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Niche Notch Signaling Supports Dental MSC-like Perivascular Cell Function

Review of “Notch signaling in the dynamics of perivascular stem cells and their niches” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Research led by Thimios A. Mitsiadis (University of Zurich, Switzerland) has established the importance of the Notch pathway, a fundamental cell communication mechanism, in regulating stem cell behavior in dental pulp tissue niches [1-3]. Studies by the Mitsiadis group also reported that the mesenchymal stem cell (MSC)-like perivascular cells that lie close to dental pulp stem cells also express Notch receptors [4] and that, overall, Notch signaling represents a fundamental signaling hub that functions throughout tooth development [5-7].

Even given this wealth of data, we lack a complete understanding of the role of Notch signaling in dental tissues homeostasis and regeneration; for this reason, Pagella et al. investigated the role of Notch signaling in the interactions of dental MSC-like perivascular cells with their niches based on their composition and gene expression patterns at single-cell resolution. These findings, detailed in their recent STEM CELLS Translational Medicine article, provide additional support for the pivotal importance of Notch signaling in the crosstalk between dental MSC-like perivascular cells and their niches in tissue homeostasis and regeneration [8].

Single-cell RNA sequencing data analysis [9] revealed that the MSC-like perivascular cells of the human dental pulp and periodontal tissues expressed NOTCH3. While NOTCH3 expression correlated to the maintenance of osteogenic, adipogenic, and chondrogenic differentiation capacity, the differentiation of MSC-like perivascular cells led to a significant decrease in NOTCH3 expression. Interestingly, cellular and molecular cues deriving from the microenvironment, including the expression of all five NOTCH ligands (JAG1, JAG2, DLL1, DLL3, and DLL4) from endothelial cells (constituting a conserved perivascular niche), modulated the behavior of these NOTCH3-expressing MSC-like perivascular cells.

The authors also discovered the essential nature of NOTCH3-expressing MSC-like perivascular cells to the response to traumatic injuries (cavity preparations) in vivo in a transgenic mouse model – they accumulated close to the injured site and gave rise to odontoblast-like cells but not activated fibroblasts, immune cells, or Schwann cells. Meanwhile, an analysis of the dental pulp of carious human teeth linked the disorganization of the odontoblasts and the significant dilatation of the blood vessels correlated to the more widely distributed pattern of NOTCH3 expression compared to healthy dental pulps.

Overall, these exciting findings highlight the general importance of NOTCH signaling between dental MSC-like perivascular cells and the endothelial cell niche in the control of dental tissue homeostasis and regeneration. Furthermore, the authors envisage that this data may also foster the development of advanced MSC-based regenerative approaches to dental disease and disorders.

For more on the importance of NOTCH3 signaling in dental MSC-like perivascular cells, stay tuned to the Stem Cells Portal!


  1. Mitsiadis TA, Feki A, Papaccio G, et al., Dental Pulp Stem Cells, Niches, and Notch Signaling in Tooth Injury. Advances in Dental Research 2011;23:275-279.
  2. Mitsiadis TA, Catón J, Pagella P, et al., Monitoring Notch Signaling-Associated Activation of Stem Cell Niches within Injured Dental Pulp. Frontiers in Physiology 2017;8:372-372.
  3. Mitsiadis TA, Roméas A, Lendahl U, et al., Notch2 protein distribution in human teeth under normal and pathological conditions. Experimental Cell Research 2003;282:101-109.
  4. Shi S and Gronthos S, Perivascular Niche of Postnatal Mesenchymal Stem Cells in Human Bone Marrow and Dental Pulp. Journal of Bone and Mineral Research 2003;18:696-704.
  5. Mitsiadis TA, Lardelli M, Lendahl U, et al., Expression of Notch 1, 2 and 3 is regulated by epithelial-mesenchymal interactions and retinoic acid in the developing mouse tooth and associated with determination of ameloblast cell fate. Journal of Cell Biology 1995;130:407-418.
  6. Mitsiadis TA, Henrique D, Thesleff I, et al., Mouse Serrate-1 (Jagged-1): expression in the developing tooth is regulated by epithelial-mesenchymal interactions and fibroblast growth factor-4. Development 1997;124:1473-1483.
  7. Mitsiadis TA, Hirsinger E, Lendahl U, et al., Delta–Notch Signaling in Odontogenesis: Correlation with Cytodifferentiation and Evidence for Feedback Regulation. Developmental Biology 1998;204:420-431.
  8. Pagella P, de Vargas Roditi L, Stadlinger B, et al., Notch signaling in the dynamics of perivascular stem cells and their niches. STEM CELLS Translational Medicine 2021;10:1433-1445.
  9. Pagella P, de Vargas Roditi L, Stadlinger B, et al., A single-cell atlas of human teeth. iScience 2021;24:102405-102405.