In vivo survival and differentiation of Friedreich ataxia iPSC-derived sensory neurons transplanted in the adult dorsal root ganglia.

Serena Viventi,Mirella Dottori,Kwaku Dad Abu-Bonsrah,Stefano Frausin,Jeffrey R Mcarthur,Wayne Ng,Lachlan Thompson,Sara E Howden,Rocio K Finol-Urdaneta,Shiang Y Lim,Jason Ivanusic

doi:10.1002/sctm.20-0334

Abstract

Friedreich ataxia (FRDA) is an autosomal recessive disease characterized by degeneration of dorsal root ganglia (DRG) sensory neurons, which is due to low levels of the mitochondrial protein Frataxin. To explore cell replacement therapies as a possible approach to treat FRDA, we examined transplantation of sensory neural progenitors derived from human embryonic stem cells (hESC) and FRDA induced pluripotent stem cells (iPSC) into adult rodent DRG regions. Our data showed survival and differentiation of hESC and FRDA iPSC‐derived progenitors in the DRG 2 and 8 weeks post‐transplantation, respectively. Donor cells expressed neuronal markers, including sensory and glial markers, demonstrating differentiation to these lineages. These results are novel and a highly significant first step in showing the possibility of using stem cells as a cell replacement therapy to treat DRG neurodegeneration in FRDA as well as other peripheral neuropathies.

Highlights

The peripheral nervous system (PNS) is one of the primary and most significant sites of degeneration occurring in Friedreich ataxia (FRDA)
Results from RT-qPCR analyses performed on FRDA-derived sensory neurons confirmed expression of Overall, the expression profile analyses revealed the presence of cells that show positivity for a variety of dorsal root ganglia (DRG) sensory neuronal markers of nociceptor, mechanoreceptor, and proprioceptor subtypes. These results suggest that FRDA induced pluripotent stem cells (iPSC) are capable of differentiating to most, if not all, DRG sensory neuronal subpopulations in vitro
We have previously reported that the human pluripotent stem cells (hPSCs) sensory differentiation protocol gives rise to similar proportions of TRKA, B and C expression in vitro,[37] it is well documented that HPSC sensory neuronal differentiation may be highly variable between experiments.[43]

Summary

Introduction

The peripheral nervous system (PNS) is one of the primary and most significant sites of degeneration occurring in Friedreich ataxia (FRDA). The neurological symptoms result from progressive degeneration of large sensory neurons (proprioceptive neurons) in the DRG and their axonal projection in the posterior columns, as well as from degeneration of the spinocerebellar and corticospinal tracts of the spinal cord.[3] FRDA is due to the presence of a trinucleotide GAA repeat expansion in the first intron of the FRATAXIN (FXN) gene, causing reduced levels of full-length FXN transcript and lower synthesis of the mitochondrial protein FXN. Large sensory DRG neurons and cerebellar neurons are mainly affected within the nervous system. As clinical assessments are becoming more sensitive, several other neurological pathways appear to be affected, including the auditory and visual systems as well as speech.[7,8,9] These findings suggest that neurodegeneration occurs within multiple neuronal cell types

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