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Neural Progenitor Cells Model Aspects of Schizophrenia

April 14, 2014. Neural progenitor cells (NPCs) derived from the skin cells of patients with schizophrenia show abnormal neuronal migration and elevated levels of oxidative stress—alterations that are suspected in the illness—reports a new study published online April 1 in Molecular Psychiatry. Led by Kristen Brennand and Fred Gage of the Salk Institute in La Jolla, California, the report also demonstrates that using NPCs to model aspects of schizophrenia is a viable alternative to their more high-maintenance neuronal descendants that have garnered so much attention.

iPSC-derived neurons
The ground-breaking 2006 report from Shinya Yamanaka demonstrating that human and mouse fibroblasts could be reprogrammed into induced pluripotent stem cells (iPSCs) and then differentiated into any desired cell type, including neurons, marked a new way to study the neurobiology of brain diseases and test potential therapeutics. However, despite substantial efforts, differentiating iPSCs into neurons has proved to be more challenging than expected (see SRF related conference report).

The technique first came to schizophrenia in 2011, when Gage and Brennand, then a postdoc in Gage’s lab, reported that iPSC-derived neurons from four schizophrenia patients exhibited reduced connectivity and neurite number, as well as many gene expression changes (see SRF related news report; SRF related conference report). In addition, treatment with the antipsychotic loxapine reversed many of these deficits.

The use of iPSC-derived neurons as a model of schizophrenia has several caveats. Within a single culture, not all neurons have the same fate or age, and consequently they form artificial networks that are both immature and lack myelination. In addition, coaxing iPSCs into pyramidal cells and interneurons is a very labor-intensive process that takes several months. But the biggest caveat is that just how these in vitro phenotypes will relate to the human disease process is currently unknown.

Neuronal precursors
In the current study, Brennand (now at Mt. Sinai School of Medicine, New York City) and Gage focused on the same patients’ neural precursor cells (NPCs)—the intermediaries between iPSCs and neurons. NPCs aren’t neurons, of course, and therefore don’t form synapses, but they can be used to assay a cellular phenotype distinct from that of iPSCs. They are much easier to grow than neurons—they don’t require months in culture to mature—and in the new report the researchers show that NPCs derived from schizophrenia patients have a gene expression signature that overlaps significantly with that of the iPSC-derived neurons from the earlier study.

By comparing the microarray gene expression profiles of the NPCs and neurons to that of human tissue from the Allen BrainSpan Atlas, the researchers found that the gene expression profiles of both the iPSC-derived NPCs and neurons most closely matched tissue from a third trimester fetus. “That’s why we’re careful to say we’re modeling the predisposition to [the illness], and not schizophrenia per se,” said Brennand at an April 8 presentation of the new data at the 4th Schizophrenia International Research Society Conference in Florence, Italy.

A total of 481 genes had aberrant expression levels in the NPCs from patients compared to controls. Using weighted gene co-expression network analysis, the researchers found five modules of co-expressed genes from within the 481: neuron differentiation and synaptic transmission (the one with the most differentially expressed genes), glutamate receptor signaling, insulin signaling, neuronal migration, and synaptic vesicle function. Gene ontology analyses suggested that the abnormally expressed genes were involved in synapse formation, synaptic transmission, and cell adhesion. A quantitative protein mass spectroscopy analysis was not able to replicate the synaptic gene expression changes; however, it did find altered levels of many cytoplasmic cytoskeleton proteins (such as profilins and cofilins) as well as those involved in oxidative stress (such as thioredoxin).

These data prompted Brennand and colleagues to look for perturbed neuronal migration as well as evidence of elevated oxidative stress in the patient-derived NPCs. Using three different assays—neurosphere migration, microfluidic device migration, and laminin spot chaining—the researchers observed reduced migration in the patient-derived NPCs. In her talk, Brennand emphasized that the results suggest aberrant migration rather than decreased migration, because a fourth assay actually revealed increased migration in the patient-derived NPCs. The findings also point to cell adhesion differences rather than motility deficits in the cells.

To assay oxidative stress, Brennand and colleagues used a dye called JC1 that changes from red to green fluorescence as the potential across the inner mitochondrial membrane decreases, an indicator of oxidative stress. The schizophrenia NPCs showed significantly more oxidative stress than control-derived NPCs. Two other groups have also reported evidence of increased oxidative stress in schizophrenia patient-derived NPCs (Paulsen et al., 2012; Robicsek et al., 2013).

“While iPS is still a very new field for studying schizophrenia,” said Brennand, “three groups in three different countries have all now shown one common phenotype: oxidative stress,” a process that is gaining increasing attention in schizophrenia (see SRF related news report; SRF related conference report).

Fellow symposium speaker Akira Sawa of Johns Hopkins University in Baltimore, Maryland, commented that the oxidative stress findings are a “really important confirmation” of the multitude of animal studies implicating the process in the illness that have not yet been extended to humans (Emiliani et al., 2014).

Although NPCs are certainly not a perfect model of the intact schizophrenia brain, they still have a lot to offer. “The goal is not to replace clinical- or animal-based models,” remarked Brennand. “It’s to see if we can potentially add on [to other research] with this new model.”—Allison A. Curley.

Reference:
Brennand K, Savas JN, Kim Y, Tran N, Simone A, Hashimoto-Torii K, Beaumont KG, Kim HJ, Topol A, Ladran I, Abdelrahim M, Matikainen-Ankney B, Chao SH, Mrksich M, Rakic P, Fang G, Zhang B, Yates JR, Gage FH. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry . 2014 Apr 1. Abstract

 
Comments on News and Primary Papers
Primary Papers: Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia.

Comment by:  Christopher Ross
Submitted 9 April 2014 Posted 9 April 2014

Schizophrenia Redux?
Sometimes a longer follow-up paper can be just as significant as an initial, shorter paper in a higher-impact journal. This may be the case with the recent paper by Brennand et al. in Molecular Psychiatry, which follows from the initial study of Brennand et al. (Brennand et al., 2011) in Nature. The second paper has a great deal of new data, but more strikingly, has two provocative hypothesizes about iPS cell models of schizophrenia.

The advent of human iPS cell technology has the potential to transform research into brain diseases such as schizophrenia. Ongoing studies of iPS cell models of neurodegenerative diseases illustrate the potential. For instance, in studies from the HD iPS cell consortium, we find that HD iPS cells show CAG-expansion length-dependent cell toxicity, which can be rescued with BDNF (HD iPS Cell Consortium, 2012), and in our ongoing studies, with small molecules, indicating utility for both pathogenesis and experimental...  Read more


View all comments by Christopher Ross

Comment by:  Nao GamoAkira Sawa (SRF Advisor)
Submitted 7 May 2014 Posted 7 May 2014

This study introduces a novel use of neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSCs) to address mechanisms that may possibly underlie a predisposition to schizophrenia. Brennand et al. (2014) generated hiPSC-derived NPCs from patients with schizophrenia and control subjects. These NPCs, as well as six-week-old neurons differentiated from them, showed gene expression profiles similar to those of the fetal forebrain. Thus, these cells were used to address early disease etiology, in particular, focusing on mechanisms related to disruptions in prefrontal cortical development. Interestingly, the researchers found overlap in gene signatures between the six-week-old neurons and NPCs from patients, raising the possibility that disease predisposition may already be established at the NPC stage.

Particularly striking is the reduced migration of schizophrenia NPCs relative to control NPCs as they differentiated into neurons. This reduced migration may be due to schizophrenia NPCs remaining in a proliferative state before differentiating, as...  Read more


View all comments by Nao Gamo
View all comments by Akira Sawa

Comment by:  Bryan MowrySamuel Nayler
Submitted 29 May 2014 Posted 29 May 2014

In a recent follow-up to their 2011 paper, Brennand et al. report considerable progress toward generation of a defined neuronal population generated from patient-derived induced pluripotent stem (iPS) cells. The advent of the iPS cell has been somewhat Promethean in that pluripotent stem cells are now a commonly utilized laboratory tool for disease modeling. While marked progress has occurred on a number of fronts, it is still not known to what degree stem cell-derived neurons truly resemble mature neurons that exist in the brain of a living human. Moreover, it is an open question what these cells can tell us about the onset of a clinically heterogeneous, polygenic disease such as schizophrenia.

Using gene expression analysis, Brennand et al. compare their samples to a developmental spectrum of samples from the Allen Brain Atlas to show that their iPSC-derived neurons most closely resemble early fetal forebrain neurons. This may provide precisely the model system that will allow researchers to validate the neurodevelopmental theory of schizophrenia, provided early...  Read more


View all comments by Bryan Mowry
View all comments by Samuel Nayler
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