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Regionally-Derived Second-Trimester Primary hfNSCs Have Different Neurogenic Capacity for Neuronal Differentiation

Yiping Fan, Tong Zi Ping, Eyleen Goh, Mahesh Choolani and Jerry KY Chan

Parkinson disease is a debilitating neurodegenerative disease, which is incurable and treatment has been focused on reducing the symptoms and delaying disease progression. Cellular therapy involving grafting of fetal dopaminergic (DA) neurons or fetal mesencephalic tissues rich in DA neurons has been promising. Human fetal neural Stem Cells (hfNSCs) have the potential to be an ideal cell source and hence, we aimed to investigate DA differentiation capacity of eight regionally-derived hfNSCs while defining the differences between regionally-derived hfNSCs.

The differences in regionally-derived hfNSCs response to brain-derived neurotrophic factor, dopamine, forskolin and retinoic acid (DM2) or interleukin 1β and fetal bovine serum (DM1) indicated different intrinsic neurogenic potentials within the developing fetal brain. DM2 induced more efficient DA differentiation (Tyrosine Hydroxylase (TH)+) than DM1 in the spinal cord (SC), brain stem (BS) and sub-ventricular zone (SVZ) derived hfNSCs, although statistical significance was reached only for SC (p=0.02). Similarly, DM2 induced more efficient neuronal differentiation (myelin-associated protein 2a and b (MAP2ab)+) than DM1 in SC, posterior cerebrum, SVZ, thalamus, and BS NSCs, with statistical significance reached only for SC-NSCs (p=0.03). Collectively for all eight regional NSCs, TH and MAP2ab positive neuronal differentiation with DM2 was higher than DM1 (10.4 vs 4.6%, p=0.01, and 27.6 vs 11.6%, p=0.01 respectively). Whole genome expression array showed that BS and SC-NSCs are transcriptionally most similar, while the SVZ and cerebellum-derived NSCs have the largest differences in differentially regulated genes compared to the BS-NSCs. Compared to BS-NSCs, anterior cerebrum and hippocampal NSCs exhibited differences in all three gene ontology (growth factor binding, cytokine binding, and neurogenesis) interrogated, while SC, cerebellum and thalamus only exhibited significant differences in neurogenesis pathway compared to BS-NSCs.

By defining the basic neurogenic differentiation capacity and key molecular differences of regionally-derived hfNSCs, our data may facilitate the choice of regionally-derived hfNSCs for different clinical scenarios such as neurodegenerative or traumatic brain injuries.