The Autism Spectrum Disorders Stem Cell Resource at Children's Hospital of Orange County: Implications for Disease Modeling and Drug Discovery

Abstract

The autism spectrum disorders (ASDs) comprise a set of neurodevelopmental disorders that are, at best, poorly understood but are the fastest growing developmental disorders in the United States. Because animal models of polygenic disorders such as the ASDs are difficult to validate, the derivation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming offers an alternative strategy for identifying the cellular mechanisms contributing to ASDs and the development of new treatment options. Access to statistically relevant numbers of ASD patient cell lines, however, is still a limiting factor for the field. We describe a new resource with more than 200 cell lines (fibroblasts, iPSC clones, neural stem cells, glia) from unaffected volunteers and patients with a wide range of clinical ASD diagnoses, including fragile X syndrome. We have shown that both normal and ASD-specific iPSCs can be differentiated toward a neural stem cell phenotype and terminally differentiated into action-potential firing neurons and glia. The ability to evaluate and compare data from a number of different cell lines will facilitate greater insight into the cause or causes and biology of the ASDs and will be extremely useful for uncovering new therapeutic and diagnostic targets. Some drug treatments have already shown promise in reversing the neurobiological abnormalities in iPSC-based models of ASD-associated diseases. The ASD Stem Cell Resource at the Children's Hospital of Orange County will continue expanding its collection and make all lines available on request with the goal of advancing the use of ASD patient cells as disease models by the scientific community.

Integrated transcriptome analysis of human iPS cells derived from a fragile X syndrome patient during neuronal differentiation

“…We obtained a FXS-iPSC cell line (named SC128) from Dr. Philip H. Schwartz at Children's Hospital of Orange County, USA (Brick et al, 2014). This cell line has been stably and homogenously expanded for over 28 passages and kept maintaining ESC-like morphology (data not shown).…”

“…We obtained HDF2-iPSC cell line from UCLA Stem Cell Core (Liao et al, 2010) and FXS-iPSC cell line (named SC128) from Dr. Philip H. Schwartz at Children's Hospital of Orange County, USA (Brick et al, 2014). Cells were maintained at 37°C and 5% CO2, and the media changed every three days.…”

“…To test this hypothesis, we obtained and examined a FXS-iPSC cell line (a kind gift from Dr. Philip H. Schwartz) from the fibroblasts of a FXS patient with expanded CGG repeats on the FMR1 promoter (Brick et al, 2014). We then differentiated FXS-iPSC, along with a healthy iPS cell line HDF2-iPSC as control, into post-mitotic neurons through different stages, i.e., iPSC aggregates (IA), neuroepithelia (NE), neuroepithelia aggregates (NA).…”

Modeling Fragile X Syndrome Using Human Pluripotent Stem Cells

“…Second, it can serve as a powerful tool for disease modeling, in that iPSCs can be easily derived from somatic cells of patients by any stem cell investigating lab. In fact, many mutant iPSC lines have already been established for FXS, and is the main approach for creating human-based disease models of dynamic mutations that otherwise cannot/are difficult to artificially induce in hESCs [31,32,33,34,35,36,37,38,39]. Nevertheless, despite the great similarity between hESCs and iPSCs, there are some discrepancies between both cell types which can be crucial and should be taken in to consideration when addressing unresolved questions related to FXS.…”

Culturing Human Pluripotent and Neural Stem Cells in an Enclosed Cell Culture System for Basic and Preclinical Research

“…A cell production facility that can address both contamination risks and gas concentrations and that can be qualified to meet cGMP criteria 9 provides high quality cells for basic science research as well as clinical applications 1,6,7 . Such a cell production facility consists, at a minimum, of the following components: a process chamber, which acts as a heated workspace for the feeding and manipulation of cell cultures; a laminar flow hood, for the initial sterilization of reagents, tubes, and tools; two buffering airlock chambers in between the hood and the process chamber; two cell culture incubators accessible from the process chamber; a microscope chamber adjacent to the process chamber; and finally, computer software to set and monitor the conditions within these modules.…”