Transplantation in HD: Are We Transplanting the Right Cells?

Abstract

Cell replacement therapy is a viable option for the treatment of Huntington's disease (HD), where the aim is to replace the lost medium spiny projection neurons of the striatum. The intra-striatal engraftment of developing striatal precursors harvested from the foetal brain has provided proof of concept in both rodent models and human patients that these primary foetal tissue grafts can bring about a degree of functional recovery in a HDdegenerated brain. With the advent of pluripotent stem cell technologies, novel, potential alternative donor cell sources have become available. Ongoing studies are assessing the capacity of these cells to differentiate towards striatal precursors for transplantation in HD. Here, we review the characteristics of potential donor cells for HD with respect to available cell markers, functional properties and maturity of cells upon transplantation. We consider the optimal composition of the donor cell population, that is, whether a heterogeneous population containing all cell types from the developing striatum (the whole ganglionic eminence) is preferable to a more homogeneous population of striatal projection neurons, as directed by differentiation protocols applied to pluripotent stem cells. Furthermore, we consider what might be required to improve transplant efficacy and success, with respect to striatal differentiation of transplanted cells and functional improvement.

Induced pluripotent stem cells derived from the developing striatum as a potential donor source for cell replacement therapy for Huntington disease

“…Intra-STR allografts of MSN progenitors derived from primary fetal whole ganglionic eminence (WGE), the primordial striatum, have been shown to express DARPP-32 ( PPP1R1B ), the principal marker of MSNs, and bring about motor and cognitive functional recovery in HD rat models. Similarly, expression of DARPP-32 donor-derived cells, along with functional improvements, has been observed in xenografts of human WGE (hWGE) in the HD rat striatum [4] . CRT clinical trials have provided evidence of safety and feasibility of intra-STR transplantation of primary hWGE in HD patients.…”

“…Human pluripotent stem cells (hPSCs), principally human embryonic stem cells (hESCs) and human induced PSCs (iPSCs), are an appropriate alternative donor source, as they are renewable, accessible for quality control and theoretically capable of differentiating toward an STR fate [4] . There is evidence that iPSCs inherit some epigenetic features associated with the cells from which they were derived, which results in some retained phenotypic features [ 8 , 9 ].…”