Stem cells hold the key to wound healing including in teeth


Stem cells hold the key to wound healing, as they develop into specialised cell types throughout the body – including in teeth.

Now an international team of researchers has found a mechanism that could offer a potential novel solution to tooth repair.

Published today (Friday 9 August) in Nature Communications, the study showed that a gene called Dlk1 enhances stem cell activation and tissue regeneration in tooth healing.

The work was led by Dr. Bing Hu from the University of Plymouth’s Peninsula Dental School, with collaboration from researchers worldwide.

Pictured is a group of mesenchymal stem cells (traced in green) migrating into a tooth to further regenerate the tissue and organ Credit: University of Plymouth

The science behind the discovery

Dr. Hu and his team discovered a new population of mesenchymal stem cells (the stem cells that make up skeletal tissue such as muscle and bone) in a continuously growing mouse incisor model.

They showed that these cells contribute to the formation of tooth dentin, the hard tissue that covers the main body of a tooth.

Importantly, the work showed that when these stem cells are activated, they then send signals back to the mother cells of the tissue to control the number of cells produced, through a molecular gene called Dlk1.

This paper is the first to show that Dlk1 is vital for this process to work.

In the same report, the researchers also proved that Dlk1 can enhance stem cell activation and tissue regeneration in a tooth wound healing model.

This mechanism could provide a novel solution for tooth reparation, dealing with problems such as tooth decay and crumbling (known as caries) and trauma treatment.

Further studies need to take place to validate the findings for clinical applications, in order to ascertain the appropriate treatment duration and dose, but these early steps in an animal model are exciting, as Dr. Hu explains.

What the authors say

Dr. Hu, who is also part of the University’s Institute of Translational and Stratified Medicine (ITSMed), said: “Stem cells are so important, as, in the future, they could be used by laboratories to regenerate tissues that have been damaged or lost due to disease—so it’s vital to understand how they work.

“By uncovering both the new stem cells that make the main body of a tooth and establishing their vital use of Dlk1 in regenerating the tissue, we have taken major steps in understanding stem cell regeneration.

“The work has taken place in lab models at this stage, and further work needs to be done before we can bring them in to human use. But it’s a really big breakthrough in regenerative medicine that could have huge implications for patients in future.”

Professor Christopher Tredwin, Head of Peninsula Dental School and co-author of the paper, said: “We are highly excited by the recent progresses in Dr. Bing Hu’s group. This new work, together with a recent high-impact paper published in The EMBO Journal (DOI: 10.15252/embj.201899845), which is about another type of stem cells in the tooth: epithelial stem cells, puts Plymouth at the front of the world’s dental and craniofacial stem cell research and regenerative medicine.

We expect those researchers will soon provide dental patients better time and cost-effective solutions to serious tooth problems—from trauma to caries.”

Significance Statement

Stem cells play a crucial role in the regeneration of the tooth/supporting tissue that is lost or damaged because of the periodontal diseases.

The review summarizes the translational potential of the developed regenerative approaches using either culture‐expanded or host‐mobilized stem cells for periodontal regeneration.

To facilitate the translation of ex vivo manipulated stem cells into clinical use, concerted research endeavors should be placed on making cell therapy and tissue engineering more practical and economical as well as safer.

To enable the use of endogenous cells for therapeutics, the current and future designs should focus on directing more cells to the site of injury and making the target site more suitable for cell differentiation and new tissue growth.

Periodontitis, an oral disease with a high prevalence worldwide, affects the function of teeth and constitutes one of the main oral health burdens 1.

An epidemiological survey has suggested that more than half of all adults are affected by periodontal disease to varying degrees 234, and a remarkable surge (25.4% increase) in the prevalence rates of periodontal disease was observed from 2005 to 2015 56.

Periodontitis can consistently disrupt tooth‐investing tissues and lead to tooth loss if left untreated 57.

Periodontitis is also closely associated with the occurrence and prognosis of various systemic diseases, including cardiovascular diseases, cancer, obesity, diabetes, and chronic nephritis 891011. Therefore, the exploration of effective and safe periodontal therapies that can be translated into the clinic is an urgent health need worldwide.

The ambitious purpose of periodontal therapy is to regenerate multiple periodontal tissues, including the alveolar bone, cementum, and periodontal ligament (PDL) in the damaged periodontium 12.

Although nonsurgical periodontal therapies (e.g., scaling and root planning) can prevent disease progression by physically removing the pathogens and necrotic tissues, only a small amount of periodontal tissue can be regenerated at the treated sites 7.

The application of technologies such as guided tissue regeneration (GTR) for periodontal surgery can erratically restore the alveolar bone and soft tissues, but the overall outcomes are not necessarily satisfactory and show a lack of clinical predictability 13.

Although new biomaterials and growth factors have enriched the methods for managing periodontal defects, clinical trials have revealed that their efficacy is still controversial, and the structural and functional regeneration of lost periodontal structures remains challenging 12.

Stem cells can self‐renew and differentiate into multiple cell types and thus have tremendous therapeutic potential.

The identification of stem cells from human PDL tissues, termed PDL stem cells (PDLSCs), in 2004, led to a new era of research on periodontal regeneration 14.

Since then, other stem cells have been found to possess the ability to form multiple periodontal tissues under appropriate induction conditions 15.

In addition to their regenerative potential, the ability of stem cells to undergo immunomodulation plays an equally important role in achieving a successful outcome (reviewed in 16).

Today, the use of stem cells is considered as a mainstream strategy for periodontal treatment, particularly for complete regeneration of the periodontal complex, which implies not only the reconstruction of appropriate alveolar bone but also the induction of cementogenesis along the root surfaces with the oriented insertion of newly formed PDL tissue 131718.

Based on therapeutics using ex vivo‐expanded stem cells, the regeneration of the periodontal complex has been demonstrated to be feasible in a variety of models tested (reviewed in 1718).

However, in vitro cell culture places a heavy financial burden on patients and is associated with multiple other difficulties, including an insufficient stem cell source that is available for use, time‐consuming culture procedures, and safety issues 1920.

To accelerate the clinical use of stem cell technology, the mobilization/homing of resident stem cells for regeneration based on endogenous healing mechanisms has become a new concept in regenerative medicine, which we herein definitively term endogenous regeneration medicine (ERM) 21222324.

ERM is particularly promising in periodontal research because of the high incidence rate of periodontitis, and mounting evidence indicates that endogenous stem cells can be directed to the periodontium to exert regenerative and immunomodulating functions; this strategy is similar to or more effective than the use of transplanted foreign stem cells (e.g., see 2526).

In the future, ERM could offer a safer as well as more effective and economical method for periodontal regeneration than current cell‐based therapies.

In this concise review, we summarize the current periodontal regenerative approaches based on either in vitro cell‐material design (cell delivery and transplantation) or in vivo cell‐material interactions (cell recruitment and homing; Fig. ​Fig.1)1) and highlight the most recent evidence supporting their translational potential toward widespread use in the clinic for combating highly prevalent periodontal diseases.

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Figure 1
Periodontal regeneration can potentially be achieved via either in vitro designed cell‐material constructs for transplantation to the area of damage, where the transplants undergo remodeling and revascularization to integrate with the host tissue, or in vivo manipulation of the cell‐material interplay at the target site, where biomaterials and molecules coax the recruitment of endogenous stem cells to regrow new tissues.

Stem Cell Delivery Shows Promise for Periodontal Healing

Any cell type with an enormous proliferative capacity and a multipotent nature, particularly stem cells, can be used to replenish destroyed cells under certain conditions 2728.

The discovery and therapeutic application of stem cells have offered a new concept for periodontal regeneration.

The current stem cell‐based therapies in periodontics rely mainly on the delivery of culture‐expanded cells to the periodontal defect to enhance wound healing, and many elegant studies have documented positive outcomes using either intraoral or extraoral stem cells (reviewed in 2930).

Single‐cell suspensions prepared in vitro or cells suspended in medium can be directly injected into the site of injury easily, and this method is simple and minimally invasive 31. Bone marrow‐derived mesenchymal stem cells (BMMSCs) locally injected into mouse periodontal defects exert anti‐inflammatory and immunomodulatory effects at the target site and contribute to the regeneration of new tissue 32.

In addition, an early‐phase study also showed that in the clinic, the transplantation of expanded autologous fibroblasts might be efficacious for curing papillary insufficiency following a papilla priming procedure 33.

However, there are drawbacks associated with the injection of cell suspensions, such as an insufficient cell supply following an injection, poor engraftment, spread of injected cells to surrounding healthy tissue, and loss of cell fate control (reviewed in 31).

The therapeutic outcomes of delivered cells at the transplanted sites could potentially be improved with the aid of cell sheet/pellet technology, a scaffold‐free approach for cell transplantation (reviewed in 2034).

In this context, confluent cells that are cultured/expanded are harvested as intact cell sheets, and monolayer or stacked cell sheets are notably easier to deliver and transplant than fluid cells and result in minimal cell loss/damage (reviewed in 35).

Because stem cells are delivered together with their extracellular matrix (ECM) produced during ex vivo culture, cells with cell‐cell and cell‐matrix contacts are expected to remain engrafted for a long time after their introduction into the body without changes in their viability and function, which would lead to enhanced tissue regeneration compared with that observed with the injection of cells alone.

In fact, the transplantation of cell sheets instead of fluid cells has revealed improvements in animal periodontitis with bone defects (e.g., see 3637).

In many cases, stem cell sheets are transplanted into the damaged periodontium with bone substitutes, such as hydroxyapatite/tricalcium phosphate (TCP; e.g., see 3839), bovine bone (e.g., see 40), synthetic hydrogels (e.g., see 41), and their composites (e.g., see 42), to increase the stability of the cells within the defect (reviewed in 35).

Irrespective of the animal model used and cell/defect type, substantial evidence from preclinical animal studies indicates that the local delivery of foreign cellular materials can benefit the outcome of periodontal disease management (reviewed in 43).

Although human case studies (e.g., see 44) and randomized clinical trials (e.g., see 40) have demonstrated the feasibility and safety of stem cells, more well‐designed human studies should be performed to examine the beneficial effects of stem cells on periodontal regeneration. In addition, future translational research is still needed to identify cell populations with highly regenerative potential and to optimize the delivery methods. In addition, the therapeutic procedure should be sufficiently practical for use in a clinical setting.

More information: Transit Amplifying Cells Coordinate Mouse Incisor Mesenchymal Stem Cell Activation , Nature Communications (2019). DOI: 10.1038/s41467-019-11611-0

Journal information: Nature Communications
Provided by University of Plymouth


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