Human Dental Pulp Stem Cells Display a Potential for Modeling Alzheimer Disease-Related Tau Modifications

Abstract

We present here the first description of tau in human dental pulp stem cells (DPSCs) evidenced by RT-PCR data on expression of the gene MAPT and by immunocytochemical detection of epitopes by 12 anti-tau antibodies. The tau specificity of eight of these antibodies was confirmed by their affinity to neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) postmortem brain samples. We therefore used DPSCs and AD brain samples as a test system for determining the probability of the involvement of tau epitopes in the mechanisms converting tau into NFT in AD. Three antibodies to non-phosphorylated and seven antibodies to phosphorylated epitopes bound tau in both DPSCs and AD NFTs, thus suggesting that their function was not influenced by inducers of formation of NFTs in the AD brain. In contrast, AT100, which recognizes a hyperphosphorylated epitope, did not detect it in the cytoplasm of DPSCs but detected it in AD brain NFTs, demonstrating its AD diagnostic potential. This indicated that the phosphorylation/conformational events required for the creation of this epitope do not occur in normal cytoplasm and are a part of the mechanism (s) leading to NFT in AD brain. TG3 bound tau in the cytoplasm and in mitotic chromosomes but did not find it in nuclei. Collectively, these observations characterize DPSCs as a novel tau-harboring neuronal lineage long-term propagable in vitro cellular system for the normal conformational state of tau sites, detectable by antibodies, with their state in AD NFTs revealing those involved in the pathological processes converting tau into NFTs in the course of AD. With this information, one can model the interaction of tau with inducers and inhibitors of hyperphosphorylation toward NFT-like aggregates to search for drug candidates. Additionally, the clonogenicity of DPSCs provides the option for generation of cell lineages with CRISPR-mutagenized genes of familial AD modeling.

Neurogenic Potential of Human Dental Stem Cells

“…The epitope of the 12th antibody, AT100, bound NFT of Alzheimer's disease brains but did not bind tau of normal dental cells, and since this antibody is known as a major diagnostic tool for the disease, its failure to bind to normal tau is taken as evidence that its epitope is not formed in normal cells, but is formed in aggregated NFT tau cells, in accordance with previously described process [75]. As an additional property linked to neurodegeneration, dental cells were shown to contain the amyloid precursor (APP) and GSK3β (68) kinase (see [63]) associated with the tau pathological modifications.…”

“…Considering the above, we investigated the presence of tau in both stem cells of primary teeth (SHED) and stem cells of permanent teeth (in preparation). In both lineages, tau was present in significant quantities [63]. As a specific goal of the present study, we reprogrammed cells from one of the third molars and established a neural crest and mesenchymal embryonic developmental stages, of which only the latter stage cells contained tau protein.…”

“…The lack of sufficient information about the initial stages of transformation of normal tau into NFT to show the dependence of pathogenesis on this event makes the current view on tauopathies elusive. The use of 12 anti-tau antibodies highlighted tau epitopes and thus the presence of tau in stem cells of primary teeth (SHED) and compared these results with the tau of postmortem AD brain samples [63]. Eleven antibodies bound to epitopes both normal tau in dental cells and to modified tau (NFT) in Alzheimer's disease brain samples, demonstrating that the regions of tau where the epitopes are located are conserved in normal (dental) and in diseased (brain) cells.…”

Adult Mesenchymal Stem Cells from Oral Cavity and Surrounding Areas: Types and Biomedical Applications

“…Tau is the major component of neurofibrillary tangles (NFTs); therefore, antibodies against Tau and NFTs have allowed the characterization of the pathogenesis of neurofibrillary tangles (NFTs) in Alzheimer disease (EA). A study that has emerged for the first time describes an endogenous Tau protein in human DPSCs detected by its phosphorylated and unphosphorylated epitopes, demonstrating its potential to model normal Tau status and the possibility of inducing changes that mimic the modifications associated with neurodegeneration in AD [ 137 ]. In any case, despite the promising advances and preclinical studies in transgenic mouse models of AD, this has not been the case with clinical trials in humans due to the multifactorial nature and complex pathophysiology present in AD.…”

Platelet rich plasma enhanced neuro-regeneration of human dental pulp stem cells in vitro and in rat spinal cord

“…For example, Hochuli et al(19) found that neural induced deciduous tooth stem cells may be more useful for the treatment of spinal cord injury. Gazarian et al(20) used okadaic acid induction to detect the therapeutic effect of hDPSCs in the Alzheimer's disease model in vitro, and proved that it can significantly improve the viability of model cells and reduce apoptosis.These latest research results provide new insights into the future clinical application of dental pulp stem cells. Dental pulp provides potential stem cell resources for clinic, is beneficial to the cell therapy of various systemic diseases, and has the potential to provide a powerful tool for regenerative medicine.…”