Gum Nerve Cells Become Tooth-Specific Mesenchymal Stem Cells


Stem cells self-renew and also produce progeny that differentiate into more mature cell types. The neurons and glia that compose nervous systems are examples of mature cells and these cells can be produced from embryonic stem cells, induced pluripotent stem cells, or neural stem cells. However, the reverse does not occur during development; more mature cells do not de-differentiate into less mature cells types. Development tends to be a one-direction event.

However, researchers have now discovered that inside teeth, nervous system cells can transform back into stem cells. This unexpected source of stem cells potentially offers stem cell scientists a new starting point from which to grow human tissues for therapeutic or research purposes without using embryos.

“More than just applications within dentistry, this finding can have very broad implications,” says developmental biologist Igor Adameyko of the Karolinska Institute in Stockholm, who led this new work. “These stem cells could be used for regenerating cartilage and bone as well.”

The soft “tooth pulp” in the center of teeth has been known to contain a small population of tooth-specific mesenchymal stem cells, which can typically differentiate into tooth-specific structures, bones, and cartilage. However, no one has conclusively determined where these stem cells came from. Adameyko hypothesized that if he could trace their developmental lineage, he should be able to recapitulate their development in the laboratory. This might offer new ways of growing stem cells for tissue regeneration.

Adameyko and his and colleagues had already studied glial cells, which are nervous system cells that surround neurons and support them. Several of the nerves that wind through the mouth and gums help transmit pain signals from the teeth to the brain are associated with glial cells.

Adameyko and others used fluorescent labels to mark the glial cells in the gum. When the gum-specific glial cells were observed over time, some of these cells migrated away from neurons in the gums into teeth, where they differentiated into mesenchymal stem cells. These same cells then matured into tooth cells. This work was reported in the journal Nature.

a–c, Incisor traced for 3 days from adult PLP-CreERT2/R26YFP mouse. Note protein gene product 9.5 (PGP9.5)+ nerve fibres (a). b, c, Magnified areas from a. d, e, Incisor traced for 30 days from adult PLP-CreERT2/R26YFP mouse. Note collagen IV+ blood vessels (d). e, YFP+ odontoblasts and adjacent pulp cells. f, Incisor traced for 30 days from Sox10-CreERT2/R26YFP mouse. g–k, Incisor traced for 40 days from PLP-CreERT2/R26Confetti incisor. h–j, Magnified areas from g. Arrow in h indicates a cluster of odontoblasts; arrow in j points at CFP+ and RFP+ cells in proximity to a cervical loop at the base of CFP+ and RFP+ streams shown in g and i. k, Streams of CFP+ and RFP+ pulp cells next to i and j. l, m, Incisor traced for 40 days from PLP-CreERT2/R26Confetti mouse with YFP+ and RFP+ pulp cells adjacent to clusters of odontoblasts with corresponding colours. m, Magnified region from l. n, Stream of pulp cells (arrows) in proximity to the cervical loop; yellow and red isosurfaces mark YFP+ and RFP+ cells. o, p, Progenies of individual MSCs intermingle with neighbouring clones in pulp (o) and odontoblast layer (p), projections of confocal stacks. q, r, Clonal organization of mesenchymal compartment in adult incisor. a–n, Dotted line, enamel organ and mineralized matrix. Scale bars, 100 µm (a, d, f, g, k, l); 50 µm (b, c, e, m–p). CL1 and CL2 indicate labial and lingual aspects of cervical loop. d.p.i., days post-injection. s, Incidence of mesenchymal clones depending on fraction of odontoblasts within the clone. t–v, Proximity of dental MSCs (dMSCs) to cervical loop (CL) correlates with clonal size and proportion of odontoblasts in clone.
a–c, Incisor traced for 3 days from adult PLP-CreERT2/R26YFP mouse. Note protein gene product 9.5 (PGP9.5)+ nerve fibres (a). b, c, Magnified areas from a. d, e, Incisor traced for 30 days from adult PLP-CreERT2/R26YFP mouse. Note collagen IV+ blood vessels (d). e, YFP+ odontoblasts and adjacent pulp cells. f, Incisor traced for 30 days from Sox10-CreERT2/R26YFP mouse. g–k, Incisor traced for 40 days from PLP-CreERT2/R26Confetti incisor. h–j, Magnified areas from g. Arrow in h indicates a cluster of odontoblasts; arrow in j points at CFP+ and RFP+ cells in proximity to a cervical loop at the base of CFP+ and RFP+ streams shown in g and i. k, Streams of CFP+ and RFP+ pulp cells next to i and j. l, m, Incisor traced for 40 days from PLP-CreERT2/R26Confetti mouse with YFP+ and RFP+ pulp cells adjacent to clusters of odontoblasts with corresponding colours. m, Magnified region from l. n, Stream of pulp cells (arrows) in proximity to the cervical loop; yellow and red isosurfaces mark YFP+ and RFP+ cells. o, p, Progenies of individual MSCs intermingle with neighbouring clones in pulp (o) and odontoblast layer (p), projections of confocal stacks. q, r, Clonal organization of mesenchymal compartment in adult incisor. a–n, Dotted line, enamel organ and mineralized matrix. Scale bars, 100 µm (a, d, f, g, k, l); 50 µm (b, c, e, m–p). CL1 and CL2 indicate labial and lingual aspects of cervical loop. d.p.i., days post-injection. s, Incidence of mesenchymal clones depending on fraction of odontoblasts within the clone. t–v, Proximity of dental MSCs (dMSCs) to cervical loop (CL) correlates with clonal size and proportion of odontoblasts in clone.

Before this experiment, it was generally believed that nervous system cells were unable to de-differentiate or revert back to a flexible stem cell state. Therefore, Adameyko said that it was very surprising to see such a process in action. He continued: “Many people in the community were convinced … that one cell type couldn’t switch to the other. But what we found is that the glial cells still very much maintain the capacity” to become stem cells. If stem cell researchers and physicians could master those chemical cues in the teeth pulp that signals glial cells to transform into mesenchymal stem cells, they could generate a new way to grow and make stem cells in the lab.

“This is really exciting because it contradicts what the field had thought in terms of the origin of mesenchymal stem cells,” says developmental biologist Ophir Klein of the University of California, San Francisco, who was not involved in the new work. But it’s also just the first step in understanding the interplay between the different cell populations in the body, he adds. “Before we really put the nail in the coffin in terms of where mesenchymal stem cells are from, it’s important to confirm these findings with other techniques.” If that confirmation comes, a new source of stem cells for researchers will be invaluable, he says.

First Human Study Using Dental Stem Cells


This is an old paper, but it is still a good read.

November 12th 2009 the first clinical study involving human dental stem cells was published in the journal European Cells and Materials journal.

This study examined patients with impacted wisdom teeth who also had bone loss (resorption) at the site of impaction. Such a bone defect does not repair on its own after the wisdom teeth are removed. Therefore, the researchers used a mixture of dental pulp stem cells harvested from the patient’s non-impacted, upper wisdom teeth and placed them onto a “scaffold” made of collagen sponge. They then used this mixture to fill in the injured areas that remained after the impacted teeth were removed from the lower jaw. The area in the upper jaw served as a control, or comparison, since no dental stem cells were used in that region.

Three months after treatment, the bone had completely regenerated at the injury site and the periodontal tissue had been restored. In the seven patients who returned for one-year follow-up examinations, optimal bone regeneration was observed. The investigators concluded that dental stem cells embedded onto a collagen sponge scaffold can completely restore bone defects in the human jaw. Furthermore, these cells have the potential to repair and/or regenerate tissues and organs.

Before the publication of this paper, jaw defects had been repaired using dental stem cells in an animal model, but never in humans. In fact, no dental stem cell therapies have ever been used in human patients. This bone grafting study is very exciting for the future promise of dental stem cell therapies. It does not matter if the dental stem cells come from a dental stem cell bank, such as the National Dental Pulp Laboratory, or individuals who wish to preserve their own or their children’s pulp in order to have a source of stem cells that they might be able to put to use for future medical needs.

Dental Stem Cells for Therapeutic Purposes


Brazilian and American scientists have made induced pluripotent stem cells (iPSCs) from stem cells found in teeth. These adult stem cells are immature enough so that forming iPSCs from that is relatively easy.

Human immature dental pulp stem cells (IDPSCs) are found in dental pulp. Dental pulp is the soft living tissue inside a tooth, and it houses various stem cell populations. These stem cells express a whole cluster of genes normally found in very young and immature cells. Therefore, IDPSCs are “primal” cells that are very young and undifferentiated.

According to Dr. Patricia C.B. Bealtrao-Braga of the National Institute of Science and Technology in Stem and Cell Therapy in Ribeirao Preto, Brazil, human IDPSCs are easily isolated from adult or baby teeth during routine dental visits. IDPSCs are not viewed as foreign by the immune system and can be used in the absence of any drugs that suppress the immune system. They have very valuable cell therapy applications, including the reconstruction of large cranial defects.

Another research project in the Republic of Korea, at the college of Veterinary Medicine, Gyeongsang National University, Republic of Korea have examined a stem cell population from third molars called human dental papilla stem cells (DpaSCs). DpaSCs can form dentin and dental pulp, but they also have biological features that are similar to those of bone marrow-derived mesenchymal stem cells (MSCs).

MSCs have been very heavily studied. While these stem cells have remarkable therapeutic capabilities, they have the disadvantage of only being able to grow in culture or a short period of time. After growing in culture for about a week, MSCs tend to go to sleep and not grow anymore.

DPaSCs, however, have a remarkable capacity to grow in culture. Data from work done in the laboratory of Gyu-Jin Ryo has shown they can grow for a longer period of time than MSCs in culture without going to sleep. Therefore, they not only can form a greater number of progeny, but they can also, potentially, form larger tissues and structures.

Based on their increased culture capabilities, DPaSCs can provide a source of stem cells for tooth regeneration and repair and, possibly, a source of cells for a wide variety of regenerative medical applications.