(630d) hESC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington’s Disease Mouse Model

Huntington’s disease (HD) is an inherited neurological disorder characterized by the progressive degeneration of striatal medium spiny neurons (MSNs), which eventually leads to fatal deficits in movement, cognition, and behavior. One promising approach for treating HD is cell replacement therapy, where lost cells are replaced by striatal MSNs or MSN progenitors derived from human pluripotent stem cells (hPSCs). While remarkable prior work paved the way to generate MSNs from hPSCs for application towards HD treatment, as with many stem cell differentiation processes the current state-of-the-art methods for producing striatal MSNs rely on 2D culture systems that typically include poorly defined components, limit scalability, and have yielded mixed therapeutic outcomes in animal models of HD. To take a next step towards clinical translation, here we develop an approach for the efficient generation of striatal progenitors from human embryonic stem cells (hESCs) within a fully defined and scalable PNIPAAm-PEG 3D hydrogel. Specifically, a 2-fold higher fraction of DARPP32⁺ striatal neurons were generated in the 3D biomaterial, which demonstrated functional electrophysiological maturity 30 days earlier, relative to cells differentiated on conventional 2D surfaces. Following their efficient derivation, transplantation of 3D-derived striatal progenitors into a transgenic mouse model of HD slowed disease progression, improved motor coordination, and significantly increased lifespan by 41%. Importantly, 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.