A major advance in regenerative dentistry shows Notch signaling and DLX3 as central regulators of enamel formation, with mature enamel-forming cells generated from human stem cells using a robust organoid platform for tooth development research, disease modeling, and therapy exploration.

DLX3 is essential for final ameloblast maturation; cells lacking DLX3 become early ameloblasts but fail to activate the full enamel-secreting gene program even under strong Notch stimulation.

Researchers employed single-cell RNA sequencing, human iPSCs differentiated into odontoblasts and ameloblasts, and three-dimensional ameloblast organoids to study maturation with and without odontoblasts.

Leading authors include Dr. Hannele Ruohola-Baker and Dr. Anjali P. Patni from the University of Washington, with the study published online in the International Journal of Oral Science on March 2, 2026.

The study paper is titled Soluble Notch agonist enables human ameloblast maturation and enamel-like tissue formation for tooth regeneration, and it carries the DOI https://doi.org/10.1038/s41368-026-00429-4.

Engineered organoids exhibited features of mature enamel-forming cells, including epithelial polarity and upregulated maturation markers such as ODAM, KLK4, TUFT1, FAM83H, and WDR72, and when transplanted under the kidney capsule in mice, formed enamel-like mineralized material.

In vivo enamel-like mineralization was observed after transplant of engineered organoids under the kidney capsule of immunodeficient mice, indicating functional potential.

Notch-activated organoids showed enamel-like properties, including epithelial polarity and upregulation of maturation markers, with enamel-like mineralization seen in mouse transplantation studies.