Abstract
BackgroundDown syndrome (DS) is a common developmental disorder resulting from the presence of an additional copy of chromosome 21. Abnormalities in dopamine signaling are suggested to be involved in cognitive dysfunction, one of the symptoms of DS, but the pathophysiological mechanism has not been fully elucidated at the cellular level. Stem cells from human exfoliated deciduous teeth (SHED) can be prepared from the dental pulp of primary teeth. Importantly, SHED can be collected noninvasively, have multipotency, and differentiate into dopaminergic neurons (DN). Therefore, we examined dopamine signaling in DS at the cellular level by isolating SHED from a patient with DS, differentiating the cells into DN, and examining development and function of DN.MethodsHere, SHED were prepared from a normal participant (Ctrl-SHED) and a patient with DS (DS-SHED). Initial experiments were performed to confirm the morphological, chromosomal, and stem cell characteristics of both SHED populations. Next, Ctrl-SHED and DS-SHED were differentiated into DN and morphological analysis of DN was examined by immunostaining. Functional analysis of DN was performed by measuring extracellular dopamine levels under basal and glutamate-stimulated conditions. In addition, expression of molecules involved in dopamine homeostasis was examined by quantitative real-time polymerase chain reaction and immunostaining. Statistical analysis was performed using two-tailed Student’s t-tests.ResultsCompared with Ctrl-SHED, DS-SHED showed decreased expression of nestin, a neural stem-cell marker. Further, DS-SHED differentiated into DN (DS-DN) exhibiting decreased neurite outgrowth and branching compared with Ctrl-DN. In addition, DS-DN dopamine secretion was lower than Ctrl-DN dopamine secretion. Moreover, aberrant expression of molecules involved in dopaminergic homeostasis was observed in DS-DN.ConclusionsOur results suggest that there was developmental abnormality and DN malfunction in the DS-SHED donor in this study. In the future, to clarify the detailed mechanism of dopamine-signal abnormality due to DN developmental and functional abnormalities in DS, it is necessary to increase the number of patients for analysis. Non-invasively harvested SHED may be very useful in the analysis of DS pathology.
Highlights
Down syndrome (DS) is a common developmental disorder resulting from the presence of an additional copy of chromosome 21
The presence of 3 copies of chromosome 21 in the nuclei of DS-Stem cells from human exfoliated deciduous teeth (SHED) was verified by Fluorescence in situ hybridization (FISH) (Fig. 1b)
dopaminergic neurons (DN) differentiated from DS-SHED (DS-DN) expressed β-tubulin III and tyrosine hydroxylase (TH) (Fig. 2a), but neurite length and branching were reduced compared to DN differentiated from Ctrl-SHED (Ctrl-DN)
Summary
Down syndrome (DS) is a common developmental disorder resulting from the presence of an additional copy of chromosome 21. Abnormalities in dopamine signaling are suggested to be involved in cognitive dysfunction, one of the symptoms of DS, but the pathophysiological mechanism has not been fully elucidated at the cellular level. We examined dopamine signaling in DS at the cellular level by isolating SHED from a patient with DS, differentiating the cells into DN, and examining development and function of DN. It has been suggested that disturbance of the DA signaling system causes the cognitive impairments observed in DS [5,6,7]. As observed in patients with DS, varied amounts of DA have been reported in mouse models of DS [6, 7, 11, 12], suggesting that variable DA levels are associated with abnormal brain development. The role of the DA signaling system in DS pathology has yet to be analyzed at a cellular level
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