Abstract:

The striatum is the main input structure of the basal ganglia and is involved in voluntary motor control, habit learning and reward processing. Medium spiny neurons (MSNs) comprise 80 and 95% of striatal neurons in primates and rodents, respectively, while the remaining population is made up of GABAergic and cholinergic interneurons. Up to 90% of MSNs are specifically lost in Huntington’s disease (HD), which is an inherited neurodegenerative disorder caused by an extended CAG-repeat mutation in the Huntingtin (HTT) gene. Although the exact mechanism by which mutant Htt protein disrupts striatal cell homeostasis and leads to MSN loss remains largely unknown, several studies using induced pluripotent stem cells (iPSCs) derived from patients have proven that this could be a powerful platform for understanding HD. Furthermore, with no disease-modifying treatment currently available, cell replacement has long been recognised as a potential therapy for HD. Human foetal tissue from the ganglionic eminences, the developmental birthplace of striatal neurons, has been used as a proof-of-principle in both pre-clinical animal studies and clinical trials. However, foetal tissue is in limited supply, involves ethical concerns and therapeutic product derived from it is impossible to quality-control; all of which could be avoided by using human PSCs (hPSCs) as a source of tissue for transplantation. In order to exploit the full potential of hPSCs, a robust differentiation paradigm is required to obtain an enriched population of MSNs in vitro and in vivo following transplantation. This Perspective will be focused on a recent discovery of a novel approach to generate MSNs from hPSCs using Activin A.