‘Living fillings’ could restore enamel, study finds

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enamel-growing organoids
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US scientists have created enamel-growing organoids which could help to restore and regrow damaged teeth.

The multi-disciplinary team of scientists from the University of Washington, Seattle, created organoids from stem cells to secrete the proteins that form dental enamel, publishing their findings in Developmental Cell.

“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,” co-author Professor Hai Zhang said.

Enamel is made during tooth formation by specialised cells called amelobasts. 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 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 specialised enamel-producing cells.

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,” Professor Ruohola-Baker said.

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.

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 organised 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 mineralisation process that is essential for forming enamel with the requisite hardness would follow.

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. 

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