Kristen J Brennand

Publications (6)100.69 Total impact

• Article: Concise review: the promise of human induced pluripotent stem cell-based studies of schizophrenia.

  Kristen J Brennand, Fred H Gage
  [show abstract] [hide abstract]
  ABSTRACT: Schizophrenia (SCZD) is a heritable developmental disorder. Although the molecular mechanism of disease remains unclear, insights into the disorder have been made through a vast array of experimental techniques. Together, magnetic resonance brain imaging, pharmacological, and post-mortem pathological studies have observed decreased brain volume, aberrant neurotransmitter signaling, reduced dendritic arborization, and impaired myelination in SCZD. Genome-wide association studies (GWAS) have identified common single nucleotide polymorphisms as well as rare copy number variants that contribute to SCZD, while mouse models of candidate SCZD genes show behavioral abnormalities and anatomical perturbations consistent with human disease. The advent of human induced pluripotent stem cells (hiPSCs) makes it possible to study SCZD using live human neurons with a genetic predisposition toward SCZD, even without knowledge of the genes interacting to produce the disease state. SCZD 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 GWAS. SCZD hiPSC neurons represent a new tool to look beyond phenotype and begin to dissect the molecular mechanisms of SCZD.
  Stem Cells 12/2011; 29(12):1915-22. · 7.78 Impact Factor
• Article: Modelling schizophrenia using human induced pluripotent stem cells.

  Kristen J Brennand, Anthony Simone, Jessica Jou, Chelsea Gelboin-Burkhart, Ngoc Tran, Sarah Sangar, Yan Li, Yangling Mu, Gong Chen, Diana Yu, Shane McCarthy, Jonathan Sebat, Fred H Gage
  Nature 10/2011; · 36.28 Impact Factor
• Article: Modeling psychiatric disorders through reprogramming.

  Kristen J Brennand, Fred H Gage
  [show abstract] [hide abstract]
  ABSTRACT: Psychiatric disorders, including autism spectrum disorders and schizophrenia, are extremely heritable 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 with genetic backgrounds that are known to result in psychiatric disorders, 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 elucidate the cellular and molecular 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.
  Disease Models and Mechanisms 09/2011; 5(1):26-32. · 4.94 Impact Factor
• Article: Induced pluripotent stem cells (iPSCs) and neurological disease modeling: progress and promises.

  Maria C Marchetto, Kristen J Brennand, Leah F Boyer, Fred H Gage
  [show abstract] [hide abstract]
  ABSTRACT: The systematic generation of neurons from patients with neurological disorders can provide important insights into disease pathology, progression and mechanism. This review will discuss recent progress in modeling neurodegenerative and neurodevelopmental diseases using induced pluripotent stem cells (iPSCs) and highlight some of the current challenges in the field. Combined with other technologies previously used to study brain disease, iPSC modeling has the promise to influence modern medicine on several fronts: early diagnosis, drug development and effective treatment.
  Human Molecular Genetics 08/2011; 20(R2):R109-15. · 7.64 Impact Factor
• Source

  Available from: genethique.org

  Article: Modelling schizophrenia using human induced pluripotent stem cells.

  Kristen J Brennand, Anthony Simone, Jessica Jou, Chelsea Gelboin-Burkhart, Ngoc Tran, Sarah Sangar, Yan Li, Yangling Mu, Gong Chen, Diana Yu, Shane McCarthy, Jonathan Sebat, Fred H Gage
  [show abstract] [hide abstract]
  ABSTRACT: Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80-85%. Although post-mortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (Supplementary Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder.
  Nature 05/2011; 473(7346):221-5. · 36.28 Impact Factor
• Source

  Available from: Amy L Firth

  Article: Brief report: efficient generation of hematopoietic precursors and progenitors from human pluripotent stem cell lines.

  Niels-Bjarne Woods, Aaron S Parker, Roksana Moraghebi, Margaret K Lutz, Amy L Firth, Kristen J Brennand, W Travis Berggren, Angel Raya, Juan Carlos Izpisúa Belmonte, Fred H Gage, Inder M Verma
  [show abstract] [hide abstract]
  ABSTRACT: By mimicking embryonic development of the hematopoietic system, we have developed an optimized in vitro differentiation protocol for the generation of precursors of hematopoietic lineages and primitive hematopoietic cells from human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSCs). Factors such as cytokines, extra cellular matrix components, and small molecules as well as the temporal association and concentration of these factors were tested on seven different human ESC and iPSC lines. We report the differentiation of up to 84% human CD45+ cells (average 41% ± 16%, from seven pluripotent lines) from the differentiation culture, including significant numbers of primitive CD45+/CD34+ and CD45+/CD34+/CD38- hematopoietic progenitors. Moreover, the numbers of hematopoietic progenitor cells generated, as measured by colony forming unit assays, were comparable to numbers obtained from fresh umbilical cord blood mononuclear cell isolates on a per CD45+ cell basis. Our approach demonstrates highly efficient generation of multipotent hematopoietic progenitors with among the highest efficiencies reported to date (CD45+/CD34+) using a single standardized differentiation protocol on several human ESC and iPSC lines. Our data add to the cumulating evidence for the existence of an in vitro derived precursor to the hematopoietic stem cell (HSC) with limited engrafting ability in transplanted mice but with multipotent hematopoietic potential. Because this protocol efficiently expands the preblood precursors and hematopoietic progenitors, it is ideal for testing novel factors for the generation and expansion of definitive HSCs with long-term repopulating ability.
  Stem Cells 05/2011; 29(7):1158-64. · 7.78 Impact Factor