Kristen Brennand | Mount Sinai School of Medicine (original) (raw)

My current work focuses on using induced pluripotent stem cells to study schizophrenia. Briefly, I obtained skin samples from patients with schizophrenia as well as healthy controls. I then reprogrammed these skin cells into stem cells. I can now direct these stem cells to become neurons. Thus, from a small skin sample, I can generate near limitless quantities of live healthy and schizophrenia neurons which I can compare in the laboratory. I hope that by identifying differences between healthy and diseased neurons, I will soon be able to screen for new drugs with which to reverse the cellular defects present in schizophrenia.

My most significant scientific accomplishments:

1. Demonstrated that fully differentiated cell types could be reprogrammed to induced pluripotent stem cells (Stadtfeld et al, Current Biology, 2009; Ruiz et al, PLOS One, 2011). The first report of the generation of induced pluripotent stem cells (iPSCs) in 2006 was hailed as an end of the need for research using embryonic stem cells and as an important tool with which to study normal development and the progression of disease. Early reprogramming attempts were extremely inefficient and an important question in the field was if any cell type, or if only rare adult stem cells, could be reprogrammed. Together with collaborators, we demonstrated that fully differentiated and genetically marked pancreatic β-cells can give rise to iPSCs that expressed pluripotency markers, formed teratomas, and contributed to cell types of all germ layers in chimeric animals. In a similar study, of human cells, we showed that human astrocytes could be reprogrammed into human induced pluripotent stem cells (hiPSCs), with efficiencies similar to those already reported for fibroblasts, keratinocytes and peripheral blood cells.

2. Improving and understanding neuronal differentiation from human induced pluripotent stem cells (McConnell et al, Science, 2013; Hartley et al, Molecular Psychiatry, 2015; Topol et al, J. Vis. Exp. 2015). A requirement of human iPSC-based disease models is that hiPSC-derived neural cells can be rapidly and robustly differentiated into defined populations of mature neurons that capture the genetic, epigenetic and functional characteristics that define human neurons in vivo.

3. Modeling schizophrenia (SZ) using hiPSC Neurons (Brennand et al Nature, 2011; Yu et al Stem Cell Reports, 2013; Hook et al Stem Cell Reports, 2013; Lee et al npj Schizophrenia, 2015). SZ patients 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 were the first to reprogram skin samples from SZ patients into hiPSCs and then to subsequently differentiate these cells into live human neurons. SZ hiPSC neurons exhibit diminished neuronal connectivity, decreased neurite number, reduced synaptic maturation, altered neurotransmitter activity and reduced synaptic activity. These findings are remarkably consistent with findings from human postmortem tissue and animal models.

4. Modeling predisposition to SZ using hiPSC Neural Progenitor Cells (NPCs) (Brennand et al Molecular Psychiatry, 2015; Hashimoto-Torii et al, Neuron 2014; Topol et al, Biological Psychiatry, 2015; Topol et al, Translational Psychiatry, 2015). While the characteristic symptoms of schizophrenia generally appear late in adolescence, it is often predated by a prodromal period that can appear in early childhood. Gene expression comparisons of hiPSC-derived NPCs and 6-week-old neurons to the Allen BrainSpan Atlas routinely demonstrate that hiPSC-derived NPCs and neurons resemble fetal rather than adult brain tissue, indicating that hiPSC-based models may be more appropriate for the study of SZ predisposition, rather than the late features of disease. We and others have found that SZ hiPSC NPCs show evidence of aberrant migration, altered WNT signaling, increased oxidative stress, perturbed responses to environmental stressors; and distorted global protein translation. We posit that some of the factors contributing to perturbed neuronal function in SZ neurons may be more easily studied in NPCs.
Supervisors: Douglas Melton and Fred Gage
Address: Mount Sinai School of Medicine,
1425 Madison Ave
New York, NY
10029

less