StemCell Therapy

NIDCR-Supported Researchers Explore Basic Biology & Therapeutic Potential

More than 15 years ago, NIDCR researcher Pamela Robey, PhD, and colleagues made the surprising discovery that humanbaby teeth and wisdom teeth contain adaptable cells known as stem cells, which can transform into other cell types. These readily accessible cells raised early hopes that they might revolutionize repair of teeth and oral tissues, and possibly lead to new therapies for diabetes, heart disease, and neural conditions.

But scientists soon realized that the complex biology of dental stem cells made it challenging to move from animal models to human patients. The US FDA has yet to approve the use of dental stem cells in medical procedures, Robey says.

Based on current evidence, clinical use of dental stem cells may be closest to fruition for root canal therapy or repair of bone defects caused by gum disease. However, the possibility of regenerating whole teeth and other uses may be many more decades down the road.

To fully explore the potential of these versatile cells, NIDCR supports a range of scientists who are working to better understand dental stem cells and their therapeutic promise.

Basic Questions

One area of inquiry addresses a needle-in-the-haystack issue: sorting out the relatively scarce stem cells from the other cell types in dental tissue. To be used in experiments or in the clinic, dental stem cells must first be identified, isolated through a process called enrichment, then assessed to ensure theyre at the right stage of development.

In order to identify and enrich stem cells, NIDCR-supported researchers are looking for proteins or genes specifically expressed by dental stem cells that can serve as identifiers, or markers, to distinguish them from other cells. We have pretty good markers for the mature progeny of dental stem cells, Robeysays. But more and better markers are needed to isolate highly enriched stem cell populations that will enable high-quality experiments.

Nadya Lumelsky, PhD, director of NIDCRs Tissue Engineering and Regenerative Medicine Program, notes that highly enriched dental stem cell populations will also be key to developing potential therapies. Separating the irrelevant cells from a population means that a higher fraction are true stem cells, which means the replacement tissue is higher quality and can more reliably repair defects, Lumelsky says. Better methods of enriching and expanding dental stem cells will also be important for generating sufficient numbers of cells to be used at the scale needed for clinical studies.

More reliable markers for dental stem cells will help scientists trace the process of stem cell development and differentiation as it naturally occurs in the body during normal growth or after tissue injury or damage. Much research has been done on dental stem cell behavior in culture. But stem cells in a dish behave differently from stem cells in their natural environment, Robey notes. Some insights into the natural behavior of dental stem cells have been gleaned through studies of mice and their continuously renewing incisors. Yet the differences between mouse and human dental stem cells remain unclear.

Identifying the cellular and molecular signals that guide stem cell repair processes in the body will help researchers develop strategies for recreating these processes in stem cell therapies. It could also help scientists learn how to reliably prompt cells to differentiate into one cell type and not anotherin the case of dental stem cells, how to produce the hard tissue called dentin instead of pulp, for instance.

Instead of removing and re-implanting stem cells, alternative approaches called autotherapies employ small molecules or other minimally invasive methods to trigger stem cells healing properties inside the body. For example, some NIDCR-supported scientists are exploring ways to repair teeth by recruiting dental stem cells to the site of damage or decay and prompting them to regenerate pulp and dentin.

A Path to the Clinic

Beyond the basic investigations of dental stem cell biology, some NIDCR-supported scientists are exploring how the cells might be used in the clinic to help to repair bone and teeth. A major area of research involves the potential usedental stem cells in root canal therapy. Dental specialists perform root canal procedureswhen pulp becomes inflamed or infected. A clinician removes the dental pulp, cleans the inside of the tooth, then fills and seals the space. However, repaired teeth that lack pulp may become brittle and more likely to break. To improve root canal outcomes, several NIDCR-supported researchers are exploring the use of dental stem cells to replace inflamed tissue and regenerate healthy pulp.

Jacques Nr, DDS, PhD,at the University of Michigan, is one of these scientists. Several years ago, Nrs group loaded dental stem cells into a human tooth slice that contained a physical support structure, or scaffold, for the cells.

Transplanting these constructs into mice resulted in dental pulp tissue approximating normal dental pulp, Nr says. His group is now addressing a common barrier to much of the regenerative medicine field: providing a blood supply to regenerated tissue. Integrating blood vessels is vital for effective tissue regeneration, and dental pulp is no exception.

Nrs group has directed dental pulp stem cells to generate structures resembling blood vessels that integrate with the mouses own vasculature. How this happens is still unclear, though, and his group continues to explore the question. Understanding the molecular signals that guide this process will allow us to develop a successful pulp regeneration strategy for eventual clinical use, Nr says. The findings from this research may also apply to the use of dental stem cells in other therapeutic contexts, such as potential bone regeneration.

Other researchers are looking for markers to identify and isolate bone-forming dental stem cells. These studies also entail finding the precise molecular recipe to prompt the cells to form bone.

Once dental stem cells are implanted in a defect, whether tooth or bone, the proper physical and chemical atmospherecalled a microenvironmentis necessary to keep the cells growing and alive. NIDCR-supported scientists are working to optimize stem cell microenvironments for given therapies. One important facet is optimizing scaffolds for the cells. Regenerative therapies cant work without the proper structure to corral and guide cell growth, and different tissues require different scaffolds.

While much work remains to be done before dental stem cells enter the clinic, Nr remains optimistic that the cells easy accessibility and regenerative properties make them a valuable asset.

These unique cells may translate into helping patients in the not-too-distant future, Nr says. Its important to strike the right balance between caution and hope.

References

Sipp D, Robey PG, Turner L. Clear up this stem-cell mess. Nature. 2018 Sep;561(7724):455-457. doi: 10.1038/d41586-018-06756-9.

Zhang Z, Nor F, Oh M, Cucco C, Shi S, Nr JE. 36. Wnt/-Catenin Signaling Determines the Vasculogenic Fate of Postnatal Mesenchymal Stem Cells. Stem Cells. 2016 Jun;34(6):1576-87. doi: 10.1002/stem.2334.

Bento LW, Zhang Z, Imai A, Nr F, Dong Z, Shi S, Araujo FB, Nr JE. Endothelial differentiation of SHED requires MEK1/ERK signaling. J Dent Res. 2013 Jan;92(1):51-7. doi: 10.1177/0022034512466263. Epub 2012 Oct 31.

Sakai VT, Zhang Z, Dong Z, Neiva KG, Machado MA, Shi S, Santos CF, Nr JE. SHED differentiate into functional odontoblasts and endothelium. J Dent Res. 2010 Aug;89(8):791-6. doi: 10.1177/0022034510368647. Epub 2010 Apr 15.

Cordeiro MM, Dong Z, Kaneko T, Zhang Z, Miyazawa M, Shi S, Smith AJ, Nr JE. Dental pulp tissue engineering with stem cells from exfoliated deciduous teeth. J Endod. 2008 Aug;34(8):962-9. doi: 10.1016/j.joen.2008.04.009.

Miura M, Gronthos S. Zhao M, Lu B, Fisher LW, Robey PG, Shi S. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci USA. May 13;100(10):5807-12. Epub 2003 Apr 25.

Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13625-30.

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