Derivation of autism spectrum disorder-specific induced pluripotent stem cells from peripheral blood mononuclear cells

Abstract

Induced pluripotent stem cells (iPSCs) hold tremendous potential both as a biological tool to uncover the pathophysiology of disease by creating relevant cell models and as a source of stem cells for cell-based therapeutic applications. Typically, iPSCs have been derived by the transgenic overexpression of transcription factors associated with progenitor cell or stem cell function in fibroblasts derived from skin biopsies. However, the need for skin punch biopsies to derive fibroblasts for reprogramming can present a barrier to study participation among certain populations of individuals, including children with autism spectrum disorders (ASDs). In addition, the acquisition of skin punch biopsies in non-clinic settings presents a challenge. One potential mechanism to avoid these limitations would be the use of peripheral blood mononuclear cells (PBMCs) as the source of the cells for reprogramming. In this article we describe the derivation of iPSC lines from PBMCs isolated from the whole blood of autistic children, and their subsequent differentiation in GABAergic neurons.

Human induced pluripotent stem cells for modelling neurodevelopmental disorders

“…An alternative protocol, that combined dual SMAD inhibition with retinoid signaling led to a 95% efficiency of neuronal differentiation 40 and has been used to model Alzheimer disease and schizophrenia 41–43 . In addition, many more variations of 2D protocols exist, which have been developed and successfully used to generate specific neuronal subtypes, such as GABAergic inhibitory neurons 44 , glutamatergic neurons 44, and hippocampal granule neurons 45 (see table 1 for more information on different monolayer protocols).…”

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

“…X chromosome inactivation status in female human induced pluripotent stem cells (hiPSCs) and their differentiation into neurons have shown complexities. A small number of recent papers have begun to explore cellular phenotypes of autism observed in hiPSC-derived neurons [121][122][123].…”

The need for a comprehensive molecular characterization of autism spectrum disorders

“…Neuronal cultures derived from iPSCs can be used to investigate disease phenotypes and molecular disease pathology, and there is also potential that they can be used for drug screening (Marchetto et al, 2010;Sheridan et al, 2011). New techniques have also emerged which can derive iPSCs from cells in blood (DeRosa et al, 2012) and urine (Zhou et al, 2012), which is less invasive than the skin punch biopsy approach that is generally used in fibroblast generation. To generate iPSCs from these starting materials the somatic cells are genetically reprogrammed into a pluripotent state by viral vector introduction of stem cell transcription factors (Lowry et al, 2008;Park et al, 2008;Zhou et al, 2009).…”

“…However, none of these iPSC lines were derived from patients diagnosed solely with ASD. Up to now, one specific ASD iPSC cell line has been developed, and this was produced from patient lymphocytes (DeRosa et al, 2012). However, studies comparing these ASD-iPSCs with control iPSCs have yet to be performed.…”