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NO MORE CAVITIES? ORGANOIDS PAVE THE WAY FOR ENAMEL REGENERATION

TOPICS:DentistryPopularRegenerationStem CellsTeethUniversity of Washington

By University of Washington School of Medicine August 16, 2023

Scientists have developed organoids from stem cells capable of producing dental
enamel proteins. The research aims to use these advancements for dental
treatments, including repairing damaged teeth or entirely regenerating lost
ones.


THIS ADVANCE IS VIEWED AS A PIVOTAL INITIAL STEP TOWARD INNOVATIVE THERAPIES FOR
THE REPAIR AND REGENERATION OF TEETH.

Stem cells have been used to produce organoids that release the proteins
responsible for forming dental enamel, a substance that shields teeth from harm
and decay. This initiative was led by a multi-disciplinary team of researchers
from the University of Washington in Seattle.

“This is a critical first step to our long-term goal to develop stem cell-based
treatments to repair damaged teeth and regenerate those that are lost,” said Hai
Zhang, professor of restorative dentistry at the UW School of Dentistry and one
of the co–authors of the paper describing the research.



The findings are published today in the journal Developmental Cell. Ammar
Alghadeer, a graduate student in Hannele Ruohola-Baker’s laboratory in the
Department of Biochemistry at the UW School of Medicine was the lead author on
the paper. The lab is affiliated with the UW Medicine Institute for Stem Cell
and Regenerative Medicine.



The researchers explained that tooth enamel protects teeth from the mechanical
stresses incurred by chewing and helps them resist decay. It is the hardest
tissue in the human body.

Enamel is made during tooth formation by specialized cells called ameloblasts.
When tooth formation is complete, these cells die off. Consequently, the body
has no way to repair or regenerate damaged enamel, and teeth can become prone to
fractures or be subject to loss.

To create ameloblasts in the laboratory, the researchers first had to understand
the genetic program that drives fetal stem cells to develop into these highly
specialized enamel-producing cells.

In this lab image of a developing incisor tooth, colors identify which genes are
being expressed at each stage of development. Credit: University of Washington
Dental Organoid Research Group

To do this they used a technique called single-cell combinatorial indexing RNA
sequencing (sci-RNA-seq), which reveals which genes are active at different
stages of a cell’s development.

This is possible because RNA molecules, called messenger RNA (mRNA), carry the
instructions for proteins encoded in the DNA of activated genes to the molecular
machines that assemble proteins. That is why changes in the levels of mRNA at
different stages of a cell’s development reveal which genes are turned on and
off at each stage.

By performing sci-RNA-seq on cells at different stages of human tooth
development, the researchers were able to obtain a series of snapshots of gene
activation at each stage. They then used a sophisticated computer program,
called Monocle, to construct the likely trajectory of gene activities that occur
as undifferentiated stem cells develop into fully differentiated ameloblast.

“The computer program predicts how you get from here to there, the roadmap, the
blueprint needed to build ameloblasts,” said Ruohola-Baker, who headed the
project. She is a professor of biochemistry and associate director of the UW
Medicine Institute for Stem Cell and Regenerative Medicine.

With this trajectory mapped out, the researchers, after much trial and error,
were able to coax undifferentiated human stem cells into becoming ameloblasts.
They did this by exposing the stem cells to chemical signals that were known to
activate different genes in a sequence that mimicked the path revealed by the
sci-RNA-seq data. In some cases, they used known chemical signals. In other
cases, collaborators from the UW Medicine Institute for Protein Design created
computer-designed proteins that had enhanced effects.

Hannele Ruohola-Baker in her stem cell research lab at the University of
Washington School of Medicine in Seattle. She recently helped head a study to
develop stem-cell-based organoids that could secrete dental enamel proteins.
Credit: UW Medicine Institute for Stem Cell and Regenerative Medicine

While conducting this project, the scientists also identified for the first time
another cell type, called a subodontoblast, which they believe is a progenitor
of odontoblasts, a cell type crucial for tooth formation.

The researchers found that together these cell types could be induced to form
small, three-dimensional, multicellular mini-organs, called organoids. These
organized themselves into structures similar to those seen in developing human
teeth and secreted three essential enamel proteins: ameloblastin, amelogenin,
and enamelin. These proteins would then form a matrix. A mineralization process
that is essential for forming enamel with the requisite hardness would follow.

Zhang said the research team now hopes to refine the process to make an enamel
comparable in durability to that found in natural teeth and develop ways to use
this enamel to restore damaged teeth. One approach would be to create enamel in
the laboratory that could then be used to fill cavities and other defects.

Ruohola-Baker points out that another more ambitious approach would be to create
“living fillings” that could grow into and repair cavities and other defects.
Ultimately, the goal would be to create stem cell-derived teeth that could
replace lost teeth entirely.

Ruohola-Baker said teeth are an ideal model to work on the development of other
stem cell therapies.

“Many of the organs we would like to be able to replace, like human pancreas,
kidney, and brain, are large and complex. Regenerating them safely from stem
cells will take time,” she said. “Teeth on the other hand are much smaller and
less complex. They’re perhaps the low-hanging fruit. It may take a while before
we can regenerate them, but we can now see the steps we need to get there.”

She predicts, “This may finally be the ‘Century of Living Fillings’ and human
regenerative dentistry in general.”

Reference: “Single-cell census of human tooth development enables generation of
human enamel” by Ammar Alghadeer, Sesha Hanson-Drury, Anjali P. Patni, Devon D.
Ehnes, Yan Ting Zhao, Zicong Li, Ashish Phal, Thomas Vincent, Yen C. Lim, Diana
O’Day, Cailyn H. Spurrell, Aishwarya A. Gogate, Hai Zhang, Arikketh Devi,
Yuliang Wang, Lea Starita, Dan Doherty, Ian A. Glass, Jay Shendure, Benjamin S.
Freedman and Hannele Ruohola-Baker, 14 August 2023, Developmental Cell.
DOI: 10.1016/j.devcel.2023.07.013

This work was supported by funding from the U.S. National Institutes of Health,
the National Heart, Lung, and Blood Institute Progenitor Cell Biology
Consortium, the Eunice Kennedy Shriver National Institute of Child Health and
Human Development, UW Medicine Institute of Stem Cell and Regenerative Medicine
Fellowships and the Dr. Douglass L. Morell Research Fund. Work conducted in the
Institute for Stem Cell and Regenerative Medicine’s Genomics Core was supported
by a gift from the John H. Tietze Foundation.


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6 COMMENTS ON "NO MORE CAVITIES? ORGANOIDS PAVE THE WAY FOR ENAMEL REGENERATION"

 1. Ferozkhan | August 17, 2023 at 3:24 am | Reply
    
    I having dentail problem from long time cavities in my teeth always cool and
    hot in my teeth pls I need ur perfect advice 🙏 pls reaply in detail and
    mail me ur faithful ness

 2. PHIL | August 17, 2023 at 5:51 am | Reply
    
    Hello,
    This has already been done several times; Credontis Ag of Switzerland comes
    to mind. They have patented items that are not only for sale; there are
    several dentists in the USA using it, to reverse and protect against
    cavities. Previous news articles from years past, and science journals
    indicate that regrowing of teeth has been done before; This news article is
    just a rehash of things i have followed for over a decade. Tides-Glucib was
    a anti Alzheimer drug that had remarkable progress in regrowing damaged
    teeth as a side effect. Please research further to find the truth that this
    news article denies. Oh and Listen to Rich men North of Richmond by Oliver
    Anthony………..

 3. Randy Blackin | August 17, 2023 at 9:44 am | Reply
    
    Would this approach allow enamel to grow where gum decay has caused
    recession and exposed teeth surfaces?

 4. Ken Towe | August 17, 2023 at 11:27 am | Reply
    
    Unlike the tiny crystals in dentin, the larger size mineral
    (hydroxylapatite) in fully-formed enamel has a very high crystallographic
    preferred orientation, reproducing that will be a problem. Randomly oriented
    crystals might have a seriously different look and resistance to abrasion.

 5. Gary | August 17, 2023 at 4:41 pm | Reply
    
    I have crowding teeth since I started growing teeth more than 75 years ago.
    Now I have a mouth of pyorreha.

 6. Curt welty | August 17, 2023 at 7:04 pm | Reply
    
    When will this be available throughout the US.


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