1. Ladran IG, Tran NN, Topol A, Brennand KJ. 2013. Neural stem/progenitor cells in health and disease. WIRE Systems Biology and Medicine. In press.

Summary: Neural stem/progenitor cells (NSPCs) have the potential to differentiate into neurons, astrocytes, and/or oligodendrocytes. Because these cells can be expanded in culture, they represent a vast source of neural cells. With the recent discovery that patient fibroblasts can be reprogrammed directly into induced NSPCs, the regulation of NSPC fate and function, in the context of cell-based disease models and patient-specific cell-replacement therapies, warrants review.

2. Tran NN, Ladran IG, Brennand KJ. Modeling Schizophrenia Using Induced Pluripotent Stem Cell-Derived and Fibroblast-Induced Neurons. Schizophr Bull. 2012 Nov 19. [Epub ahead of print]. 

Summary: Although schizophrenia affects a number of brain regions and produces a range of clinical symptoms, we believe its origins lie at the level of single neurons and simple networks. Owing to this, as well as its high degree of heritability, we hypothesize that schizophrenia is amenable to cell-based studies in vitro. Using induced pluripotent stem cell-derived neurons and/or fibroblast-induced neurons, a limitless quantity of live human neurons can now be generated from patient skin biopsies. We predict that cell-based studies will ultimately contribute to our understanding of the molecular and cellular underpinnings of this debilitating disorder.

3. Brennand KJ, Simone A, Tran N, Gage FH. 2012. Modeling Psychiatric Disorders at the Cellular and Network Levels. Molecular Psychiatry. Advance online publication, 3 April 2012; doi:10.1038/mp.2012.20. 

Summary: Psychiatric disorders such as autism spectrum disorders, schizophrenia and bipolar disorder affect many brain regions and produce a complex array of clinical symptoms. The defects that contribute to these diseases at the level of single cells and simple networks remain unknown. New laboratory techniques make it possible to study these diseases by inducing neurons artificially from patient fibroblasts. It is now possible to generate limitless numbers of live human neurons from patients with psychiatric disorders. We predict that these studies will ultimately contribute to our understanding of the initiation, progression and treatment of psychiatric disorders.

4. Brennand KJ, Gage F. 2012. Modeling psychiatric disorders through reprogramming. Disease Models and Mechanism. 5(1):26-32.

Summary: Psychiatric disorders, including autism spectrum disorders and schizophrenia, are extremely complex genetic neurodevelopmental disorders. It is now possible to directly reprogram fibroblasts from psychiatric patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiate these disorder-specific hiPSCs into neurons. This means that researchers can generate nearly limitless quantities of live human neurons even without knowing which genes are interacting to produce the disease state in each patient. With these new human-cell-based models, scientists can investigate the precise cell types that are affected in these disorders and discover the cellular and genetic defects that contribute to disease initiation and progression. Here, we present a short review of experiments using hiPSCs and other sophisticated in vitro approaches to study the pathways underlying psychiatric disorders.

5. Brennand KJ, Gage F. 2011. Concise review: the promise of human induced pluripotent stem cell-based studies of schizophrenia. Stem Cells. 29(12):1915-1922.

Summary: Schizophrenia has a huge genetic component, but the exact genes responsible remain unknown. Previous imaging, drug and post-mortem studies have observed decreased brain volume, aberrant neurotransmitter signaling, reduced neuron size, and impaired myelination in SZ. The discovery of human induced pluripotent stem cells (hiPSCs) makes it possible to study SZ using live human neurons, even without knowledge of the genes interacting to produce the disease state. SZ hiPSC neurons show cellular defects comparable to those identified in post-mortem human and mouse studies, and gene expression changes are consistent with predictions made by genetic studies. SZ hiPSC neurons represent a new tool to dissect the genetic causes of SZ.

6. Brennand KJ, Simone A*, Jou J*, Gelboin-Burkhart C*, Tran N*, Sangar S, Li Y, Mu Y, Chen G, Yu D, McCarthy S, Sebat J, Gage FH. 2011. Modeling Schizophrenia Using hiPSC Neurons. Nature. 473(7346): 221-225.

Comment in Cell Stem Cell: Buxbaum JD, Sklar P. 2011. Human induced pluripotent stem cells: a new model for schizophrenia? Cell Stem Cell. 8(5):461-462.

Comment in Nat Rev Neuro Neurosci: Welberg L. 2011. Stem Cells: Zooming in on schizophrenia. 12(6):308-309.

Featured in Nature Methods: Baker, M. 2011. Nature Methods: Neurons from reprogrammed cells. 8(11):905-909.

Featured in Nature News: Callaway, E. 2011. Nature News: Schizophrenia 'in a dish'. Published online 13 April 2011 | Nature | doi:10.1038/news.2011.232 and Hayden, A.C. 2011. Nature: The growing pains of pluripotency. 473: 272-274

Summary: Schizophrenia is a debilitating psychiatric disorder that affects approximately 1 percent of people worldwide. Previous studies have shown that patients with schizophrenia have reduced brain volume, smaller neurons and abnormal brain dopaminergic activity; however, the mechanism of disease initiation and progression remains unclear. To investigate these questions, we developed a new method to generate live human brain cells for the study of schizophrenia. Specifically, we reprogrammed skin samples from patients with schizophrenia into stem cells and then differentiated these stem cells into brain cells. Brain cells from patients with schizophrenia were less connected to each other and also showed specific differences in gene expression; some of these defects were improved by treatment with antipsychotic medications. Our findings are consistent with previous studies of schizophrenia, validating that it is now possible to study schizophrenia using live human brain cells generated through our methods.

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Kristen Brennand, PhD
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