Modelling of Neurological Diseases Using Induced Pluripotent Stem Cells

Human embryonic stem cells (hESCs) were first established as an in vitro culture system (Thomson et al., 1998). hESCs are pluripotent cells that are able to self-renew and can differentiate into the three primary germ layers: endoderm, ectoderm and mesoderm. Specifically, hESCs can be used to generate gut epithelium, cartilage, bone, muscle, neuroepithelium, and embryonic ganglia (Zhang et al., 2001, Itskovitz-Eldor et al., 2000, Sottile et al., 2003, Thomson et al., 1998, Green et al., 2003). Since these hESC cell lines can be maintained for months in an undifferentiated state, they can be used as a stable resource to model human development in vitro. The conversion of hESCs to neural progenitors and subsequently to the three main neural lineages: neurons, astrocytes and oligodendrocytes was first demonstrated in 2001 (Reubinoff et al., 2001). The recent advent (Takahashi and Yamanaka, 2006) of induced pluripotent stem cells (iPSCs) makes it possible to derive pluripotent stem cells from somatic tissue. iPSCs are derived by transfecting somatic cells (e.g. skin fibroblasts) with a select group of transcription factors; Sox2, Oct4, Myc and Klf4 to induce reprogramming of the genome over a period of 3-4 weeks. This breakthrough by Yamanaka and colleagues enables the modelling of human disease by, for example, taking a patient’s skin cells, converting them to iPSCs and then differentiating it to any desired cell-type. Thus iPSC technology opens a new era of patient-specific disease modelling. Here, we review diseases of the nervous system that have been modelled using iPSC which includes; RETT syndrome (RTT), Familial dysautonomia (FD), Parkinson’s disease (PD), Huntingtons (HD) and Amyotrophic Lateral Sclerosis (ALS). To provide some background to the neurological disease modelling studies by iPSCs we begin by reviewing protocols for neural induction (differentiation) of hESC.