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Master's Dissertation
DOI
10.11606/D.5.2016.tde-25022016-145454
Document
Author
Full name
Marcus Vinicius Naghetini dos Santos
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2015
Supervisor
Committee
Krieger, Jose Eduardo (President)
Girardi, Adriana Castello Costa
Lacchini, Silvia
Title in Portuguese
Efeito anti-fibrótico da proteína SPARC em fibroblastos cardíacos (Potencial mediador dos benefícios associados ao trasplante de células-tronco derivadas de tecido adiposo no miocárdio pós-infarto)
Keywords in Portuguese
Células-tronco
Colágeno
Morte celular
Peróxido de hidrogênio
Proteômica
SPARC proteína humana
Tecido adiposo
Abstract in Portuguese
O reparo cardíaco pós-infarto do miocárdio (IM) continua sendo um desafio, apesar do grande progresso no tratamento clínico e na redução da mortalidade. Nesse sentido, estudos com modelos pré-clínicos têm demonstrado que o transplante de células-tronco adultas, como as células-tronco derivadas de tecido adiposo (ASCs), preserva a função ventricular após IM. Esta melhora não está relacionada à mecanismos de substituição tecidual, mas a ação parácrina através da liberação de moléculas bioativas pleiotrópicas. No presente estudo, nós procuramos identificar proteínas-alvo importantes relacionadas com a resposta pleiotrópica benéfica associada ao uso de ASC pós-IM. Foram realizadas análises de bioinformática do secretoma de mASC submetida à hipóxia e stretch, mimetizando o microambiente do IM, para encontrar novos alvos. Uma rede de interações incluindo três candidatos que interagem entre si: SPARC, MMP-3 e Osteopontina, foi gerada. Padronizamos o modelo de morte celular por H2O2 em cardiomiócitos, fibroblastos cardíacos e células endoteliais, os três tipos celulares principalmente encontrados no coração, e avaliamos a expressão desses fatores nessas células. Os dados mostram que o peróxido de hidrogênio altera a expressão desses fatores de forma heterogênea nessas células e induz a produção e secreção de colágeno em fibroblastos. Entretanto, o tratamento com SPARC, Osteopontina e MMP-3 não melhorou a viabilidade das células tratadas com H2O2 e nem modulou a resposta antigênica. No que se refere à produção de colágeno, a proteína SPARC conseguiu reduzir esta a níveis basais, semelhante ao que ocorreu com as células tratadas com o meio condicionado de ASC. Em conjunto, os resultados mostram que a proteína SPARC reduz a produção de colágeno assim como o meio condicionado, consistente com a ideia de que a SPARC participa, pelo menos em parte, da resposta benéfica associada ao transplante de ASC pós-infarto do miocárdio
Title in English
Anti-fibrotic effect of SPARC protein in cardiac fibroblasts (Potential mediator of the benefits associated with stem cell transplantation derived from adipose tissue post-myocardial infarction)
Keywords in English
Adipose tissue
Cell death
Collagen
Hydrogen peroxide
Proteomics
SPARC protein human
Stem cells
Abstract in English
Cardiac repair post-myocardial infarction (MI) remains a challenge despite great progress in clinical management and mortality reduction. In this sense, studies with pre-clinical models have shown that the transplantation of adult stem cells, such as stem cells derived from adipose tissue (ASCs), preserves ventricular function after MI. This improvement is not related to mechanisms of tissue replacement and cell transdifferentiation, but the paracrine action through the release of pleiotropic bioactive molecules. In the present study we tried to identify key proteins related with the beneficial pleiotropic response associated with ASC transplantation post-MI. We perform bioinformatic analyses of the proteins released by mASC subjected to stretch and hypoxia, mimmiking the MI microenvironment, to find novel targets. The network of interactions includes three candidates that interact with each other: SPARC, MMP-3 and Osteopontin. We standardized the model of cell death by H2O2 in cardiomyocytes, cardiac fibroblasts and endothelial cells, the three major cell types that form the heart, and evaluate the expression of these factors. The data show that hydrogen peroxide alters the expression of these factors heterogeneously in these cells and induces collagen production and secretion in fibroblasts. However, treatment with SPARC, Osteopontin and MMP-3 did not improve the viability of cells treated with H2O2 and does not influence the angiogenic response. Concerning to the production of collagen, SPARC protein could reduce this to basal levels, similar to what happened with the cells treated with conditioned medium of ASC. Together, these results showed that SPARC protein reduces collagen production similarly to the conditioned medium treatment, which is consistent with the idea that SPARC is responsible, at least in part, for the beneficial effects associated with the transplanted ASC post-MI
 
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Publishing Date
2016-02-25
 
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