hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model

Maroof M Adil; Thomas Gaj; Antara T Rao; Rishikesh U Kulkarni; Christina M Fuentes; Gokul N Ramadoss; Freja K Ekman; Evan W Miller; David V Schaffer

doi:10.1016/j.stemcr.2018.03.007

hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model

Stem Cell Reports. 2018 May 8;10(5):1481-1491. doi: 10.1016/j.stemcr.2018.03.007. Epub 2018 Apr 5.

Authors

Maroof M Adil¹, Thomas Gaj², Antara T Rao³, Rishikesh U Kulkarni⁴, Christina M Fuentes², Gokul N Ramadoss¹, Freja K Ekman⁴, Evan W Miller⁵, David V Schaffer⁶

Affiliations

¹ Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA 94720, USA.
² Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA.
³ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁴ Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
⁵ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; The Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
⁶ Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: schaffer@berkeley.edu.

Abstract

Huntington disease (HD) is an inherited, progressive neurological disorder characterized by degenerating striatal medium spiny neurons (MSNs). One promising approach for treating HD is cell replacement therapy, where lost cells are replaced by MSN progenitors derived from human pluripotent stem cells (hPSCs). While there has been remarkable progress in generating hPSC-derived MSNs, current production methods rely on two-dimensional culture systems that can include poorly defined components, limit scalability, and yield differing preclinical results. To facilitate clinical translation, here, we generated striatal progenitors from hPSCs within a fully defined and scalable PNIPAAm-PEG three-dimensional (3D) hydrogel. Transplantation of 3D-derived striatal progenitors into a transgenic mouse model of HD slowed disease progression, improved motor coordination, and increased survival. In addition, the transplanted cells developed an MSN-like phenotype and formed synaptic connections with host cells. Our results illustrate the potential of scalable 3D biomaterials for generating striatal progenitors for HD cell therapy.

Keywords: Huntington disease; biomaterials; cell replacement therapy; differentiation; human pluripotent stem cells; medium spiny neurons.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / drug effects
Animals
Cell Differentiation / drug effects
Cell Survival / drug effects
Corpus Striatum / pathology*
Disease Models, Animal
Hedgehog Proteins / metabolism
Humans
Huntington Disease / pathology*
Huntington Disease / therapy*
Hydrogels / pharmacology*
Mice
Neurons / drug effects
Neurons / metabolism
Neurons / pathology
Phenotype
Pluripotent Stem Cells / cytology
Pluripotent Stem Cells / drug effects
Pluripotent Stem Cells / transplantation*
Wnt Signaling Pathway / drug effects

Substances

Hedgehog Proteins
Hydrogels

Abstract

Publication types

MeSH terms

Substances

Grants and funding