Understanding the Influence of Target Acquisition on Survival, Integration, and Phenotypic Maturation of Dopamine Neurons within Stem Cell-Derived Neural Grafts in a Parkinson's Disease Model

• DOI: 10.1523/jneurosci.2431-21.2022
• Publication Date: 2022-05-24T17:51:03Z
• Authors: Niamh Moriarty; Jessica A. Kauhausen; Chiara Pavan; Cameron P.J. Hunt; Isabelle R. de Luzy; Vanessa Penna; Charlotte M. Ermine; Lachlan H. Thompson; Clare L. Parish
• Keywords: Medium spiny neuron; Oxidopamine

Midbrain dopaminergic (DA) neurons include many subtypes characterized by their location, connectivity and function. Surprisingly, mechanisms underpinning the specification of A9 [responsible for motor function, including within ventral midbrain (VM) grafts treating Parkinson9s disease (PD)] over adjacent A10, remains largely speculated. We assessed impact synaptic targeting on survival, integration, phenotype acquisition VM generated from fetal tissue or human pluripotent stem cells (PSCs). progenitors were grafted into female mice with 6OHDA-lesions host dopamine neurons, some animals also receiving intrastriatal quinolinic acid (QA) injections to ablate medium spiny (MSN), neuron primary target. While loss MSNs variably affected graft it significantly reduced striatal yet increased cortical innervation. Consequently, showed A10 specification, more DA failing mature either subtype. These findings highlight importance target subtype during development repair. <b>SIGNIFICANCE STATEMENT</b> Parish colleagues highlight, in a rodent model (PD), integration phenotypic derived cells. Ablation resulted survival grafts, re-routing fibers alternate targets consequential (the subpopulation critical restoration function) increase neurons.