Hollow conduits of natural or synthetic origins have shown acceptable regeneration results in short nerve gap repair;however,results are still not comparable with the current gold standard technique“autografts”.Holl...Hollow conduits of natural or synthetic origins have shown acceptable regeneration results in short nerve gap repair;however,results are still not comparable with the current gold standard technique“autografts”.Hollow conduits do not provide a successful regeneration outcome when it comes to critical nerve gap repair.Enriching the lumen of conduits with different extracellular materials and cells could provide a better biomimicry of the natural nerve regenerating environment and is expected to ameliorate the conduit performance.In this study,we evaluated nerve regeneration in vivo using hollow chitosan conduits or conduits enriched with fibrin-collagen hydrogels alone or with the further addition of adipose-derived mesenchymal stem cells in a 15 mm rat sciatic nerve transection model.Unexpected changes in the hydrogel consistency and structural stability in vivo led to a failure of nerve regeneration after 15 weeks.Nevertheless,the molecular assessment in the early regeneration phase(7,14,and 28 days)has shown an upregulation of useful regenerative genes in hydrogel enriched conduits compared with the hollow ones.Hydrogels composed of fibrin-collagen were able to upregulate the expression of soluble NRG1,a growth factor that plays an important role in Schwann cell transdifferentiation.The further enrichment with adipose-derived mesenchymal stem cells has led to the upregulation of other important genes such as ErbB2,VEGF-A,BDNF,c-Jun,and ATF3.展开更多
Neurotrophins play a major role in the regulation of neuronal growth such as neurite sprouting or regeneration in response to nerve injuries. The role of nerve growth factor, neurotrophin-3, and brain-derived neurotro...Neurotrophins play a major role in the regulation of neuronal growth such as neurite sprouting or regeneration in response to nerve injuries. The role of nerve growth factor, neurotrophin-3, and brain-derived neurotrophic factor in maintaining the survival of peripheral neurons remains poorly understood. In regenerative medicine, different modalities have been investigated for the delivery of growth factors to the injured neurons, in search of a suitable system for clinical applications. This study was to investigate the influence of nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor on the growth of neurites using two in vitro models of dorsal root ganglia explants and dorsal root ganglia-derived primary cell dissociated cultures. Quantitative data showed that the total neurite length and tortuosity were differently influenced by trophic factors. Nerve growth factor and, indirectly, brain-derived neurotrophic factor stimulate the tortuous growth of sensory fibers and the formation of cell clusters. Neurotrophin-3, however, enhances neurite growth in terms of length and linearity allowing for a more organized and directed axonal elongation towards a peripheral target compared to the other growth factors. These findings could be of considerable importance for any clinical application of neurotrophic factors in peripheral nerve regeneration. Ethical approval was obtained from the Regione Piemonte Animal Ethics Committee ASLTO1(file # 864/2016-PR) on September 14, 2016.展开更多
Spinal muscular atrophy(SMA)is a hereditary pediatric motor neuron(MN)disease:survival motor neuron 1(SMN1)gene mutation determines MN degeneration and,consequently,muscle atrophy,breathing and swallowing difficulties...Spinal muscular atrophy(SMA)is a hereditary pediatric motor neuron(MN)disease:survival motor neuron 1(SMN1)gene mutation determines MN degeneration and,consequently,muscle atrophy,breathing and swallowing difficulties,and,in the most severe cases,premature death.A second unaffected gene(SMN2)is present,but it can only produce a limited amount of functional protein,modulating the disease severity and progression.SMN,ubiquitously expressed,is mainly展开更多
Nerve regeneration after delayed nerve repair is often unsuccessful. Indeed, the expression of genes associated with regeneration, including neurotrophic and gliotrophic factors, is drastically reduced in the distal s...Nerve regeneration after delayed nerve repair is often unsuccessful. Indeed, the expression of genes associated with regeneration, including neurotrophic and gliotrophic factors, is drastically reduced in the distal stump of chronically transected nerves; moreover, Schwann cells undergo atrophy, losing their ability to sustain regeneration. In the present study, to provide a three-dimensional environment and trophic factors supporting Schwann cell activity and axon re-growth, we combined the use of an effective conduit(a chitosan tube) with a promising intraluminal structure(fresh longitudinal skeletal muscle fibers). This enriched conduit was used to repair a 10-mm rat median nerve gap after 3-month delay and functional and morphometrical analyses were performed 4 months after nerve reconstruction. Our data show that the enriched chitosan conduit is as effective as the hollow chitosan conduit in promoting nerve regeneration,and its efficacy is not statistically different from the autograft, considered the "gold standard" technique for nerve reconstruction. Since hollow tubes not always lead to good results after long defects(> 20 mm), we believe that the conduit enriched with fresh muscle fibers could be a promising strategy to repair longer gaps, as muscle fibers create a favorable three-dimensional environment and release trophic factors. All procedures were approved by the Bioethical Committee of the University of Torino and by the Italian Ministry of Health(approval number: 864/2016/PR) on September 14, 2016.展开更多
Brain plasticity is heterogeneous in mammals:Brain regeneration and repair are the dream of every neurobiologist as well as every common citizen in the world who knows that most neurological diseases,dementia and othe...Brain plasticity is heterogeneous in mammals:Brain regeneration and repair are the dream of every neurobiologist as well as every common citizen in the world who knows that most neurological diseases,dementia and other age-related problems affecting the central nervous system(CNS)do represent a heavy health and social burden.Efficacious re-展开更多
Alzheimer’s disease(AD)is a progressive neurodegenerative condition that goes f rom mild cogni t ive impai rment in prodromal disease to severely disabling deficits in advanced stages.The risk for AD development,as w...Alzheimer’s disease(AD)is a progressive neurodegenerative condition that goes f rom mild cogni t ive impai rment in prodromal disease to severely disabling deficits in advanced stages.The risk for AD development,as well as progression and severity,clearly differ between men and women(Pike,2017).Epidemiological studies have shown that there is a significantly increased prevalence in the development of AD in women compared to men,which is usually explained by the longer lifespan of women.This increased frequency may be due to the interplay between age and sex,in which genetic factors together with hormonal and metabolic patterns play a crucial role.Moreover,cognitive impairment has been confirmed to be greater in women than in men at the same stage of AD,likely due to reduced estrogen levels in postmenopausal women(Laws et al.,2016).展开更多
Peripheral nerves form a complex network connecting the central nervous system and the body.Injuries to peripheral nerves often lead to partial or complete loss of motor,sensory and autonomic functions,thus interferin...Peripheral nerves form a complex network connecting the central nervous system and the body.Injuries to peripheral nerves often lead to partial or complete loss of motor,sensory and autonomic functions,thus interfering with many aspects of an individual’s life.Despite the spontaneous ability of the peripheral nerve to regenerate,the technical surgical progresses and the significant advances in basic science,the study of展开更多
Schwann cells(SCs)and peripheral nerve regeneration:SCs are the principal glial cells of the peripheral nervous system(PNS).In a healthy nerve,myelinating SCs wrap around larger caliber motor and sensory axons to form...Schwann cells(SCs)and peripheral nerve regeneration:SCs are the principal glial cells of the peripheral nervous system(PNS).In a healthy nerve,myelinating SCs wrap around larger caliber motor and sensory axons to form the myelin sheath,whereas non-myelinating SCs envelop and support multiple small diameter sensory axons to form Remak bundles.Moreover,they form a basal lamina which surround each SC-axon unit(Hall,2005).When a peripheral nerve injury occurs,extensive changes展开更多
Brain regeneration from an evolutionary perspective:Brain regeneration(the full restoration of tissue after loss from injury or disease)is the most sought after goal for researchers working in developmental neurobiolo...Brain regeneration from an evolutionary perspective:Brain regeneration(the full restoration of tissue after loss from injury or disease)is the most sought after goal for researchers working in developmental neurobiology.It also appears to be the most challenging to achieve when considering the mammalian brain.Whereas remarkable regenerative capacities can be present in the central nervous systems of many non-mammalian vertebrates(e.g.,fish,amphibians),these kinds of processes appear to be dramatically reduced in mammals(Bonfanti,2011).展开更多
The amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder primarily involving motoneurons in the cerebral cortex, brainstem, and spinal cord. SOD1-G93A mice, which express multiple ...The amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder primarily involving motoneurons in the cerebral cortex, brainstem, and spinal cord. SOD1-G93A mice, which express multiple copies of the mutant form of the human Cu/Zn SOD, are one of the most widely used animal models for ALS pathology. However, the onset of the disease can vary between animals of 1-2 weeks while the progression is quite fast. In order to evaluate the efficacy of any treatment, it is very important to treat all animals at the early onset of the disease, instead of at a fixed age-point. To this aim, we performed behavioral analysis and measured hSOD1 mRNA expression to identify the appearance of the first motor deficits. Rotarod and PaGE tests revealed to be the most sensitive approaches to detect the beginning of the symptomatic phase of the disease, while neurological score and weight monitoring showed significant differences only at later stages in ALS pathology. Furthermore, we found a better correlation between hSOD1 mRNA expression with disease onset than with a transgene copy number. Therefore, the association of behavioral tests and molecular analysis represents a sensible and accurate tool to early detect the murine symptoms.展开更多
Brain plasticity-A universal tool with many variations:The study of brain plasticity has been gaining interest since almost a century and has now reached a huge amount of information(>80,000 results in PubMed).Over...Brain plasticity-A universal tool with many variations:The study of brain plasticity has been gaining interest since almost a century and has now reached a huge amount of information(>80,000 results in PubMed).Overall,different types of plasticity,including stem cell-driven genesis of new neurons(adult neurogenesis),cells in arrested maturation(dormant neurons),neuro-glial and synaptic plasticity,can coexist and contribute to grant plastic changes in the brain,from a cellular to system level(Benedetti and Couillard-Despres,2022;Bonfanti et al.,2023).展开更多
基金funded by the Spanish “Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Ministerio de Economía y Competitividad (Instituto de Salud Carlos Ⅲ),grants Nos. FIS PI14-1343, FIS PI17-0393, and FIS PI20-0318 co-financed by the “Fondo Europeo de Desarrollo Regional ERDF-FEDER European Union”grant No. P18-RT-5059 by “Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020),Consejería de Transformación Económica, Industria, Conocimiento y Universidades, Junta de Andalucía, España”grant No. A-CTS-498-UGR18 by “Programa Operativo FEDER Andalucía 2014–2020, Universidad de Granada, Junta de Andalucía, España”, co-funded by ERDF-FEDER, the European Union (all to VC)
文摘Hollow conduits of natural or synthetic origins have shown acceptable regeneration results in short nerve gap repair;however,results are still not comparable with the current gold standard technique“autografts”.Hollow conduits do not provide a successful regeneration outcome when it comes to critical nerve gap repair.Enriching the lumen of conduits with different extracellular materials and cells could provide a better biomimicry of the natural nerve regenerating environment and is expected to ameliorate the conduit performance.In this study,we evaluated nerve regeneration in vivo using hollow chitosan conduits or conduits enriched with fibrin-collagen hydrogels alone or with the further addition of adipose-derived mesenchymal stem cells in a 15 mm rat sciatic nerve transection model.Unexpected changes in the hydrogel consistency and structural stability in vivo led to a failure of nerve regeneration after 15 weeks.Nevertheless,the molecular assessment in the early regeneration phase(7,14,and 28 days)has shown an upregulation of useful regenerative genes in hydrogel enriched conduits compared with the hollow ones.Hydrogels composed of fibrin-collagen were able to upregulate the expression of soluble NRG1,a growth factor that plays an important role in Schwann cell transdifferentiation.The further enrichment with adipose-derived mesenchymal stem cells has led to the upregulation of other important genes such as ErbB2,VEGF-A,BDNF,c-Jun,and ATF3.
基金supported by the research start-up and the MWU’s intramural grant(to MF)the Italian MURST-MIUR foundation(to SG and IP)
文摘Neurotrophins play a major role in the regulation of neuronal growth such as neurite sprouting or regeneration in response to nerve injuries. The role of nerve growth factor, neurotrophin-3, and brain-derived neurotrophic factor in maintaining the survival of peripheral neurons remains poorly understood. In regenerative medicine, different modalities have been investigated for the delivery of growth factors to the injured neurons, in search of a suitable system for clinical applications. This study was to investigate the influence of nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor on the growth of neurites using two in vitro models of dorsal root ganglia explants and dorsal root ganglia-derived primary cell dissociated cultures. Quantitative data showed that the total neurite length and tortuosity were differently influenced by trophic factors. Nerve growth factor and, indirectly, brain-derived neurotrophic factor stimulate the tortuous growth of sensory fibers and the formation of cell clusters. Neurotrophin-3, however, enhances neurite growth in terms of length and linearity allowing for a more organized and directed axonal elongation towards a peripheral target compared to the other growth factors. These findings could be of considerable importance for any clinical application of neurotrophic factors in peripheral nerve regeneration. Ethical approval was obtained from the Regione Piemonte Animal Ethics Committee ASLTO1(file # 864/2016-PR) on September 14, 2016.
文摘Spinal muscular atrophy(SMA)is a hereditary pediatric motor neuron(MN)disease:survival motor neuron 1(SMN1)gene mutation determines MN degeneration and,consequently,muscle atrophy,breathing and swallowing difficulties,and,in the most severe cases,premature death.A second unaffected gene(SMN2)is present,but it can only produce a limited amount of functional protein,modulating the disease severity and progression.SMN,ubiquitously expressed,is mainly
基金supported by the European Community’s Seventh Framework Programme(FP7-HEALTH-2011),No.278612(to SG)by Compagnia di San Paolo,No.D86D15000100005InTheCure project(to SR)
文摘Nerve regeneration after delayed nerve repair is often unsuccessful. Indeed, the expression of genes associated with regeneration, including neurotrophic and gliotrophic factors, is drastically reduced in the distal stump of chronically transected nerves; moreover, Schwann cells undergo atrophy, losing their ability to sustain regeneration. In the present study, to provide a three-dimensional environment and trophic factors supporting Schwann cell activity and axon re-growth, we combined the use of an effective conduit(a chitosan tube) with a promising intraluminal structure(fresh longitudinal skeletal muscle fibers). This enriched conduit was used to repair a 10-mm rat median nerve gap after 3-month delay and functional and morphometrical analyses were performed 4 months after nerve reconstruction. Our data show that the enriched chitosan conduit is as effective as the hollow chitosan conduit in promoting nerve regeneration,and its efficacy is not statistically different from the autograft, considered the "gold standard" technique for nerve reconstruction. Since hollow tubes not always lead to good results after long defects(> 20 mm), we believe that the conduit enriched with fresh muscle fibers could be a promising strategy to repair longer gaps, as muscle fibers create a favorable three-dimensional environment and release trophic factors. All procedures were approved by the Bioethical Committee of the University of Torino and by the Italian Ministry of Health(approval number: 864/2016/PR) on September 14, 2016.
基金supported by MIUR-PRIN2015(grant 2015Y5W9YP)University of Turin(Ricerca locale 2016)
文摘Brain plasticity is heterogeneous in mammals:Brain regeneration and repair are the dream of every neurobiologist as well as every common citizen in the world who knows that most neurological diseases,dementia and other age-related problems affecting the central nervous system(CNS)do represent a heavy health and social burden.Efficacious re-
文摘Alzheimer’s disease(AD)is a progressive neurodegenerative condition that goes f rom mild cogni t ive impai rment in prodromal disease to severely disabling deficits in advanced stages.The risk for AD development,as well as progression and severity,clearly differ between men and women(Pike,2017).Epidemiological studies have shown that there is a significantly increased prevalence in the development of AD in women compared to men,which is usually explained by the longer lifespan of women.This increased frequency may be due to the interplay between age and sex,in which genetic factors together with hormonal and metabolic patterns play a crucial role.Moreover,cognitive impairment has been confirmed to be greater in women than in men at the same stage of AD,likely due to reduced estrogen levels in postmenopausal women(Laws et al.,2016).
基金funding from the European Community’s Seventh Framework Program(FP7-HEALTH-2011)under grant agreement,No.278612(BIOHYBRID)
文摘Peripheral nerves form a complex network connecting the central nervous system and the body.Injuries to peripheral nerves often lead to partial or complete loss of motor,sensory and autonomic functions,thus interfering with many aspects of an individual’s life.Despite the spontaneous ability of the peripheral nerve to regenerate,the technical surgical progresses and the significant advances in basic science,the study of
文摘Schwann cells(SCs)and peripheral nerve regeneration:SCs are the principal glial cells of the peripheral nervous system(PNS).In a healthy nerve,myelinating SCs wrap around larger caliber motor and sensory axons to form the myelin sheath,whereas non-myelinating SCs envelop and support multiple small diameter sensory axons to form Remak bundles.Moreover,they form a basal lamina which surround each SC-axon unit(Hall,2005).When a peripheral nerve injury occurs,extensive changes
文摘Brain regeneration from an evolutionary perspective:Brain regeneration(the full restoration of tissue after loss from injury or disease)is the most sought after goal for researchers working in developmental neurobiology.It also appears to be the most challenging to achieve when considering the mammalian brain.Whereas remarkable regenerative capacities can be present in the central nervous systems of many non-mammalian vertebrates(e.g.,fish,amphibians),these kinds of processes appear to be dramatically reduced in mammals(Bonfanti,2011).
文摘The amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder primarily involving motoneurons in the cerebral cortex, brainstem, and spinal cord. SOD1-G93A mice, which express multiple copies of the mutant form of the human Cu/Zn SOD, are one of the most widely used animal models for ALS pathology. However, the onset of the disease can vary between animals of 1-2 weeks while the progression is quite fast. In order to evaluate the efficacy of any treatment, it is very important to treat all animals at the early onset of the disease, instead of at a fixed age-point. To this aim, we performed behavioral analysis and measured hSOD1 mRNA expression to identify the appearance of the first motor deficits. Rotarod and PaGE tests revealed to be the most sensitive approaches to detect the beginning of the symptomatic phase of the disease, while neurological score and weight monitoring showed significant differences only at later stages in ALS pathology. Furthermore, we found a better correlation between hSOD1 mRNA expression with disease onset than with a transgene copy number. Therefore, the association of behavioral tests and molecular analysis represents a sensible and accurate tool to early detect the murine symptoms.
基金supported by Progetto Trapezio,Compagnia di San Paolo(67935-2021.2174)to LB,Fondazione CRT(Cassa di Risparmio di Torino,RF=2022.0618)to LB。
文摘Brain plasticity-A universal tool with many variations:The study of brain plasticity has been gaining interest since almost a century and has now reached a huge amount of information(>80,000 results in PubMed).Overall,different types of plasticity,including stem cell-driven genesis of new neurons(adult neurogenesis),cells in arrested maturation(dormant neurons),neuro-glial and synaptic plasticity,can coexist and contribute to grant plastic changes in the brain,from a cellular to system level(Benedetti and Couillard-Despres,2022;Bonfanti et al.,2023).