summary: A new study has revealed a link between astrocytes derived from patients with schizophrenia and the formation of narrowed blood vessels in the brain. The results indicate that astrocytes from patients with schizophrenia reduce angiogenesis.
A study conducted in Brazil and reported in an article published in Molecular Psychiatry It indicates that schizophrenia may be associated with changes in the blood vessels in certain areas of the brain.
Researchers at Campinas State University (UNICAMP), the D’Or Institute for Research and Education (IDOR) and the Federal University of Rio de Janeiro (UFRJ) have found a link between astrocytes (central nervous system cells) from patients with schizophrenia and the formation of narrowed blood vessels.
Schizophrenia is a severe, multifactorial mental health disorder affecting approximately 1% of the world’s population. Common symptoms include loss of contact with reality (psychosis), hallucinations (hearing voices, for example), delusions or delirium, erratic motor behaviour, loss of motivation and cognitive impairment.
In the study, the researchers focused on the role of astrocytes in disease progression. These glial cells are the housekeepers of the central nervous system and are important for its defense. They are the central elements of neurovascular units that integrate neural circuits with local blood flow and provide neurons with metabolic support.
The study points to new treatment targets and advances scientists’ understanding of the molecular mechanisms behind schizophrenia.
We have shown that astrocytes may be involved in a change in the thickness of blood vessels in the brain, which in turn may be related to decreased metabolic flux in certain brain regions, and is a major factor in schizophrenia.
“Our findings highlight the role of astrocytes as a central component of disease and suggest that they can be a target for novel therapies,” said Daniel Martins de Souza, penultimate author of the article and a professor at UNICAMP’s Institute of Biology. Agência FAPESP.
The study was supported by FAPESP through a thematic project and a postdoctoral grant awarded to Giuliana Minardi Nascimento, first author of the article, along with Pablo Trindade, research associate with UFRJ and IDOR.
Abnormal blood vessels
The researchers compared astrocytes derived from the skin cells of patients with schizophrenia with other astrocytes from people without the disease. This part of the study was conducted in the lab of Stevens Rehen, an IDOR researcher and professor at the UFRJ Institute of Biology.
To this end, they reprogrammed epithelial cells from schizophrenia patients and a control group to become induced pluripotent stem cells (iPSCs). They then induced the differentiation of iPS cells into neural stem cells, which can give rise to both neurons and astrocytes.
Previous research suggested that both molecular and functional abnormalities of astrocytes could be involved in the pathogenesis of schizophrenia. In our study, we demonstrated this involvement using iPSCs. Without this technology, it would be impossible to study astrocytes the way we did,” said Martins de Souza.
The researchers conducted two series of tests using astrocytes derived from patients and healthy controls. The first was a proteomic analysis in which all proteins in each sample were determined in order to detect differences between the two groups of astrocytes. This part was performed at UNICAMP’s Neuroproteomics Laboratory.
“In our analysis of cell proteins, we observed immune changes associated with astrocytes. In the case of cells from patients with schizophrenia, we also found differences in the levels of pro-inflammatory cytokines and several other proteins that indicate vasculature functioning in the vasculature of the brain,” Nascimento said.
Angiogenesis is the physiological process by which new blood vessels form from pre-existing ones. It is a normal part of growth and healing but can play a role in disease.
After the proteomic analysis, the researchers conducted functional experiments to show that the inflammatory response in astrocytes from patients with schizophrenia was altered and that the cells secreted substances that affected blood vessels. These tests were part of Pablo Trindade’s postdoctoral research.
The model of the vascular system they used is known as the chicken placental membrane (CAM) assay. Derived from chicken eggs, CAM contains a dense network of blood vessels and is widely used to study angiogenesis.
The test was carried out by researchers at the University of Chile in Santiago, Chile. Simply put, we placed conditioned astrocyte medium containing all the substances secreted by these cells into the vascular region of the fertilized oocyte.
As the angiogenesis cells multiplied, it was possible to see how angiogenesis progressed as egg vessels could be either stimulated or inhibited by the secreted substances,” Trindade said.
In addition to their effect on blood vessels, astrocytes derived from patients with schizophrenia showed chronic inflammation.
“Astrocytes are known to regulate the immune response in the central nervous system, so it is possible that they promote immature or less efficient vasculature. Astrocytes from the patient secrete more interleukin-8 (IL-8) than the control group. Interleukin-8 is pro- inflammation and is suspected to be the main factor of vascular dysfunction associated with schizophrenia.”
According to the authors, the findings reinforce a role for neurodevelopment in schizophrenia and clearly show that astrocytes are important as mediators.
Symptoms of the disease usually appear in adulthood, but as our study shows, the glial cells of these patients differ from the onset, affecting the neurodevelopment of the fetus. Both differentiation and brain formation are altered. Therefore, the reason may be that systemically altered blood vessels lead to early brain circuit deformation, which in turn leads to later schizophrenia,” Nascimento said.
Another point in the article is how important astrocytes are to neurological disorders.
“The role of glial cells, including astrocytes, not only in schizophrenia but also in neurological disorders in general was discovered relatively recently. The prevailing view was that researchers should focus on neurons. Our vision and understanding of the disease is evolving,” said Martins de Souza. expansion.
About this schizophrenia and neuroscience research news
author: Heloisa Rennert
Contact: Heloisa Reinert – FAPESP
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“Induced stem cell-derived astrocytes from patients with schizophrenia show an inflammatory phenotype that affects angiogenesis.Written by Daniel Martins de Souza et al. Molecular Psychiatry
Induced stem cell-derived astrocytes from patients with schizophrenia show an inflammatory phenotype that affects angiogenesis.
Molecular and functional abnormalities of astrocytes have been linked in the etiology and pathogenesis of schizophrenia (SCZ).
In this study, we examined the proteins, inflammatory responses, and effects of secretion on the vasculature of human induced stellate cells (hiPSC) from SCZ patients.
Proteomic analysis revealed changes in proteins related to immune and vascular function. Decreased expression of the nuclear factor kappa B (NF-κB) p65 subunit was observed in these astrocytes, with no increased secretion of cytokines after tumor necrosis factor-alpha (TNF-α) stimulation.
Among the inflammatory cytokines, secretion of interleukin (IL)-8 was particularly elevated in SCZ medium derived from astrocytes (ASBScm). In the chicken chorionic membrane (CAM) assay, ASBSCM reduced the diameter of the newly implanted vessels. This effect can be simulated by exogenous addition of IL-8.
Taken together, our results indicate that SCZ astrocytes are immunologically impaired and may therefore influence angiogenesis through secreted factors.