Stem Cells at Work – (It’s called “Wingless”) — Brains and Teeth Decay and Repair the Same Way

teeth

Stem-cell enhancing drugs can successfully promote teeth to repair themselves, at least in mice, according to a new study but this research is about far more than tooth decay….it actually is based on research in “brain decay” and the technology they employ here promises to be of use throughout many tissues and organs in our bodies.

It is actually startling and disappointing to see that the medical paparazzi are focused on the “drug” used as an Alzheimer’s drug…whereas the process taking place is one that characterizes the life and death of all cells throughout nature, and has been found to be very close to the heart of regulation of the development and maturation of stem cells into pluripotent progenitor cells and their subsequent differentiation into cells in every tissue and organ of our body.  The “wingless” gene which is impacted gets it name from Drosophila…and, yes, it operates throughout all life in all of nature

When a tooth loses dentin, the boney layer beneath the enamel, stems cells deep in their pulpy centers can help regrow lost tissue. Normally, this mechanism is only able to repair small cavities and cracks. But Paul Sharpe and colleagues at King’s College London found that applying Tideglusib, an Alzheimer’s drug, can enhance this process.

As we are now finding with the advent of the use of pluripotent progenitor cells in all the various tissues and organ systems of the body, the principles are very much the same and the “usual suspects’ are indeed the same ones in multiple systems. The brain’s “neurogenic niches” operate in a way very much like those niches in other tissues.

The activation of Wnt/β-cat (Wingless) signalling is an immediate early response to tissue damage and appears to be essential for stimulating the cellular-based repair in all tissues and provides a potential route for enhancing natural repair by overstimulating this pathway Wnt/βcatenin signalling has thus emerged as a major target in tissue regeneration and repair and this pathway activity can be stimulated in a number of different ways.

The Wingless (Wnt) signaling pathway is highly studied and conserved from lower to higher organisms, where it plays a variety of roles in almost all tissues.

As an indicator of just how universal these pathways are can be seen by the origins of the term “wingless”. The wg gene, the Drosophila counterpart of vertebrate Wnt-1, was first identified as a hypomorphic mutation leading to wing deficient flies. The presence and clear identification in the fruitfly, led researchers to characterize other previously known genes, labelled but not related, as the Drosophila gene known as Wingless (Wg). Wingless family became the Wnt family and int1 became Wnt1. The name Wnt stands for “Wingless-related integration site” When they speak of “the WNT signalling pathway” they are referring to a process very much like that which creates wingless fruitflies…as well as neurogenesis.

Broadly speaking, Wnt signaling in the brain can be divided into two main pathways: (i) “canonical” signaling that results in the stabilization of the protein β-catenin , which upon stabilization, can exert functions at the plasma membrane or in the nucleus and can act as a transcription factor that modulates the expression of target genes ; and (ii) “non-canonical” β-catenin-independent signaling Interestingly, many of the proteins in both signaling pathways localize to the synapse and play important functions in synaptic growth and maturation ].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137220/

Here the researchers aiming to trigger stem cell function to regrowth of dentine tissues in the mouse, reasoned that addition of Wnt signaling agonists may provide an effective way to stimulate reparative dentine formation and thus restore lost dentine following caries removal with naturally-generated new dentine

Since upregulated Wnt activity in response to damage is an immediate early response we aimed to achieve rapid release of small molecule agonists and reasoned a sponge was the most effective way of ensuring this.

Numerous small molecule inhibitors of glycogen synthase kinase 3 (GSK3) have been developed and shown to efficiently do just that. The nihibitors of GSK-3 upregulate Wnt activity in different experimental contexts Both BIO and CHIR99021 have been extensively used experimentally to elevate Wnt activity while Tideglusib is in clinical trials for systemic use in the treatment of neurological disorders include Alzheimers disease

GSK-3 is apparently a key factor in the pathogenesis of Alzheimer’s as well as in the prevention of proper tooth repair. The molecule is a pivotal molecule in the development of Alzheimer’s disease (AD). GSK-3beta is involved in the formation of paired helical filament (PHF)-tau, which is an integral component of the neurofibrillary tangle (NFT) deposits that disrupt neuronal function, and a marker of neurodegeneration in AD. Results strongly suggest that GSK-3 activation is a critical step in brain aging and the cascade of detrimental events in AD

https://www.ncbi.nlm.nih.gov/pubmed/16914869

As a further example of its ubiquity, selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), which are used to treat depression, potentially by increasing hippocampal neurogenesis in mice, have been shown to antagonize canonical Wnt signaling, which causes a reduction in expression of the serotonin transporter (SERT). Lithium is a well-known treatment for bipolar disorder, and one of its main activities is inhibition of GSK-3β, which positively stimulates the canonical Wnt pathway . Stimulants such as Methylphenidate (e.g., Ritalin) can function as a negative regulator of the canonical pathway by activating GSK-3.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137220/

The many areas in which GSK3 has been found in our brains have led it to being called “a master switch”. More aptly, it is key in the neurogenesis process..and that process is essential for the maintenance of the life and death of old cells and their replacement by newly matured cells from the neurogenenic niches.

Glycogen synthase kinase 3 inhibitors promote adult hippocampal neurogenesis

: In the central nervous system, developing neurons are derived from quiescent multipotent or neural stem cells. Throughout life, neural progenitors in the sub ventricular zone of the lateral ventricles and the sub-granular zone of the dentate gyrus of the hippocampus give rise to interneurons of the olfactory bulb and neurons of the granule cell layer of the dentate gyrus. Glycogen synthase kinase-3 beta (GSK-3beta) is a regulator of glycogen metabolism

But, not coincidental;y and very much in connection with how epigenetic and metabolic factors impact on our health by action on the development and maturation of new cells (truly the issue in most disease states) it also plays a pivotal role in in regulating neuronal differentiation and in particular, in hippocampal stem/progenitor cells.

Studies have shown that inhibitors of GSK-3 beta are potent inducers of neuroblasts formation in the sub granular zone of the dentate gyrus of the hippocampus (one of the regions in which neurogenesis takes place in the adult brain) of adult rats. Also, in vitro studies demonstrate that inhibition of GSK-3 beta induces proliferation, migration, and differentiation of neural stem cells towards a neuronal phenotype.

http://digital.csic.es/handle/10261/102108

To antagonize the GSK-3 in the teeth of the mice, the researchers drilled holes in their tiny teeth and filling the cavities with a biodegradable drug-soaked collagen sponge. Six weeks later, they found that the treatment had helped the mice regrow the lost dentin in their teeth. In a manner parallel to the way that GSK3 antagonists function in our brains, the use of these GSK3 antagonists promotes the natural processes of reparative dentine formation to completely restore dentine The researchers are now testing whether the treatment can scale up to rat teeth and, ultimately, human teeth. And why not, the same approach is being studied in trials with Alzheimer’s patients.

http://www.the-scientist.com/?articles.view/articleNo/47960/title/Enhancing-Stem-Cells-Helps-Regenerate-Damaged-Teeth-in-Mice/

“Almost everyone on the planet has tooth decay at some time—it’s a massive volume of people being treated.” Sharpe told The Guardian. “We’ve deliberately tried to make something really simple, really quick and really cheap.”

If a simple method can be developed that acts to enhance the natural processes of dentine restoration by stimulating tertiary dentine formation, then large injuries that would certainly lead the dental pulp to undergo necrosis could be repaired by enabling reparative dentine to be formed at the site of damage.

Small molecule Wnt signalling agonists delivered via a biodegradable collagen sponge provide an effective repair of experimentally-induced deep dental lesions by promotion of reparative dentine formation

http://www.nature.com/articles/srep39654

All three agonists showed significantly increased mineralisation at the site of damage compared to the use of the sponge alone or MTA treatment. More significantly the localization of the reparative dentine formed indicated that with the treatments, the mineral replaced the biodegradable sponge and restored the cavity in the dentine made by the burr. With MTA the cavity remains permanently filled with mineral aggregate and this non-degradable material can only affect reparative dentine formation on the pulp chamber aspect.

The small localised doses of these agonists used were effective at increasing the formation of reparative dentine to the extent that almost complete repair of the lesion was observed after 6 weeks. These doses are substantially lower that those used in clinical trials of Tideglusib where 500–1000 mg were delivered systemically daily for 26 weeks

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