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Looking for the origins of schizophrenia
In a new study conducted on human tissues and in chicken eggs, low levels of blood vessel forming proteins in schizophrenic patients are identified as probable cause for schizophrenia. That schizophrenia may be related to an inability to create a rich vascular system in the brain, is the result of a collaborative study between D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil; the Laboratory of Stem Cells and Development, Universidad de Chile, Santiago, Chile; and the Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (UFRJ).
The results of this collaborative study broaden our understanding of what causes schizophrenia, a severely disabling disorder affecting about 1% of the world's population.
"A [previous] partnership between Brazilian and Chilean groups allowed us to create this singular study, combining expertise on neurodevelopment and formation of blood vessels to investigate schizophrenia," explains neuroscientist Stevens Rehen PhD, a researcher at D'Or Institute and UFRJ — and a study coordinator. Veronica Palma at the University of Chile, led the study with Rehen. Their combined approaches allowed for the creation of an environment that could mimick conditions for embryonic brain development. The end result of their work published February 22, 2018 in the journal Translational Psychiatry from the Nature Publishing Group.
Characterized by episodes of hallucinations, confused thoughts and delusions, schizophrenia has no cure and the available treatment is only partially effective. Investigating causes for the disease may bring new therapeutic solutions and/or early diagnostic tools.
Previous studies on post-mortem brains and blood samples, indicate how patients with schizophrenia had deficiencies in blood vascularization of the brain. It is accepted that the interaction between blood vessels and neurons is essential to development of the brain with dense vascularization allowing for a steady supply of oxygen and nutrients to neural cells, as well as for the constant removal of harmful substances.
The collaborative group used the ability of human neural cells to aid in the formation of blood vessels during brain development, to investigate what was going on. Using human induced pluripotent stem (iPS) cells created by the D'Or Institute for Research and Education (IDOR), made from the skin cells of three patients with schizophrenia, the scientists compared them to IPS cells from three people without the disorder. The iPS cells were transformed into neural stem cells, and induced to become nerve cells. The scientists also used neurospheres - three-dimensional clusters of neural stem cells — to initiate the transformation into neurons.
Neural cells made from the skin cells of patients with schizophrenia, produced smaller amounts of two proteins essential in making blood vessels. The cells had lower concentrations of VEGFA, one of the most important angiogenic (blood vessel forming) proteins — but higher concentrations of TIMP-1 an anti-angiogenic protein.
"This is the first profile of angiogenic protein expression using neural stem cells from patients with schizophrenia to show these patients had a less angiogenic profile when compared to controls", explains Verónica Palma PhD, Laboratory of Stem Cells and Development, Universidad de Chile, Santiago, Chile.
To confirm angiogenesis was compromised in patients with schizophrenia, a second experiment was performed using human umbilical cord epithelial cells, or cells that line the umbilical cord. Epithelial cells were exposed to proteins produced by nerve cells from the schizophrenic brains. Then chicken eggs were injected with the same concentration of proteins and from the same source as the previous experiment.
Chick umbilical cord epithelial cells have a great capacity to form blood vessels in the membrane just beneath the eggshell. Chosen to test whether molecules produced by neural stem cells of schizophrenic patients alter the angiogenic capacity of chick epithelial cells, results confirmed that substances produced by schizophrenic patients' nerve cells restrict the blood vessel capacity of embryonic chicks.
"Advances on this subject bring new perspectives to the treatment and diagnosis of schizophrenia," says Stevens Rehen. Soon, he and his team plan to develop biological indicators that can detect the presence of the disease and identify the disorder regardless of the prescence of outward symptoms. Rehen: "This is a completely new approach, measuring neuro-vascular mechanisms in mental disorders."
Schizophrenia is a neurodevelopmental disease characterized by cerebral connectivity impairment and loss of gray matter. It was described in adult schizophrenia patients (SZP) that concentration of VEGFA, a master angiogenic factor, is decreased. Recent evidence suggests cerebral hypoperfusion related to a dysfunctional Blood Brain Barrier (BBB) in SZP. Since neurogenesis and blood-vessel formation occur in a coincident and coordinated fashion, a defect in neurovascular development could result in increased vascular permeability and, therefore, in poor functionality of the SZP’s neurons. Here, we characterized the conditioned media (CM) of human induced Pluripotent Stem Cells (hiPSC)-derived Neural Stem Cells of SZP (SZP NSC) versus healthy subjects (Ctrl NSC), and its impact on angiogenesis. Our results reveal that SZP NSC have an imbalance in the secretion and expression of several angiogenic factors, among them non-canonical neuro-angiogenic guidance factors. SZP NSC migrated less and their CM was less effective in inducing migration and angiogenesis both in vitro and in vivo. Since SZP originates during embryonic brain development, our findings suggest a defective crosstalk between NSC and endothelial cells (EC) during the formation of the neuro-angiogenic niche.
Authors: Bárbara S. Casas, Gabriela Vitória, Marcelo N. do Costa, Rodrigo Madeiro da Costa, Pablo Trindade, Renata Maciel, Nelson Navarrete, Stevens K. Rehen, Verónica Palma.
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The first week of embryonic life of a chick is devoted to creating a rich vascular system to nuture that chick. VEGFA and TIMP-1 proteins affect how these blood vessels form. Image credit: Pinterest.