Abstract
Emerging evidence indicates that a strong relationship exists between brain regenerative therapies and nutrition. Early life nutrition plays an important role during embryonic brain development, and there are clear consequences to an imbalance in nutritional factors on both the production and survival of mature neuronal populations and the infant’s risk of diseases in later life. Our research and that of others suggest that vitamins play a fundamental role in the formation of neurons and their survival. There is a growing body of evidence that nicotinamide, the water-soluble amide form of vitamin B3, is implicated in the conversion of pluripotent stem cells to clinically relevant cells for regenerative therapies. This study investigated the ability of nicotinamide to promote the development of mature catecholaminergic neuronal populations (associated with Parkinson’s disease) from mouse embryonic stem cells, as well as investigating the underlying mechanisms of nicotinamide’s action. Nicotinamide selectively enhanced the production of tyrosine hydroxylase-expressing neurons and serotonergic neurons from mouse embryonic stem cell cultures (Sox1GFP knock-in 46C cell line). A 5-Ethynyl-2´-deoxyuridine (EdU) assay ascertained that nicotinamide, when added in the initial phase, reduced cell proliferation. Nicotinamide drove tyrosine hydroxylase-expressing neuron differentiation as effectively as an established cocktail of signalling factors, reducing the proliferation of neural progenitors and accelerating neuronal maturation, neurite outgrowth and neurotransmitter expression. These novel findings show that nicotinamide enhanced and enriched catecholaminergic differentiation and inhibited cell proliferation by directing cell cycle arrest in mouse embryonic stem cell cultures, thus driving a critical neural proliferation-to-differentiation switch from neural progenitors to neurons. Further research into the role of vitamin metabolites in embryogenesis will significantly advance cell-based regenerative medicine, and help realize their role as crucial developmental signalling molecules in brain development.
Highlights
There is a wealth of evidence indicating that diet and nutrition play a key role during sensitive windows of brain development, when early organizational processes such as differentiation and maturation of specific neuronal pathways are underway [1,2,3]
Nicotinamide (10 mM) elicited a significant increase in the percentage of βIII-tubulin-expressing neurons measured at 14 days of culture (t = 8.7; p
Nicotinamide treatment elicited a significant increase in the percentage of TH+ immunoreactive neurons within the whole cell population in comparison to control cultures (t = 6.1; p
Summary
There is a wealth of evidence indicating that diet and nutrition play a key role during sensitive windows of brain development, when early organizational processes such as differentiation and maturation of specific neuronal pathways are underway [1,2,3]. Pluripotent stem cells provide an important in vitro model system to investigate early events during human development and the therapeutic use of stem cells is a promising approach to combat neurodegenerative processes in the brain, e.g. the replacement of midbrain dopamine neurons in Parkinson’s disease (PD) [8] or serotonergic neurons in neuropsychiatric disorders [9]. While a number of these signalling pathways have already been identified (e.g. Lmx1a [12], Pitx3 [13], Nurr [14]), it is likely that there are as yet undiscovered factors that modulate the fate of specific midbrain neuronal cell populations during development
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