www.thelancet.com/neurology Vol 10 April 2011 383 Review Lancet Neurol 2011; 10: 383–94 Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA (V B Mattis PhD, Prof C N Svendsen PhD) Correspondence to: Prof Clive N Svendsen, 8700 Beverly Boulevard, SSB 352, Los Angeles, CA 90048, USA clive.svendsen@cshs.org Induced pluripotent stem cells: a new revolution for clinical neurology? Virginia B Mattis, Clive N Svendsen Why specific neuronal populations are uniquely susceptible in neurodegenerative diseases remains a mystery. Brain tissue samples from patients are rarely available for testing, and animal models frequently do not recapitulate all features of a specific disorder; therefore, pathophysiological investigations are difficult. An exciting new avenue for neurological research and drug development is the discovery that patients’ somatic cells can be reprogrammed to a pluripotent state; these cells are known as induced pluripotent stem cells. Once pluripotency is reinstated, cell colonies can be expanded and differentiated into specific neural populations. The availability of these cells enables the monitoring in vitro of temporal features of disease initiation and progression, and testing of new drug treatments on the patient’s own cells. Hence, this swiftly growing area of research has the potential to contribute greatly to our understanding of the pathophysiology of neurodegenerative and neurodevelopmental diseases. Introduction Neurodegenerative diseases are increasing in prevalence worldwide as the population ages. For some disorders, genomic studies have revealed underlying genetic mutations, but progress linking them to changes in neuronal function has been slow. 1 For instance, the genetic cause of Huntington’s disease, an autosomal dominantly inherited neurological disorder, has been known since 1993; however, few new drugs have been developed after decades of research. In other neurological diseases, patients classified as having sporadic disease do not apparently carry any genetic mutations but might have developed the disorder through a combination of genetic and environmental factors. Hence, creation of accurate animal models of these diseases is difficult. The technology that enables generation of induced pluripotent stem (iPS) cells is around 4 years old. While this specialty is still in its scientific infancy, it is rapidly evolving. In this Review we discuss how iPS cells might be used to fill the gaps in modelling of human neurological diseases by creating a novel approach known as “disease in a dish”. The therapeutic potential of pluripotent stem cells has been described and will not be discussed here. 2–5 As with any new technology, however, caveats and hurdles hinder rapid introduction of this technology into the mainstream of modelling studies. Induced pluripotent stem cells The study of induced pluripotency has its roots in stem- cell biology and mammalian cloning. Primitive embryonic stem (ES) cells can be isolated from the inner cell mass of mouse, monkey, and human blastocysts. These cells may be expanded in culture while retaining pluripotency, or the ability to make all cells in the body. 6–8 Additionally, cloning of a sheep from an adult somatic cell showed that cells from mature mammalian tissue can be used to make a whole new organism. 9,10 In 2006, a landmark paper by Takahashi and Yamanaka 11 described how adult mouse fibroblasts could be reprogrammed back to a primitive state by overexpression of four genes expressed in ES cells: Pou5f1, Sox2, Klf4, and cMyc (figure 1). These reprogrammed cells, named iPS cells, were similar to ES cells and had the capacity to generate any cell in the body. 10 On the basis of these findings three independent groups successfully used similar genes to reprogramme human fibroblasts into iPS cells. 12–14 ES cells are grown in small colonies in a two-dimensional culture system, and require a feeder layer (generally mouse embryonic fibroblasts [MEFs]) or a feeder-free synthetic substrate (generally matrigel) to survive (figure 2). Similarly Figure 1: Generation of iPS cells Somatic cells (eg, fibroblasts, keratinocytes, leucocytes, or myocytes) are recovered from biopsy samples taken from a patient, and are reprogrammed to a pluripotent state. Reprogramming can be accomplished by use of a virus to transduce pluripotency genes, or with a combination of proteins, messenger RNAs, or various small molecules. Once reprogrammed, the cells are seeded on to MEFs (pink cells) and form colonies (blue cells). iPS=induced pluripotent stem. MEFs=mouse embryonic fibroblasts. Tissue cell type Fibroblasts Keratinocytes + Leucocytes Myocytes iPS cell colonies on MEFs Virus Proteins Reprogramming tools Pharmacological compounds RNA