Neural grafting and circuit reconstructions to treat neurodegenerative diseases: perspects from the field

Limited capacity of the adult human brain to generate new neurons impairs its ability to repair after injury or disease. The promising therapeutic strategy for treatment of various neurodegenerative diseases is cell replacement by transplantation of human fetal- and stem-cell-derived neurons. Current protocols for fetal and stem cell differentiation allow the generation of transplantable progenitors with the capability to survive, mature and form functional connections with host targets. One of the most studied neurodegenerative diseases in prospect of cell replacement therapy is Parkinson's disease (PD). A number of preclinical studies has already shown successful survival and innervation of transplanted midbrain dopamine neurons(mDA), and subsequent motor function restoration. Transplant connectivity in-depth understanding was enabled with the application of novel strategies like optogenetics, pharmacogenetics, transsynaptic tracing and usage of genetic constructs for visualisation of graft and its input-output host cells. Despite the existing achievements in the field, there are plenty of factors whose role in graft integration remains elusive. In clinical trials of PD cell therapy conducted by now, transplanted neurons were placed ectopically to decrease the distance the engrafted mDA axons must grow to innervate appropriate targets and enable motor function restoration. Though for some of the patients therapy was effective, overall functional recovery was incomplete, which may be linked to absence of innervation of other structures but striatum. Several preclinical studies have now investigated the impact of ectopic or homotopic graft placement on graft inputs and outputs including both striatal and extrastriatal regions. Recent studies showed that engrafted cell type, and thus cell-intrinsic factors, determine graft-derived axonal innervation, while synaptic inputs from host neurons primarily reflect the graft location. Another topic under investigation is the possibility of axonal growth stimulation from the engrafted mDA. Moriarty et al. analysed the influence of growth-promoting cue like GDNF(glial-cell line-derived neurotrophic factor) delivery to forebrain regions and showed that over-expression of GDNF resulted in better innervation of mDA neurons’ targets, larger proportion of A9 and A10 mDA neurons in the graft, and greater fraction of A9 cells forming connections. Besides this, GDNF-treated animals showed motor function correction in behavioural tests and reinstatement of striatal dopamine level in comparison to no GDNF. The results of previously mentioned studies, while confirming integration of the graft into the host network, did not cover the circuit reconstruction for different types of mDA neurons and its resemblance to the one of intact brain. Aldrin-Kirk et al. studied this topic with the application of method of monosynaptic rabies-based tracing and demonstrated several distinct regions with differential host inputs to A9 and A10 mDA neurons depending on their projections. The newly formed graft-derived connections displayed close similarity to the circuits in the intact brain. The presented results suggest the possibility to re-establish most of the endogenous circuitry by means of human mDA neuron grafts. Therefore, human fetal- or stem-cell-derived neurons transplation can be considered as a promising approach to treat neurodegenerative diseases with high potential of translation to clinics.