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

Research output: Contribution to journalArticle

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. 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.

Original languageEnglish (US)
Pages (from-to)1481-1491
Number of pages11
JournalStem Cell Reports
Volume10
Issue number5
DOIs
StatePublished - May 8 2018
Externally publishedYes

Fingerprint

Corpus Striatum
Pluripotent Stem Cells
Hydrogel
Huntington Disease
Stem cells
Neurons
Recovery
Cell- and Tissue-Based Therapy
Biocompatible Materials
Genetic Models
Nervous System Diseases
Transgenic Mice
Action Potentials
Disease Progression
Transplantation
Polyethylene glycols
Scalability
Phenotype
Survival

Keywords

  • Huntington disease
  • biomaterials
  • cell replacement therapy
  • differentiation
  • human pluripotent stem cells
  • medium spiny neurons

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model. / Adil, Maroof M.; Gaj, Thomas; Rao, Antara T.; Kulkarni, Rishikesh U.; Fuentes, Christina M.; Ramadoss, Gokul N.; Ekman, Freja K.; Miller, Evan W.; Schaffer, David V.

In: Stem Cell Reports, Vol. 10, No. 5, 08.05.2018, p. 1481-1491.

Research output: Contribution to journalArticle

Adil, MM, Gaj, T, Rao, AT, Kulkarni, RU, Fuentes, CM, Ramadoss, GN, Ekman, FK, Miller, EW & Schaffer, DV 2018, 'hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model', Stem Cell Reports, vol. 10, no. 5, pp. 1481-1491. https://doi.org/10.1016/j.stemcr.2018.03.007
Adil, Maroof M. ; Gaj, Thomas ; Rao, Antara T. ; Kulkarni, Rishikesh U. ; Fuentes, Christina M. ; Ramadoss, Gokul N. ; Ekman, Freja K. ; Miller, Evan W. ; Schaffer, David V. / hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model. In: Stem Cell Reports. 2018 ; Vol. 10, No. 5. pp. 1481-1491.
@article{519c3d6f5cfd4918a43e1782218cefe3,
title = "hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model",
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. 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.",
keywords = "Huntington disease, biomaterials, cell replacement therapy, differentiation, human pluripotent stem cells, medium spiny neurons",
author = "Adil, {Maroof M.} and Thomas Gaj and Rao, {Antara T.} and Kulkarni, {Rishikesh U.} and Fuentes, {Christina M.} and Ramadoss, {Gokul N.} and Ekman, {Freja K.} and Miller, {Evan W.} and Schaffer, {David V.}",
year = "2018",
month = "5",
day = "8",
doi = "10.1016/j.stemcr.2018.03.007",
language = "English (US)",
volume = "10",
pages = "1481--1491",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "5",

}

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.

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

UR - http://www.scopus.com/inward/record.url?scp=85044758179&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044758179&partnerID=8YFLogxK

U2 - 10.1016/j.stemcr.2018.03.007

DO - 10.1016/j.stemcr.2018.03.007

M3 - Article

C2 - 29628395

AN - SCOPUS:85044758179

VL - 10

SP - 1481

EP - 1491

JO - Stem Cell Reports

JF - Stem Cell Reports

SN - 2213-6711

IS - 5

ER -