- Mouse incisor teeth contain stem cells that produce the epithelial cells required for the growth of teeth.
- Dental stem cells transplanted into the mouse mammary fat pad generate epithelial cells that produce milk and structures like mammary gland ducts.
- Adult dental stem cells could be used in the future to regenerate diseased tissue, particularly mammary tissue.
Sometimes science stuns. It unnervingly reminds us of how little we know but also how much it could change the future, and for the better. A recent publication  described how investigators isolated stem cells from adult mouse teeth and then transplanted these cells into mouse mammary fat tissue devoid of the highly specialized mammary epithelial cells that produce milk during late pregnancy and after birth. The stunning result was that mammary tissue was regenerated from the dental stem cells. Amazingly, the new mammary tissue contained cells that produced milk proteins during pregnancy and formed structures somewhat like mammary tissue ducts. The certainty of established scientific ideas about cell fate is now much more fluid.
The Grand Enigma: What Is a Stem Cell?
Scientists report that stem cells, ideally, have the unique ability to generate all the different types of highly specialized cells that characterize each organ, like muscle cells, nerve cells, connective tissue cells (e.g., skin, tendons, and bronchial tubes in lungs), and epithelial cells (e.g., the surface of the gastrointestinal tract, mammary tissue, and dental pulp) . No other cell type in the body has this enigmatic capability. Stem cells do not have any tissue-specific structures that perform specialized functions, i.e., they are unspecialized cells. This disguise hides their remarkable abilities. Under the right conditions, stem cells can also replicate by cell division and renew their population . Highly specialized cells cannot replicate, and once these cells are lost or damaged, they need to be replaced. That’s when stem cells come to the fore. Stem cells reside in most adult tissues but only in small numbers, and they are usually in a dormant state. When stem cells receive specific molecular and cellular signals from their surrounding tissue, they awaken and generate the highly specialized cells required by the tissue.
The biological functions of stem cells are to maintain the cellular composition of a tissue and regenerate a tissue when it is damaged or diseased, or when the tissue loses cells through normal tissue activities . In the latter case, some highly regenerative tissues, like the gastrointestinal tract and mammary tissue during the lactation cycle, have large requirements for new highly specialized cells. Hence, they strongly rely on resident stem cells for tissue regeneration. When scientists artificially grow stem cells in the laboratory, the cells become immortal, unlike every day specialized cells whose demise is as certain as the tide and taxes after a fixed number of cell divisions. Thus, scientists think that stem cells may also teach them a lot about the mechanism of aging and also the birth of cancer cells .
Embryonic stem cells are the most versatile stem cells as they can form all the major cell types . Adult stem cells, in contrast, are much less versatile than embryonic stem cells. Adult stem cells are often restricted to only generating the specific specialized cells that characterize the organ in which the adult stem cells were originally found. For them, the acorn doesn’t fall far from the tree. Thus, scientists conclude that adult stem cells may be less useful than embryonic stem cells for regenerating diseased tissue [2, 4]. Scientists have also taken a handfull of genes and artificially activated them in highly specialized cells, like skin cells . They explain that this procedure “reprograms” the specialized cells and makes them become unspecialized, and similar to embryonic stem cells, with the ability to generate a wide range of specialized cell types . This idea was scientific heresy not so long ago, but science evolves, and this remarkable achievement of two pioneer scientists was awarded the Nobel Prize for Physiology or Medicine in 2012.
Dental Stem Cells Generate Mammary Tissue
Some highly specialized tissues, like teeth and mammary tissue, are considered by scientists as “appendages” with similar origins from the outer layer of cells in the very early embryo . Thus, despite the enormous structural, functional, and anatomical differences of these mature tissues, they have a lot in common during their very early stages of development [1, 5, 6]. The similar early life developmental process involves embryonic stem cells; however, in later life, specific adult stem cells generate the highly specialized epithelial cells that characterize each tissue. The continually growing mouse incisor teeth contain adult stem cells that generate all the specialized cells required to support the growth of teeth . However, scientists had not realized the potential of adult dental stem cells to regenerate unrelated tissues.
For the first time, investigators recently demonstrated that adult dental stem cells can generate a non-dental tissue, mammary tissue, and thereby they highlight an unexpected versatility of dental stem cells . The investigators reported their research in the scientific journal Cells. The team of four investigators was based at the University of Zurich in Switzerland and the Iwate Medical University in Japan.
“Make the Green One Red” (W. Shakespeare)
Initially, the investigators isolated adult stem cells from mouse incisor teeth. This was not an easy task. These cells had identifying protein markers on their cell surface that characterized them as stem cells, but they also had markers of epithelial cell fate. The implication was that these adult stem cells were restricted to generating only dental epithelial cells. The dental stem cells were mixed with mouse mammary epithelial cells and then injected into mammary fat pads after the normally resident mammary epithelial cells in the tissue were completely removed.
The investigators highlighted their research finesse by using a sophisticated experimental technique that ensured any epithelial cells generated from the transplanted dental stem cells were colored fluorescent green, while the added mammary epithelial cells were colored fluorescent red. The investigators then used a special microscope to separately visualize new mammary epithelial cells derived from the transplanted dental stem cells and the added mammary epithelial cells at the transplantation site eight weeks later. About a third of the total number of mammary epithelial cells at the site was green and therefore derived from the transplanted dental stem cells. Some of the female mice with transplanted stem cells were then mated, and during the pregnancies, their green mammary epithelial cells at the transplantation site were shown by the investigators to produce milk proteins. Thus, the transplanted adult dental stem cells had potentially regenerated milk-producing mammary tissue.
The investigators then performed a similar experiment, but this time they did not transplant any mouse mammary epithelial cells with the dental stem cells. The green epithelial cells that were generated from the dental stem cells at the transplantation site now formed small duct-like structures and sometimes cysts. The newly formed ducts suggested a similarity with the ducts that normally collect milk in mammary tissue. The investigators concluded that the added mammary epithelial cells had somehow taught the dental stem cells to generate mammary epithelial cells that could produce milk at the transplantation site. The inference is that the dental stem cells had a very robust but private conversation with cells and molecules in the local environment of the transplantation site. A cell is changed by the company it keeps.
Stem Cell Therapies
Stem cells have the potential to regenerate diseased or injured human tissues . It’s a big promise for the future and with immense consequences. The most acclaimed example of the success of stem cell therapy is the medical treatment of blood cell disorders, typically cancer in children [2, 7]. Fifty years ago, the prospects for these children were dire. This outcome radically changed for the better when radiation or chemotherapy was used to kill the diseased blood cells and then bone marrow, containing adult stem cells, was transplanted into these individuals, which then regenerated normal blood cells [2, 7]. There are many other outstanding successes  but also challenges [2, 4, 8]. In many cases, it is still early days. Commercial stem cell therapies now abound for all manner of minor medical and cosmetic applications, however, the US Food and Drug Administration warns that some are unproven and unapproved . “A soothsayer tells you to beware” (W. Shakespeare).
The investigators showed that adult dental stem cells transplanted into mammary fat pads regenerated new mammary tissue that produced milk proteins. This result demonstrated that adult stem cells can have more versatile cell fates than previously thought by scientists. The clinical implication from the investigator’s research is that adult stem cells from teeth could, in the future, be used to regenerate some diseased or injured tissues containing epithelial cells, especially mammary tissue. Perhaps in the future, everyone will have a personalized bank of stem cells stored in the freezer. They could become very handy. “All remedies oft in ourselves do lie” (W. Shakespeare).
1. Jimenez-Rojo L, Pagella P, Harada H, Mitsiadis TA. Dental epithelial stem cells as a source for mammary gland regeneration and milk producing cells in vivo. Cells. 2019;8(10):1302.
2. Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z. Stem cells: past, present, and future. Stem Cell Res Ther. 2019;10(1):68.
3. Ullah M, Sun Z. Stem cells and anti-aging genes: double-edged sword-do the same job of life extension. Stem Cell Res Ther. 2018;9(1):3.
4. Dulak J, Szade K, Szade A, Nowak W, Józkowicz A. Adult stem cells: hopes and hypes of regenerative medicine. Acta Biochim Pol. 2015;62(3):329-337.
5. Jiménez-Rojo L, Granchi Z, Graf D, Mitsiadis TA. Stem cell fate determination during development and regeneration of ectodermal organs. Front Physiol. 2012;3:107.
6. Biggs LC, Mikkola ML. Early inductive events in ectodermal appendage morphogenesis. Semin Cell Dev Biol. 2014;25-26:11-21.
7. Henig I, Zuckerman T. Hematopoietic stem cell transplantation-50 years of evolution and future perspectives. Rambam Maimonides Med J. 2014;5(4):e0028.
8. Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17(1):11-22.
9. U.S. Food and Drug Administration. FDA warns about stem cell therapies 2019 [Available from: https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapies].
Dr. Ross Tellam (AM)