Embryonic Stem Cell-Derived Glial Precursors as a Vehicle for Sulfamidase Production in the MPS-IIIA Mouse Brain

Author:

Robinson Aaron J.1,Zhao Guoying1,Rathjen Joy2,Rathjen Peter D.2,Hutchinson Rhonda G.3,Eyre Helen J.3,Hemsley Kim M.14,Hopwood John J.14

Affiliation:

1. Lysosomal Diseases Research Unit, SA Pathology at the Women's and Children's Hospital, North Adelaide, Australia

2. School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia

3. Department of Cytogenetics, Women's and Children's Hospital, North Adelaide, Australia

4. Department of Paediatrics, University of Adelaide, Women's and Children's Hospital, North Adelaide, Australia

Abstract

Pluripotent stem cells, including human embryonic stem cells and induced pluripotent stem cells, have generated much excitement about their prospects for use in cell transplantation therapies. This is largely attributable to their virtually unlimited growth potential, their ability to be precisely genetically altered in culture, and their utility for forming differentiated cell populations with potential clinical applications. Lysosomal storage diseases such as Sanfilippo syndrome (MPS-IIIA) represent ideal candidate diseases for the evaluation of cell therapies in the central nervous system (CNS). These diseases exhibit widespread pathology yet result from a single gene deficiency, in the case of Sanfilippo syndrome the lysosomal enzyme sulfamidase. The aim of this study was to investigate mouse embryonic stem (ES) cell-derived glial precursor cells as a vehicle for sulfamidase delivery in the MPS-IIIA mouse brain. In this study we have created a mouse ES cell line genetically modified to stably express and secrete high levels of human sulfamidase and a protocol for the in vitro derivation of large numbers glial precursors from ES cells. Differentiation of sulfamidase-expressing ES cells resulted in cell populations with sustained secretion of high levels of sulfamidase, comprised primarily of glial precursor cells with minor contaminants of other neural cell phenotypes but not residual pluripotent cells. CNS implantation studies demonstrated that ES cell-derived glial precursor cells formed using this differentiation method were able to engraft and survive for at least 12 weeks following implantation. The percentage of engraftment was quantified in different regions of the brain in 2-, 4-, and 8-week-old normal and MPS-IIIA mice. No teratomas were observed in any of the cell-transplanted animals. The results of this study support the further investigation of sulfamidase-expressing glial precursor cells as a vehicle for delivery of deficient enzyme into the CNS of MPS-IIIA mice.

Publisher

SAGE Publications

Subject

Transplantation,Cell Biology,Biomedical Engineering

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