Summary: A new study reveals a link between astrocytes derived from patients with schizophrenia and the formation of tighter blood vessels in the brain. The results suggest that astrocytes from people with schizophrenia promote less vascularization.
Source: FAPESP
A study conducted in Brazil and reported in an article published in Molecular Psychiatry suggests that schizophrenia may be associated with alterations in the vascularization of certain regions of the brain.
Researchers from the State University of Campinas (UNICAMP), the Institute for Research and Education D’Or (IDOR) and the Federal University of Rio de Janeiro (UFRJ) have discovered a link between the astrocytes (central nervous system cells) of patients with schizophrenia and the formation of narrow blood vessels.
Schizophrenia is a severe multifactorial mental disorder that affects approximately 1% of the world’s population. Common symptoms include loss of touch with reality (psychosis), hallucinations (hearing voices, for example), delusions or delirium, disorganized motor behavior, loss of motivation, and cognitive impairment.
In the study, the researchers focused on the role of astrocytes in disease development. These glial cells are the guardians of the central nervous system and are important for its defense. They are the core elements of neurovascular units that integrate neural circuitry with local blood flow and provide neurons with metabolic support.
The study points to new therapeutic targets and advances scientists’ understanding of the molecular mechanisms underlying schizophrenia.
“We show that astrocytes may be involved in altered blood vessel thickness in the brain, which in turn may be associated with reduced metabolic flux in certain brain regions, a key factor in schizophrenia.
“Our results highlight the role of astrocytes as central to the disease and suggest that they could therefore be a target for new therapies,” said Daniel Martins-de-Souza, penultimate author of the study. article and professor at the UNICAMP Institute of Biology. FAPESP Agency.
The study was supported by FAPESP through a Thematic Project and a postdoctoral fellowship awarded to Juliana Minardi Nascimento, first author of the article, alongside Pablo Trindade, researcher affiliated with UFRJ and IDOR.
Abnormal vascularization
The researchers compared astrocytes derived from skin cells of schizophrenic patients with others from people without the disease. This part of the study was conducted in the laboratory of Stevens Rehen, researcher at IDOR and professor at the Institute of Biology at UFRJ.
To this end, they reprogrammed epithelial cells from patients with schizophrenia and from the control group to become induced pluripotent stem cells (iPSCs). They then induced the differentiation of iPSCs into neural stem cells, which can give rise to both neurons and astrocytes.
“Previous research has suggested that molecular and functional abnormalities of astrocytes may be involved in the pathogenesis of schizophrenia. In our study, we proved this implication using iPSCs. Without this technique, it would be impossible to study astrocytes as we have done,” said Martins-de-Souza.
The researchers conducted two series of tests with astrocytes from patients and healthy controls. The first was a proteomic analysis in which all the proteins present in each sample were identified in order to detect the differences between the two sets of astrocytes. This part was carried out at the Neuroproteomics Laboratory of UNICAMP.
“In our analysis of cell proteomes, we observed immune alterations 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 indicated angiogenic action in the cerebral vasculature,” Nascimento said.
Angiogenesis is the physiological process by which new blood vessels form from pre-existing vessels. It’s a normal part of growth and healing, but it can play a role in disease.
After the proteomic analysis, the researchers performed functional assays to show that the inflammatory response in the astrocytes of patients with schizophrenia was impaired and that the cells secreted substances that affected the vasculature. These tests were part of Pablo Trindade’s postdoctoral research.
The model of the vasculature they used is known as the chicken chorioallantoic membrane (CAM) test. Derived from chicken eggs, CAM has 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. “In simple terms, we placed conditioned astrocyte media containing all the substances secreted by these cells into the vascular region of the fertilized eggs.
As the vascular cells multiplied, it was possible to see how vessel formation proceeded since egg vascularization could be induced or inhibited by secreted substances,” Trindade said.
In addition to their effects on the vasculature, astrocytes from schizophrenic patients exhibited chronic inflammation.
“Astrocytes are known to regulate the immune response in the central nervous system, so it is possible that they promote more immature or less efficient vascularization. Our patient-derived astrocytes secreted more interleukin-8 (IL-8) than controls. IL-8 is pro-inflammatory and suspected to be the primary agent of vascular dysfunction associated with schizophrenia,” he said.
According to the authors, the results reinforce the role of neurodevelopment in schizophrenia and clearly show that astrocytes are important as mediators.
“Symptoms of the disease usually appear in early adulthood, but as our study shows, the glial cells of these patients are different from the start, which affects the neurological development of the fetus. Both differentiation and brain formation are impaired. It may therefore be that a systemically impaired vasculature leads to early brain circuit malformation, which in turn leads to schizophrenia later,” Nascimento said.
Another point raised in the article is the importance of astrocytes for neurological disorders.
“The role of glial cells, including astrocytes, not only in schizophrenia but also in neurological disorders in general has been discovered relatively recently. The prevailing view was that researchers should focus on neurons. Our vision and understanding of the disease is broadening,” Martins-de-Souza said.
Original research: Access closed.
“Astrocytes derived from induced pluripotent stem cells from patients with schizophrenia exhibit an inflammatory phenotype that affects vascularization” by Daniel Martins-de-Souza et al. Molecular Psychiatry
Summary
Astrocytes derived from induced pluripotent stem cells from patients with schizophrenia exhibit an inflammatory phenotype that affects vasculature
Molecular and functional abnormalities of astrocytes have been implicated in the etiology and pathogenesis of schizophrenia (SCZ).
In this study, we investigated the proteome, inflammatory responses, and effects of the secretome on the vasculature of astrocytes derived from induced human pluripotent stem cells (hiPSCs) from patients with SCZ.
Proteomic analysis revealed protein alterations related to immune function and vascularization. Reduced expression of nuclear factor kappa B (NF-κB) p65 subunit was observed in these astrocytes, with no additional cytokine secretion following tumor necrosis factor-alpha (TNF-α) stimulation.
Among the inflammatory cytokines, interleukin (IL)-8 secretion was particularly high in medium conditioned with astrocytes derived from SCZ patients (A SBS CM). In a chicken chorioallantoic membrane (CAM) assay, A SBS CM reduced the diameter of newly grown vessels. This effect could be mimicked with the exogenous addition of IL-8.