TY - JOUR
T1 - hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model
AU - Adil, Maroof M.
AU - Gaj, Thomas
AU - Rao, Antara T.
AU - Kulkarni, Rishikesh U.
AU - Fuentes, Christina M.
AU - Ramadoss, Gokul N.
AU - Ekman, Freja K.
AU - Miller, Evan W.
AU - Schaffer, David V.
N1 - Publisher Copyright:
© 2018 The Author(s)
PY - 2018/5/8
Y1 - 2018/5/8
N2 - 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. Adil et al. used a 3D biomaterial to generate hPSC-derived MSN progenitors, which rapidly matured into action potential firing neurons. When striatally transplanted in HD genetic model mice, 3D-generated cells significantly delayed disease onset, alleviated disease symptoms, and increased lifespan. This approach demonstrates the scalable generation of functional MSNs, with implications for clinical translation of cell replacement therapy in HD.
AB - 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. Adil et al. used a 3D biomaterial to generate hPSC-derived MSN progenitors, which rapidly matured into action potential firing neurons. When striatally transplanted in HD genetic model mice, 3D-generated cells significantly delayed disease onset, alleviated disease symptoms, and increased lifespan. This approach demonstrates the scalable generation of functional MSNs, with implications for clinical translation of cell replacement therapy in HD.
KW - Huntington disease
KW - biomaterials
KW - cell replacement therapy
KW - differentiation
KW - human pluripotent stem cells
KW - medium spiny neurons
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U2 - 10.1016/j.stemcr.2018.03.007
DO - 10.1016/j.stemcr.2018.03.007
M3 - Article
C2 - 29628395
AN - SCOPUS:85044758179
SN - 2213-6711
VL - 10
SP - 1481
EP - 1491
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 5
ER -