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Short and long TNF-alpha exposure recapitulates canonical astrogliosis events in human induced pluripotent stem cells-derived astrocytes

View ORCID ProfilePablo Trindade, View ORCID ProfileErick Correia Loiola, Juciano Gasparotto, Camila Tiefensee Ribeiro, View ORCID ProfilePablo Leal Cardozo, Sylvie Devalle, José Alexandre Salerno, Isis Moraes Ornelas, View ORCID ProfilePitia Flores Ledur, View ORCID ProfileFabiola Mara Ribeiro, Ana Lucia Marques Ventura, José Claudio Fonseca Moreira, Daniel Pens Gelain, View ORCID ProfileLisiane Oliveira Porciúncula, View ORCID ProfileStevens Kastrup Rehen
doi: https://doi.org/10.1101/722017
Pablo Trindade
Instituto D’Or de Pesquisa e Ensino (IDOR), Rio de Janeiro, BrazilPós-Graduação em Biologia Molecular e Celular, Universidade Federal do Estado do Rio de Janeiro, Brazil
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Erick Correia Loiola
Instituto D’Or de Pesquisa e Ensino (IDOR), Rio de Janeiro, Brazil
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  • ORCID record for Erick Correia Loiola
Juciano Gasparotto
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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Camila Tiefensee Ribeiro
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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Pablo Leal Cardozo
Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Sylvie Devalle
Instituto D’Or de Pesquisa e Ensino (IDOR), Rio de Janeiro, Brazil
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José Alexandre Salerno
Instituto D’Or de Pesquisa e Ensino (IDOR), Rio de Janeiro, Brazil
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Isis Moraes Ornelas
Instituto D’Or de Pesquisa e Ensino (IDOR), Rio de Janeiro, Brazil
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Pitia Flores Ledur
Instituto D’Or de Pesquisa e Ensino (IDOR), Rio de Janeiro, Brazil
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  • ORCID record for Pitia Flores Ledur
Fabiola Mara Ribeiro
Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Ana Lucia Marques Ventura
Departamento de Neurobiologia, Universidade Federal Fluminense, Niterói, Brazil
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José Claudio Fonseca Moreira
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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Daniel Pens Gelain
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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Lisiane Oliveira Porciúncula
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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Stevens Kastrup Rehen
Instituto D’Or de Pesquisa e Ensino (IDOR), Rio de Janeiro, BrazilInstituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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  • ORCID record for Stevens Kastrup Rehen
  • For correspondence: srehen@lance-ufrj.org
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Abstract

Astrogliosis comprises a variety of changes in astrocytes that occur in a context-specific manner, triggered by temporally diverse signaling events that vary with the nature and severity of brain insults. However, most mechanisms underlying astrogliosis were described using animal models, which fail to reproduce some aspects of human astroglial signaling. Here, we report an in vitro model to study astrogliosis using human induced pluripotent stem cells (iPSC)-derived astrocytes which replicates aspects temporally intertwined of reactive astrocytes in vivo. We analyzed the time course of astrogliosis by measuring nuclear translocation of NF-kB, secretion of cytokines and changes in morphological phenotypes of human iPSC-derived astrocytes exposed to TNF-α. It was observed the NF-kB nuclear translocation, increases either in the inflammation-related cytokines secretion and gene expression for IL-1β, IL-6 and TNF-α following 24 h TNF-α stimulation. After 5 days, human iPSC-derived astrocytes exposed to TNF-α exhibited increases in vimentin and GFAP immunolabeling, elongated shape and shrinkage of nuclei, which is typical phenotypes of astrogliosis. Moreover, about a 50% decrease in D-[3H] aspartate uptake was observed over the astrogliosis course with no evident cell damage, which suggests astrocytic dysfunction. Taken together, our results indicate that cultured human iPSC-derived astrocytes reproduce canonical events associated to astrogliosis in a time dependent fashion. Our findings may contribute to a better understanding of mechanisms governing human astrogliosis. Furthermore, the approach described here presents a potential applicability as a platform to uncover novel biomarkers and new drug targets to refrain astrogliosis associated to human brain disorders.

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Posted August 01, 2019.
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Short and long TNF-alpha exposure recapitulates canonical astrogliosis events in human induced pluripotent stem cells-derived astrocytes
Pablo Trindade, Erick Correia Loiola, Juciano Gasparotto, Camila Tiefensee Ribeiro, Pablo Leal Cardozo, Sylvie Devalle, José Alexandre Salerno, Isis Moraes Ornelas, Pitia Flores Ledur, Fabiola Mara Ribeiro, Ana Lucia Marques Ventura, José Claudio Fonseca Moreira, Daniel Pens Gelain, Lisiane Oliveira Porciúncula, Stevens Kastrup Rehen
bioRxiv 722017; doi: https://doi.org/10.1101/722017
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Short and long TNF-alpha exposure recapitulates canonical astrogliosis events in human induced pluripotent stem cells-derived astrocytes
Pablo Trindade, Erick Correia Loiola, Juciano Gasparotto, Camila Tiefensee Ribeiro, Pablo Leal Cardozo, Sylvie Devalle, José Alexandre Salerno, Isis Moraes Ornelas, Pitia Flores Ledur, Fabiola Mara Ribeiro, Ana Lucia Marques Ventura, José Claudio Fonseca Moreira, Daniel Pens Gelain, Lisiane Oliveira Porciúncula, Stevens Kastrup Rehen
bioRxiv 722017; doi: https://doi.org/10.1101/722017

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