Study published in the journal Molecular psychiatry suggests that schizophrenia may be related to changes in the vasculature of certain regions of the brain.
In their work, researchers from Campinas State University (Unicamp), the D’Or Teaching and Research Institute (Idor) and the Federal University of Rio de Janeiro (UFRJ) observed that neural cells (astrocytes) derive from patients with disease induce the formation of a greater number of vessels – only the thinnest ones -, which can affect the vascular network of some brain areas.
Schizophrenia is considered a serious and multifactorial mental disorder, affecting up to 1% of the world’s population.
Common symptoms include loss of contact with reality (psychosis), hallucinations (hearing voices, for example), false beliefs (delusions), abnormal thinking and behavior, decreased motivation, and worsening mental (cognitive) function.
In the study, the researchers focused on the role of astrocytes – cells essential for the maintenance of neurons and which function as energy plants in the central nervous system – in the development of the disease. In addition to indicating new therapeutic targets, the study advances the understanding of the molecular mechanisms of the disease.
“We have shown that astrocytes may be involved with a change in vessel thickness in the brain. And this may be related to an important factor in schizophrenia: the decrease in metabolic flux [produção de energia] in certain regions of the brain. “This reinforces the role of astrocytes as a central element of the disease, making them a target for new therapies,” explains Daniel Martins-de-Souza, professor at the Institute of Biology of the State University of Campinas (IB-Unicamp) and one of the authors of the article.
The work was supported by FAPESP through a thematic project and a postdoctoral fellowship granted to Juliana Minardi Nascimento, first author of the article together with Pablo Trindade, of UFRJ and Idor.
Alteration of the vascularization
The researchers compared astrocytes derived from skin cells from schizophrenia patients with those derived from people without the disease. This part of the study was conducted in the laboratory of Stevens Rehen, a researcher at Idor and a professor at the UFRJ Institute of Biology.
To do so, the team reprogrammed skin cells from schizophrenia patients and those in the control group to regress to a pluripotent stage characteristic of stem cells (induced pluripotent stem cells, or iPSCs). Then, cell differentiation was induced, transforming iPSCs into neural stem cells (which can give rise to both neurons and astrocytes).
“Previous studies had already suggested that both molecular and functional abnormalities of astrocytes might be involved in the pathogenesis of schizophrenia. In our work, we confirmed this relationship based on studies with induced pluripotent stem cells. As we did,” explains Martins-de- Suzza.
With patient-derived astrocytes and healthy controls, the researchers performed two tests.
First, a proteomic analysis (which identifies the set of proteins present in the sample) was performed at the Neuroproteomics Laboratory of Unicamp, verifying the variation of the proteins expressed in the control cells and in those of the patients suffering from schizophrenia.
“Assessing the proteomics of cells with schizophrenia, we observed astrocyte-associated immune alterations. We also found differences in inflammatory cytokines and several other proteins that indicated an angiogenic action [que favorece o crescimento de novos vasos] in the cerebral vasculature,” informs Nascimento.
After proteomic analysis, the researchers performed functional tests. It was observed that the inflammatory response of the astrocytes in the patients was altered and that the substances released by them affected the vascular supply.
Running these tests was part of Trindade’s postdoctoral studies.
For this, the researchers used a model of the vasculature based on the membrane surrounding the chick embryo. Known as CAM (English acronym for the embryonic chorioallantoic membrane of chicken eggs), the methodology has been used to study the effect of substances on tissue vascularization.
This study was conducted by collaborators from the Universidad de Chile (Chile).
“Basically, we placed the astrocyte conditioned medium, containing all the substances that these cells secrete, within the vascular region of the fertilized ova. We observe whether the substances secreted by the cultured cells induce or inhibit the vascularization of the egg,” says Trindade .
In addition to modifying the vasculature, astrocytes derived from patients with schizophrenia exhibited a profile of chronic inflammation.
“Astrocytes are known to be neural cells that have the role of regulating the immune response in the region. Therefore, it is possible that they are promoting more immature or less efficient vasculature. We verified that, compared to the control group, the patient-derived astrocytes secrete a higher amount of interleukin-8, a signal of inflammation and suspected to be the main agent of vascular dysfunction associated with schizophrenia”, explains the researcher to Agência FAPESP.
The authors emphasize that the findings reinforce the role of neurodevelopment in schizophrenia, which, by all indications, is mediated by astrocytes.
“Disease symptoms usually show up when you’re a young adult. But, as we’ve shown in the work, the glial cells in these patients are different from the start, which interferes with neurodevelopment even in the womb. The differentiation and brain formation occurs in an altered way, so it may be that, during brain maturation, events such as the one we verified in the study occur: a systematically altered vasculature that leads to the malformation of brain circuits that can trigger schizophrenia in adulthood ” says Nascimento.
Another contribution of the study was to draw attention to the importance of astrocytes in neurological diseases. “The role of glial cells, as is the case for astrocytes, not only in schizophrenia, but in neurological disease in general was a recent discovery, as there was a very neurocentric view of further investigating the role of neurons as a way to broaden our vision and understanding of the disease”, evaluates Martins-de-Souza.
The article Induced pluripotent stem cell-derived astrocytes from patients with schizophrenia exhibit an inflammatory phenotype that affects vasculature can be read at: www.nature.com/articles/s41380-022-01830-1.
This text was originally published by Agência FAPESP under the Creative Commons license CC-BY-NC-ND. Read the original here.
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