Hydrogels and cell based therapies in spinal cord injury regeneration

Spinal cord injury (SCI) is a central nervous system- (CNS-) related disorder for which there is yet no successful treatment. Within the past several years, cell-based therapies have been explored for SCI repair, including the use of pluripotent human stem cells, and a number of adult-derived stem and mature cells such as mesenchymal stem cells, olfactory ensheathing cells, and Schwann cells. Although promising, cell transplantation is often overturned by the poor cell survival in the treatment of spinal cord injuries. Alternatively, the therapeutic role of different cells has been used in tissue engineering approaches by engrafting cells with biomaterials. The latter have the advantages of physically mimicking the CNS tissue, while promoting a more permissive environment for cell survival, growth, and differentiation. The roles of both cell- and biomaterial-based therapies as single therapeutic approaches for SCI repair will be discussed in this review. Moreover, as the multifactorial inhibitory environment of a SCI suggests that combinatorial approaches would be more effective, the importance of using biomaterials as cell carriers will be herein highlighted, as well as the recent advances and achievements of these promising tools for neural tissue regeneration.The authors would like to acknowledge the Portuguese Foundation for Science and Technology (Grant no. PTDC/SAU-BMA/114059/2009; IF Development Grant to António J. Salgado); Prémios Santa Casa Neurociências for funds attributed to António J. Salgado under the scope of the Prize Melo e Castro for Spinal Cord Injury Research; cofunded by Programa Operacional Regional do Norte (ON.2—O Novo Norte), ao abrigo do Quadro de Referência Estratégico Nacional (QREN), através do Fundo Europeu de Desenvolvimento Regional (FEDER)

Citalopram administration does not promote function or histological recovery after spinal cord injury

Citalopram is a selective serotonin reuptake inhibitor, and although widely used as an antidepressant, this drug has also demonstrated interesting repairing properties leading to motor recovery and pathology amelioration in animal models of stroke and degeneration. Here, we tested the efficacy of both 7-day and 8-week citalopram treatment in a contusive spinal cord injury (SCI) rat model. A combination of behavioral tests, histological and serum cytokine analysis was used to assess overall recovery. Despite promoting a mild reduction of inflammatory cells as well as an early, but transient increase of specific serum cytokines, citalopram administration showed no overall beneficial effects on motor performance or lesion extension. Our results do not support citalopram treatment as a therapeutic strategy for SCI.This research was funded by Prémios Santa Casa Neurociências—Prize Melo e Castro for SpinalCord Injury Research, Grant Number MC-04/17 and the Portuguese Foundation for Science and Technology(FCT) through the Scientific Employment Stimulus to N. Silva and S. Monteiro (CEECIND/04794/2017 and CEECIND/01902/2017) and fellowships to RL (PD/BDE/127836/2016); EDG (SFRH/BD/103075/2014);NLV (SFRH/BD/136952/2018) and R.AS (PDE/BDE/113596/2015).This work was also funded by FEDER,through the Competitiveness Internalization Operational Program (POCI) and by National funds, throughthe Foundation for Sciences and Technology (FCT), under the scope of the projects POCI-01-0145-FEDER-007038,POCI-01-0145-FEDER-029206, POCI-01-0145-FEDER-029751 and PTDC/BTM-MAT/29968/2017. This work hasbeen funded by ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI - PortuguesePlatform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122; by National funds, through the Foundationfor Science and Technology (FCT) - project UIDB/50026/2020 and UIDP/50026/2020; and by the projectsNORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Program (NORTE2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)

Influence of different ECM-like hydrogels on neurite outgrowth induced by adipose tissue-derived stem cells

Mesenchymal stem cells (MSCs) have been proposed for spinal cord injury (SCI) applications due to their capacity to secrete growth factors and vesicles-secretome-that impacts important phenomena in SCI regeneration. To improve MSC survival into SCI sites, hydrogels have been used as transplantation vehicles. Herein, we hypothesized if different hydrogels could interact differently with adipose tissue-derived MSCs (ASCs). The efficacy of three natural hydrogels, gellan gum (functionalized with a fibronectin peptide), collagen, and a hydrogel rich in laminin epitopes (NVR-gel) in promoting neuritogenesis (alone and cocultured with ASCs), was evaluated in the present study. Their impact on ASC survival, metabolic activity, and gene expression was also evaluated. Our results indicated that all hydrogels supported ASC survival and viability, being this more evident for the functionalized GG hydrogels. Moreover, the presence of different ECM-derived biological cues within the hydrogels appears to differently affect the mRNA levels of growth factors involved in neuronal survival, differentiation, and axonal outgrowth. All the hydrogel-based systems supported axonal growth mediated by ASCs, but this effect was more robust in functionalized GG. The data herein presented highlights the importance of biological cues within hydrogel-based biomaterials as possible modulators of ASC secretome and its effects for SCI applications.This study is funded by Prémios Santa Casa Neurociências—Prize Melo e Castro for Spinal Cord Injury Research. This is also partially funded by EU-FP7-Health-2011-Collaborative Project 278612, Biohybrid—Templates for peripheral nerve regeneration, and Portuguese Foundation for Science and Technology (IF Development Grant to A. J. Salgado; postdoctoral fellowship to N. A. Silva—SFRH/BPD/97701/2013; PhD fellowships of R. C. Assunção-Silva and E. D. Gomes—PDE/BDE/113596/2015 and SFRH/BD/103075/2014, resp.). This article is a result of the project (NORTE-01-0145-FEDER-000013) supported by the Norte Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); Cofinanciado pelo ProgramaOperacional Regional do Norte(ON.2 SR&TD Integrated Program—NORTE-07-0124-FEDER-000021), ao abrigo do Quadro de Referência Estratégico Nacional (QREN), através do Fundo Europeude Desenvolvimento Regional (FEDER); Projeto Estratégico—LA 26–2011-2012 and Projeto Estratégico—LA 26–2013-2014 cofinanciado por fundos nacionais, através da Fundação para a Ciência e a Tecnologia (PEst-C/SAU/LA0026/2011; PEst-C/SAU/LA0026/2013), e pelo Fundo Europeu de Desenvolvimento Regional (FEDER), através do COMPETE (FCOMP-01-0124-FEDER-022724; FCOMP-01-0124-FEDER-037298). The authors would like to thank Professor Jeffrey Gimble at the Tulane University Center for Stem Cell Research and Regenerative Medicine and LaCell LLC (New Orleans, Louisiana, USA) for kindly providing the ASCs used in this study.info:eu-repo/semantics/publishedVersio

Systemic interleukin-4 administration after spinal cord injury modulates inflammation and promotes neuroprotection

Traumatic spinal cord injury (SCI) causes dramatic disability and dysfunction in the motor, sensory and autonomic systems. The severe inflammatory reaction that occurs after SCI is strongly associated with further tissue damage. As such, immunomodulatory strategies have been developed, aimed at reducing inflammation, but also at shaping the immune response in order to protect, repair and promote regeneration of spared neural tissue. One of those promising strategies is the intraspinal administration of the cytokine interleukin-4 (IL-4) that was shown to promote a phenotype on specific immune cells associated with neuroprotection and repair. In this work, we evaluated if a systemic delivery of IL-4 for a 7-days period was also capable of promoting neuroprotection after SCI by analyzing different neural cells populations and motor recovery. IL-4 treatment promoted an elevation of the anti-inflammatory cytokine IL-10 in the serum both at 24 h and 7 days after injury. Locally, treatment with IL-4 led to a reduction on cells expressing markers associated with inflammation, CD11b/c and iNOS. Importantly, IL-4 treatment increased the neuronal markers beta III-tubulin and NeuN, and the oligodendrocyte marker O4, suggesting a neuroprotective effect. Moreover, 100% of the animals treated with IL-4 were able to recover weight support against only 33% of saline treated animals. Overall, these results show that systemic administration of IL-4 positively impacts different aspects of spinal cord injury, creating a more favorable environment for recovery to take place.Prémios Santa Casa Neurociências—Prize Melo e Castro for Spinal Cord Injury Research; Portuguese Foundation for Science and Technology (Financiado no âmbito do Projecto 3599—Promover a Produção Científica e Desenvolvimento Tecnológico e a Constituição de Redes Temáticas (3599-PPCDT), project: PTDC/DTP-FTO/5109/2014; Post-Doctoral fellowship—SFRH/BPD/97701/2013—to N.A. Silva; IF Development Grant to A. J. Salgado; fellowships—PD/BDE/127836/2016—to R. Lima; SFRH/BD/103075/2014—to E. D. Gomes; PDE/BDE/113596/2015—to R. C. Assunção-Silva; SFRH/BD/88825/2012—to M. Morais); This article is a result of the project (NORTE-01-0145-FEDER-000013), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER); This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038info:eu-repo/semantics/publishedVersio

Induction of neurite outgrowth in 3D hydrogel-based environments

The ability of peripheral nervous system (PNS) axons to regenerate and re-innervate their targets after an injury has been widely recognized. However, despite the considerable advances made in microsurgical techniques, complete functional recovery is rarely achieved, especially for severe peripheral nerve injuries (PNIs). Therefore, alternative therapies that can successfully repair peripheral nerves are still essential. In recent years the use of biodegradable hydrogels enriched with growth-supporting and guidance cues, cell transplantation, and biomolecular therapies have been explored for the treatment of PNIs. Bearing this in mind, the aim of this study was to assess whether Gly-Arg-Gly-Asp-Ser synthetic peptide (GRGDS)-modified gellan gum (GG) based hydrogels could foster an amenable environment for neurite/axonal growth. Additionally, strategies to further improve the rate of neurite outgrowth were also tested, namely the use of adipose tissue derived stem cells (ASCs), as well as the glial derived neurotrophic factor (GDNF). In order to increase its stability and enhance its bioactivity, the GDNF was conjugated covalently to iron oxide nanoparticles (IONPs). The impact of hydrogel modification as well as the effect of the GDNF-IONPs on ASC behavior was also screened. The results revealed that the GRGDS-GG hydrogel was able to support dorsal root ganglia (DRG)-based neurite outgrowth, which was not observed for non-modified hydrogels. Moreover, the modified hydrogels were also able to support ASCs attachment. In contrast, the presence of the GDNF-IONPs had no positive or negative impact on ASC behavior. Further experiments revealed that the presence of ASCs in the hydrogel improved axonal growth. On the other hand, GDNF-IONPs alone or combined with ASCs significantly increased neurite outgrowth from DRGs, suggesting a beneficial role of the proposed strategy for future applications in PNI regenerative medicineEU-FP7-Health-2011-collaborative project 278612, Biohybrid—Templates for peripheral nerve regeneration; Prémios Santa Casa Neurociências—Prize Melo e Castro for Spinal Cord Injury Research; Portuguese Foundation for Science and Technology (IF Development Grant to A J Salgado; Post-Doctoral fellowship to N A Silva — SFRH/BPD/97701/2013); co-funded by Programa Operacional Regional do Norte (ON.2—O Novo Norte), ao abrigo do Quadro de Referência Estratégico Nacional (QREN), através do Fundo Europeu de Desenvolvimento Regional (FEDER); Professor Jeffrey Gimble at the Tulane University Center for Stem Cell Research and Regenerative Medicine and LaCell LLC (New Orleans, Louisiana, USA) for kindly providing the ASCs used in this studyinfo:eu-repo/semantics/publishedVersio

Exploiting the impact of the secretome of MSCs isolated from different tissue sources on neuronal differentiation and axonal growth

Cell transplantation using Mesenchymal stem cell (MSC) secretome have recently been presented as a possible free-based therapy for CNS related disorders. MSC secretome is rich in several bio-factors that act synergically towards the repair of damaged tissues, thus making it an ideal candidate for regenerative applications. Great effort is currently being made to map the molecules that compose the MSC secretome. Previous proteomic characterization of the secretome (in the form of conditioned media - CM) of MSCs derived from adipose tissue (ASC), bone-marrow (BMSC) and umbilical cord (HUCPVC) was performed by our group, where proteins relevant for neuroprotection, neurogenic, neurodifferentiation, axon guidance and growth functions were identified. Moreover, we have found significant differences among the expression of several molecules, which may indicate that their therapeutic outcome might be distinct. Having this in mind, in the present study, the neuroregulatory potential of ASC, BMSC and HUCPVC CM in promoting neurodifferentiation and axonal outgrowth was tested in vitro, using human telencephalon neuroprogenitor cells and dorsal root ganglion explants, respectively. The CM from the three MSC populations induced neuronal differentiation from human neural progenitor cells, as well as neurite outgrowth from dorsal root ganglion explants. Moreover, all the MSC populations promoted the same extent of neurodifferentiation, while ASC CM demonstrated higher potential in promoting axonal growth.The authors acknowledge the financial support by Premios Santa Casa Neurociencias - Prize Melo e Castro for Spinal Cord ^ Injury Research (MC-17-2013 and MC-04-2017); Portuguese Foundation for Science and Technology (Doctoral fellowships PDE/ BDE/113596/2015 and SFRH/BD/120124/2016 to R.C Assunçao Silva ~ and B. Mendes-Pinheiro, respectively; Post-doctoral fellowhip to F.G. Teixeira and Patrícia Patrício - SFRH/BPD/118408/2016 and SFRH/BPD/116249/2016; IF Starting Grant to L. Pinto and IF Development Grant to A. J. Salgado); Canada Research Chair in Biomedical Engineering (LAB). This work is funded by national funds through FCT under the scope of grante reference TUBITAK/0007/ 2014. This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology, under the scope of the project POCI-01-0145-FEDER-007038. HUCPVCs and ASCs were kindly provided by Prof. John E. Davies (University of Toronto, Canada) and Prof. Jeff Gimble (LaCell Inc, USA).info:eu-repo/semantics/publishedVersio

FATORES ASSOCIADOS À QUALIDADE DE VIDA DE INDIVÍDUOS ACOMETIDOS POR DIABETES MELLITUS

Objetivo: analisar os fatores associados à qualidade de vida de indivíduos acometidos por diabetes mellitus. Método: estudo epidemiológico, censitário, realizado com 101 indivíduos com o diagnóstico de diabetes tipo 2 atendidos em uma Unidade de Saúde da Família do município de Jequié-BA, Brasil. Foram utilizados os instrumentos de coleta de dados: sociodemográficos, estilo de vida, dados clínicos e o WHOQOL-bref. Resultados: evidenciou-se que as pessoas que fazem uso de álcool e tabaco apresentaram melhor percepção de qualidade de vida no domínio relações sociais. Verificou-se que os indivíduos sobrepeso/obeso apresentaram pior percepção de qualidade de vida no domínio psicológico. Quanto ao tempo diagnóstico, observou-se pior percepção entre os indivíduos com diagnóstico > 5 anos de diabetes mellitus e o domínio relações sociais. Conclusão: o consumo de álcool e tabaco, índice de massa corporal e o tempo diagnóstico da doença interferem na qualidade de vida do indivíduo com diabetes.Descritores: Diabetes mellitus. Estilo de vida. Qualidade de vida

Modelagem da circulação atmosférica na região da usina termoelétrica de Candiota

In this paper it is used the Regional Atmospheric Modeling System (RAMS) in order to simulate the atmospheric circulation around the Candiota Thermoelectric Power Plant. Two numerical experiments are showed. The first one describes the sensitivity of the model to the local topography. In the second one the model is initialized with data from CPTEC/INPE and the results are compared with data obtained in fields campaigns. This comparison indicates that the RAMS outputs are an useful tools to be used in atmospheric dispersion models to describe the pollutant transport emitted by the Candiota source

Epidemiological surveillance system on foodborne diseases in Brazil after 10-years of its implementation : completeness evaluation

This study aimed to evaluate the data quality of the Brazilian Epidemiological Surveillance System on Foodborne Diseases (VE-DTA) through the evaluation of the completeness of the record after 10-years of its implementation. The study evaluated the measurement of completeness by quantifying ignored, incomplete or blank responses of the data items filled. The evaluation used the percentage of completion of these items regarding the total number of notifications registered in the system. We organized the results according to the general Category of completeness of the database, by year of notification and region of occurrence. We also evaluated the overall completeness percentages of the database and the completeness levels according to the degree of recommendation of completion of each variable (mandatory, essential, and complementary) by the VE-DTA manual. The system presented 7037 outbreaks of foodborne diseases. According to the completeness classification, the database presented general classification as Category 1 since it has 82.1% (n = 5.777) of variables with the level of completion up to 75.1%. We observed that 8.6% of the database was classified as category 2; 9.2% as category 3 and 0.1% as category 4. The improvement on database quality regarding completeness can positively impact on public health and public policies, reducing the number of FBDs deaths

Bioengineered cell culture systems of central nervous system injury and disease

Cell culture systems, either 2D or explant based, have been pivotal to better understand the pathophysiology of several central nervous system (CNS) disorders. Recently, bioengineered cell culture systems have been proposed as an alternative to the traditional setups. These innovative systems often combine different cell populations in 3D environments that more closely recapitulate the different niches that exist within the developing or adult CNS. Given the importance of such systems for the future of CNS-related research, we discuss here the most recent advances in the field, particularly those dealing with neurodegeneration, neurodevelopmental disorders, and trauma.Financial support is acknowledged from Prémios Santa Casa Neurociências – Prize Melo e Castro for Spinal Cord Injury Research; Portuguese Foundation for Science and Technology [Doctoral fellowship (SFRH/BD/103075/2014) to E.D.G.; IF Development Grant to A.J.S.; Starting Grant to F. Marques; PostDoctoral fellowship SFRH/BPD/97701/2013 to N.A.S.]; this work was co-funded by Programa Operacional Regional do Norte (ON.2 – O Novo Norte), ao abrigo do Quadro de Referência Estratégico Nacional (QREN), através do Fundo Europeu de Desenvolvimento Regional (FEDER).info:eu-repo/semantics/publishedVersio