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

Abstract

SummaryHuntington 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.

Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease

“…When injury or degeneration is so severe that a cavity has formed, or when glial cells themselves are significantly damaged, there will be a deficit of glial source to enact the conversion. In such severe injury condition, it may be necessary to transplant external cells to fill the cavity first for tissue repair 49 . Another limitation is for the treatment of diseases caused by gene mutations, such as the Htt mutation in R6/2 mouse model for HD used in this study.…”

Prion-like mechanisms in neurodegenerative disease: Implications for Huntington’s disease therapy

“…The study results showed that the mice had reduced motor deficits as evidenced by reduced clasping and increased latency to fall from the rotarod. Moreover, the transplanted HD mice lived beyond their defined life span (∼19% increase) compared with the untreated, control mice . However, the transplanted cells in the HD brain contained mHTT aggregates in the nucleus, proving that the aggregates were transferred from the host cells to the transplanted cells.…”

Drug screening for human genetic diseases using iPSC models

“…Pluripotent-derived cells are amendable to organoid-based studies as they show capability of self-organization and have demonstrated the recapitulation of complex tissue architectures of the biliary tree (94), brain (95)(96)(97)(98), fallopian tube (99), intestine (100), liver (101,102), kidney (103), pancreas (104,105), retina (106)(107)(108)(109) and stomach (110). Such protocols have been applied to a host a genetic diseases including Alagille syndrome (111,112), autism (113), cystic fibrosis (94,112,114), enhanced scone syndrome (115), familial adenomatous polyposis (116), Huntington's disease (117), Leber congenital amaurosis (118), microcephaly (96), microlissencephaly (119), Miller-Dieker lissencephaly syndrome (120,121), polycystic kidney disease (122), retinitis pigmentosa (107)(108)(109), Rett syndrome (123,124) and Timothy syndrome (125). While these pluripotent-based organoids have yet to be heavily scaled they have been used as part of small-scale, targeted drug testing for Alagille syndrome (112), cystic fibrosis (94,112), familial adenomatous polyposis (116), polycystic liver disease (112) and Timothy syndrome (125).…”