A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells

Abstract

Summary Autism spectrum disorders (ASD) are complex neurodevelopmental diseases in which different combinations of genetic mutations may contribute to the phenotype. Using Rett syndrome (RTT) as an ASD genetic model, we developed a culture system using induced pluripotent stem cells (iPSCs) from RTT patients’ fibroblasts. RTT patients’ iPSCs are able to undergo X-inactivation and generate functional neurons. Neurons derived from RTT-iPSCs had fewer synapses, reduced spine density, smaller soma size, altered calcium signaling and electrophysiological defects when compared to controls. Our data uncovered early alterations in developing human RTT neurons. Finally, we used RTT neurons to test the effects of drugs in rescuing synaptic defects. Our data provide evidence of an unexplored developmental window, before disease onset, in RTT syndrome where potential therapies could be successfully employed. Our model recapitulates early stages of a human neurodevelopmental disease and represents a promising cellular tool for drug screening, diagnosis and personalized treatment.

Concise Review: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells: Close Enough or Yet Too Far Apart?

“…One example is the X chromosome inactivation in human iPSC lines of female origin. There are reports of ''ground state'' lines, where both X chromosomes are again active [16,17], while others show persistence of X chromosome inactivation [18]. But there is a general ambiguity associated with the human pluripotent lines isolated so far.…”

Neural stem cells: mechanisms and modeling

“…Rett syndrome results from mutations in the X-chromosome-linked MeCP2 gene, which regulates gene expression through modulating DNA methylation (Akbarian, 2003;Chahrour and Zoghbi, 2007). Fibroblasts of patients with Rett syndrome have been successfully reprogrammed into iPSCs (Hotta et al, 2009;Marchetto et al, 2010a). In Marchetto et al's study, the phenotypes of Rett syndrome were recapitulated in neurons differentiated from patient-derived iPSCs, and have subsequently been extensively studied.…”

Rett Syndrome: Reaching for Clinical Trials

“…More recently, embryonic fibroblasts from a mouse model with the R255X nonsense mutation were treated with gentamycin and were able to express full-length MeCP2 [74]. Gentamycin also increased dendritic spine density in neurons derived from induced pluripotent stem cells obtained from a RTT individual with a Q244X nonsense mutation [75]. However, the renal and auditory toxicity, as well as poor central nervous system penetration of aminoglycoside antibiotics, limits their applicability.…”