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Background
In the last decades, much effort has been made to overcome issues in clinical potential application of human central nervous system (CNS) precursors for transplantation in neurological diseases [1, 2]. One potent therapy consists in the use of in vitro expanded neural progenitor cells (NPCs) [3]. Precursor cells from rat embryonic ventral mesencephalon can be expanded in vitro and differentiated into dopaminergic neurons whose transplantation in hemiparkinsonian rats results in a functional recovery [4]. In addition, the transplantation into Parkinsonian rats of human dopamine neurons derived from in vitro expanded midbrain precursors results in successful grafts [5]. The success of such therapies depends on the efficiency of in vitro generation of human dopamine neurons prior to the transplantation. Numerous reports emphasize the critical impact of a simple supplementation of the culture medium with ascorbic acid (AA); doses comparable to the physiologic extracellular levels in the brain [6] facilitate the large-scale production of dopaminergic neurons from CNS precursors ([7-18]; see Table 1). AA is an essential nutrient widely admitted as an antioxidant agent in vivo [19, 20], and playing a role as cofactor in various biochemical reactions of the cell metabolism [21]. Moreover, AA treatment not only affects CNS precursor differentiation but also enhances dopamine neuron conversion from human placenta-derived mesenchymal stem cells [22], human blood embryonic stem cells [23] or adult rat skeletal muscle-derived stem cells [24], which suggests that AA could participate in the lineage cell commitment. [ Table Omitted - see PDF ]
Table 1
Overview of reports stressing that AA ameliorates the neuronal differentiation from NPC progenitors
NPC models
Differentiation factors
Enhanced effects
Refs.
Rat embryonic mesencephalic cell cultures
200 ?M AA
-Glial differentiation
-Neurite growth
-Dopamine neurons
[7]
Mouse embryonic stem cells
200 ?M AA + SHH + FGF8
-Dopamine neurons
-Serotonin neurons
[8]
Long-term basic fibroblast growth factor expanded rat mesencephalic precursors
100 ?M AA
-Dopamine neurons
[9]
Mouse embryonic stem cells
200 ?M AA + SHH + FGF8
-Dopamine neurons
[10]
Nurr1-transfected rat embryonic cortical progenitors
200 ?M AA + B27
-Dopamine neurons
[11]
Rat embryonic cortical precursors
200 ?M AA
-Astrocyte differentiation
-Neuronal differentiation and maturation
[12]
Mouse ventral mesencephalic precursors
200 ?M AA
-Astrocyte differentiation
-Dopamine neurons
-Gene responses related to cell fate determination, neuron development...