Stem Cell-Derived Human Striatal Progenitors Innervate Striatal Targets and Alleviate Sensorimotor Deficit in a Rat Model of Huntington Disease

Abstract

Huntington disease (HD) is an inherited late-onset neurological disorder characterized by progressive neuronal loss and disruption of cortical and basal ganglia circuits. Cell replacement using human embryonic stem cells may offer the opportunity to repair the damaged circuits and significantly ameliorate disease conditions. Here, we showed that in-vitro-differentiated human striatal progenitors undergo maturation and integrate into host circuits upon intra-striatal transplantation in a rat model of HD. By combining graft-specific immunohistochemistry, rabies virus-mediated synaptic tracing, and ex vivo electrophysiology, we showed that grafts can extend projections to the appropriate target structures, including the globus pallidus, the subthalamic nucleus, and the substantia nigra, and receive synaptic contact from both host and graft cells with 6.6 ± 1.6 inputs cell per transplanted neuron. We have also shown that transplants elicited a significant improvement in sensory-motor tasks up to 2 months post-transplant further supporting the therapeutic potential of this approach.

The Neurodevelopmental Hypothesis of Huntington’s Disease

“…To date, there have been multiple studies evaluating molecular and cellular mechanisms of abnormal development in HD. For example see recent studies on transcriptomics [4], and studies of induced pluripotent stem cell lines [5][6][7][8][9][10][11][12], as well as studies investigating abnormal brain development in HD animal models [13][14][15][16][17]. As a whole, this literature is rich and supports the notion that abnormal development may play a role in the pathogenesis of disease.…”

Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington’s Disease Mouse Striatum

“…Results of cell fate in our HD mouse studies uniquely appear to follow a neuronal developmental path in contrast to a more gliogenic outcome, potentially due to the differentiation potential of the starting material or the transplantation niche (Goldberg et al, 2017; Qian et al, 2020; Yoon et al, 2020). A recent study using a rat model of HD induced by intrastriatal quinolinic acid injection, showed that human embryonic stem cell-derived MSN progenitors differentiate in vitro , undergo maturation, integrate into host circuits, and display properties similar to those of the host striatum 2 months after transplantation (Besusso et al, 2020), suggesting feasibility of transplanting differentiated MSN progenitors. Notably, behavioral studies in this model demonstrated functional recovery of some impaired sensorimotor responses but not in more complex behaviors (e.g., rotarod test).…”

Neuronal Replacement as a Tool for Basal Ganglia Circuitry Repair: 40 Years in Perspective

“…The expression pattern of the DARPP-23 positive cells indicates that they are striatal projection neurons of the type normally generated by the lateral ganglionic eminence (LGE). This is further supported by their ability to establish axonal connections with downstream striatal targets, including globus pallidus and substantia nigra, accompanied by a gradual improvement in measures of sensorimotor performance on the side opposite to the excitotoxic lesion and transplantation (Ma et al, 2012;Adil et al, 2018;Besusso et al, 2020). Although the extent and functionality of the graft-derived connectivity need to be explored in greater detail, the recent study by Besusso et al (2020), using a combination of immunohistochemistry and monosynaptic rabies virus tracing, has provided initial evidence that the hESC-derived striatal grafts can become well integrated into the lesioned host striatal circuitry.…”

“…The percentage of DARPP-32+/CTIP2+ neurons generated in these protocols vary between 20 and 60%. Also, the grafts have been shown to contain other neuronal types, including GABAergic interneurons (Besusso et al, 2020), and in one case also a significant component (27%) of GFAP-positive astrocytes (Adil et al, 2018).…”