways converge to promote the regeneration of nerves.
Assuntos
Fator de Crescimento Insulin-Like I/fisiologia , Regeneração Nervosa/fisiologia , Traumatismos dos Nervos Periféricos , Nervos Periféricos/fisiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Nervos Periféricos/efeitos dos fármacosRESUMO
Angiogenesis, the formation of neovessels from the endothelium of preexisting vessels, is stimulated by soluble angiogenic factors. Insulin-like growth factor I (IGF-I) stimulates myogenesis and induces nerve regeneration after injury, and it has been shown to stimulate angiogenesis. However, the in vivo angiogenic effects of IGF-I in regenerating and diabetic muscle have yet to be described. Therefore, we studied the effects of human IGF-I (hIGF-I) delivered by a plasmid-mediated therapy on angiogenesis in mouse models of these two conditions. Plasmid hIGF-I was delivered to the injured tibialis muscle by direct intramuscular injection followed by electroporation. Initial experiments compared two muscle-specific hIGF-I-expressing constructs containing either a skeletal actin 3'UTR (pAV2001) or a human growth hormone (GH) 3'UTR (pAV2002). Skeletal actin 3'UTR mediates sequestration of hIGF-I in the muscle and was more active, while the GH 3'UTR mediated release of IGF-I into the circulation. Treatment of regenerating muscle with pAV2001 and sequestration of IGF-I in muscle led to increased expression of vascular endothelial growth factor (VEGF) and VEGF receptors fetal liver kinase-1 and FmS-like tyrosine kinase receptor-1, as well as platelet endothelial cell adhesion molecule-1, on endothelial cells. These results indicate that IGF-I can amplify angiogenic responses in regenerating muscle. In a mouse diabetic model, plasmid-mediated IGF-I therapy reversed diabetic microangiopathy, as shown by increased angiogenesis and arterial flow as analyzed by Doppler imaging. These studies show that plasmid IGF-I delivery and sequestration in muscle can augment angiogenesis in regenerating muscle and increase blood flow and angiogenesis in the diabetic limb.
Assuntos
Angiopatias Diabéticas/terapia , Terapia Genética , Fator de Crescimento Insulin-Like I/genética , Neovascularização Fisiológica , Plasmídeos , Regiões 3' não Traduzidas/genética , Actinas/biossíntese , Actinas/genética , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Experimental/terapia , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/patologia , Feminino , Técnicas de Transferência de Genes , Vetores Genéticos , Hormônio do Crescimento/biossíntese , Hormônio do Crescimento/genética , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Isquemia/etiologia , Isquemia/patologia , Isquemia/terapia , Camundongos , Camundongos Endogâmicos ICR , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/patologia , Plasmídeos/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Currently, there is no known medical treatment that hastens the repair of damaged nerve and muscle. Using IGF-1 transgenic mice that specifically express human recombinant IGF-1 in skeletal muscle, we test the hypotheses that targeted gene expression of IGF-1 in skeletal muscle enhances motor nerve regeneration after a nerve crush injury. The IGF-1 transgene affects the initiation of the muscle repair process after nerve injury as shown by increased activation of SCA-1positive myogenic stem cells. Increased satellite cell differentiation and proliferation are observed in IGF-1 transgenic mice, shown by increased expression of Cyclin D1, MyoD, and myogenin. Expression of myogenin and nicotinic acetylcholine receptor subunits, initially increased in both wild-type and IGF-1 transgenic mice, are restored to normal levels at a faster rate in IGF-1 transgenic mice, which indicates a rescue of nerve-evoked muscle activity. Expression of the IGF-1 transgene in skeletal muscle results in accelerated recovery of saltatory nerve conduction, increased innervation as detected by neurofilament expression, and faster recovery of muscle mass. These studies demonstrate that local expression of IGF-1 augments the repair of injured nerve and muscle.
