Scientists have developed organoids from stem cells that can produce tooth enamel proteins. This research aims to harness these advances in dental treatments such as repairing damaged teeth and completely regenerating lost teeth.
This progress is seen as a crucial first step towards innovative treatments for tooth restoration and regeneration.
Stem cells have been used to generate organoids that release proteins involved in the formation of tooth enamel, a substance that protects teeth from damage and caries. The effort was led by a multidisciplinary team of researchers at the University of Washington in Seattle.
“This is an important first step toward our long-term goal of developing stem cell-based therapies to repair damaged teeth and regenerate lost teeth,” said the University of Washington School of Dentistry. is a professor of dentistry and co-–The author of the paper describing the research.
The results of the survey will be published today in the magazine developmental cells. Ammar Algadia, a graduate student in the Hannelle Ruohora-Baker lab at the University of Wisconsin School of Medicine, Department of Biochemistry, was the first author of the paper. This 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 stress caused by chewing and helps resist tooth decay. It is the hardest tissue in the human body.
Enamel is made by specialized cells called ameloblasts during tooth formation. These cells die when tooth formation is complete. As a result, the body has no way to repair or regenerate the damaged enamel, leaving teeth susceptible to fracture or even tooth loss.
To create ameloblasts in the lab, researchers first had to understand the genetic program that causes fetal stem cells to develop into these highly specialized enamel-producing cells.
In this lab image of a developing incisor, colors identify which genes are 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). Reveal which genes are active at different stages of cell development.
This is possible because an RNA molecule called messenger RNA (mRNA) carries instructions to encoded proteins. DNA It transmits activated genes to the molecular machinery that assembles proteins. This is why changes in mRNA levels at different stages of cell development tell us which genes are turned on and which are turned off at each stage.
By performing sci-RNA-seq on cells at various stages of human tooth development, researchers were able to obtain a series of snapshots of gene activation at each stage. . A sophisticated computer program called Monocle was then used to construct possible trajectories of gene activity that occur as undifferentiated stem cells develop into fully differentiated ameloblasts.
“The computer program predicts how to get from here to there, the roadmap, the blueprint needed to build ameloblasts,” said Ruohora Baker, who led the project. She is Professor of Biochemistry and Associate Director of the Institute of Stem Cell and Regenerative Medicine, University of California, School of Medicine.
Planning this trajectory, the researchers, after much trial and error, succeeded in inducing undifferentiated human stem cells to become ameloblasts. They did this by exposing stem cells to chemical signals known to activate various genes in sequences that mimic pathways revealed by sci-RNA-seq data. In some cases, we used known chemical signals. In other cases, collaborators at the Protein Design Laboratory at the University of California Institute of Medicine created computer-designed proteins with enhanced efficacy.
Hannelle Ruohora Baker in the Stem Cell Lab at the University of Washington School of Medicine in Seattle. She recently headed research to develop stem cell-based organoids capable of secreting tooth enamel proteins. Credit: UW Medicine Institute for Stem Cell and Regenerative Medicine
During this project, scientists also identified for the first time another cell type called subdental cells. It is thought to be the precursor of odontoblasts, a cell type important for tooth formation.
Researchers have found that these cell types can be induced together to form small, three-dimensional, multicellular mini-organs called organoids. They organized into structures similar to those found in developing human teeth and secreted three essential enamel proteins, ameloblastin, amelogenin and enamel. These proteins form the matrix. An essential mineralization process follows to form enamel with the required hardness.
Zhang said the researchers now hope to improve the process of producing enamel that rivals the durability found in natural teeth, and develop ways to use this enamel to repair damaged teeth. It says. One approach is to create enamel in the lab that can be used to fill cavities and other imperfections.
Another, more ambitious approach, Ruohola-Baker points out, is to create “living fillings” that can grow into and repair cavities and other defects. The ultimate goal is to create stem cell-derived teeth that can completely replace missing teeth.
Ruohola-Baker said teeth are an ideal model to work on developing other stem cell therapies.
“Many of the organs we want to be able to replace, such as the human pancreas, kidneys and brain, are large and complex. It takes time to regenerate them safely from stem cells,” she says. “Teeth, on the other hand, are much smaller and less complex. Perhaps those are easy achievements to achieve. I can see the steps.”
She predicts, “This may finally be the ‘century of living fillings’ and human regenerative dentistry in general.”
References: “Single-cell investigation of human tooth development enables generation of human enamel,” Ammar Alghadeer, Sesha Hanson-Drury, Anjali P. Patni, Devon D. Ehnes, Yan Ting Zhao, Zicong Li, By Ashish Phal, Thomas Vincent, Yen C. Lim, Diana O’Day, Keirin H. Sparel, Aishwarya A. Gogate, Hai Chan, Alykes Devi, Julian Wang, Lea Stalita, Dan Doherty, Ian A. A. Glass, Jay Shendure, Benjamin S. Friedman, Hannelle Ruohora-Baker, 14 Aug. 2023, developmental cells.
DOI: 10.1016/j.devcel.2023.07.013
This research was supported by funding from the United States 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, the University of California School of Medicine Stem Cell and Regenerative Medicine Fellowship, and the Douglas L. Morell Doctoral Research Fund. Research conducted in the Genomics Core of the Institute for Stem Cell and Regenerative Medicine was supported by a donation from the John H. Tietze Foundation.
