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February 2023, Volume 73, Issue 2

Narrative Review

Mesenchymal stem cells and its translation into clinical orthodontics: current trends and future perspectives

Authors: Aqeel Ahmed  ( Department of Surgery, Aga Khan Universityand Hospital, Karachi,Pakistan )
Hafsa Qabool  ( Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan. )
Saqib Habib  ( Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan. )
Mubassar Fida  ( Department of Surgery, The Aga Khan University and Hospital, Karachi, Pakistan )
Syeda Gul Rukh Shah  ( Oral Biology, Baqai Medical University, Karachi Pakistan )

Abstract

Oral mesenchymal stem cell populations in humans have been discovered in close vicinity to oral mucosal tissues and both primary (deciduous) and secondary (permanent) teeth.  All these different kinds of stem cells have the ability to divide and replenish themselves, however they vary in their gene expression profiles and their capacity to give rise to distinct cell lineages.  They all have multipotentiality i.e. chondrogenic, osteogenic, adipogenic, and neurogenic.  Due to their relative accessibility, these cell types may form a source of stem cells with substantial potential for application in tissue regeneration.  In this review, discoveries outlining stem cell potential are discussed on various aspects as, are their various applications in orthodontics i.e. orthodontic tooth movement, fixing external root resorption, correcting craniofacial anomalies, accelerating craniofacial distraction osteogenesis, recreating the TMJ, and ensuring a stable maxillary expansion.

 

Keywords: Cell, Osteogenesis, Transcriptome, Orthodontics, Stem Cells, Membrane, Temporomandibular

 

DOI: 10.47391/JPMA.AKUS-10

 

Introduction

 

In multicellular organisms, stem cells are undifferentiated cells with the ability to self-renew or transform into a variety of cell types.  In the early embryo, archetypal totipotent stem cells contain tissue-specific and extraembryonic stem cells.  These totipotent stem cells have the potential to differentiate into every cell, however, multipotent mesenchymal stem cells (MSCs) are found in tissue of adult or mature tissue where they show limited potency to develop into different cell types.  These cells are frequently called adult stem cells and include a haematopoietic system that can differentiate into a variety of blood components, including red blood cells and platelets.  MSCs are found in several organs and tissues, and their function is to replace specific cell types during normal tissue repair or homeostasis. 

There are a variety of ways to define stem cells.  The definition of stem cells is evolving in the face of growing body of data about stem cells.  Stem cells retain a high degree of flexibility even in adults.  The following concepts are fundamental to the definition of stem cells: (1) self-rejuvenation (2) Multigenerational divergence from a common ancestor cell and (3) Regeneration of a tissue's functional capabilities in vivo.1,2 What makes MSCs appealing for use in clinical practice is that they can be taken out of a living organism, kept separate, grown in large numbers, and then transplanted into another living organism where they will function as intended. (Table I) These cells may be organ-specific or non-organic-specific.  Totipotent and pluripotent nature of stem cells that can be differentiated into many lineages make them more desirable, but, the immunological and ethical consequences of employing these cells make them less attractive.  MSCs from the oral cavity have lately garnered interest as a potentially novel cell source owing to their potential therapeutic applications and simplicity of harvesting.

 

 

Oral MSCS

 

The several MSC populations seen in oral tissues have been given names that often reflect their place of anatomical origin.

 

 

(Figure) Those MSCs found in the mouth and teeth are known as oral/dental mesenchymal stem cells (DMSCs),3,4 and it was in the extracted third permanent molar that the first dental stem cells were identified, some 20 years ago.5  Similarly, and probably not unexpectedly, DMSCs have been discovered in the pulp of human deciduous teeth that have already been shed (SHED cells).6  Furthermore, DMSCs as apical dental papilla and dental follicular progenitor stem cells have been identified from incomplete third molar root apical foramens.7,8  The periodontal ligament, the sub-epithelial gingiva and mucosa, the gingival tissue itself, the oral mucosa lamina propria progenitor stem cells, and the gingiva-derived mesenchymal stem cells are additional sources of non-dental stem cells in the mouth.9,10,11

All of these different kinds of stem cells have the ability to divide and replenish themselves, however they vary in their gene expression profiles and their capacity to give rise to distinct cell lineages.12,13 They all have multipotentiality i.e. chondrogenic, osteogenic, adipogenic, and neurogenic.  Stem cells from places like the apical foramen and the dental follicle can give rise to odontoblast like cells and a dentine-pulp-like complex, consistent with their anatomic location and the tissues from which they are harvested.14,15

 

Orthodontic applications of MSCS

 

Orthodontic tooth movement: Orthodontic tooth movement is caused by orthodontic forces to the teeth/periodontal ligament (PDL) and surrounding osseous structures, which results in remodelling processes.16,17 Application of orthodontic force creates a compression site when the periodontal ligament (PDL) is compressed.  This triggers an inflammatory cascade, which in turn recruits osteoclasts from the surrounding marrow spaces.18  Haematopoietic stem cells are the primary source from which these osteoclasts are developed.19  Hence, orthodontic tooth movement could be accelerated with the intervention of stem cells via supplying progenitor cells.

Little is known regarding the function and response of periodontal ligament stem cells during orthodontic force application.  A study used a marker of stem cells i.e. CD90 on the rodent model to demonstrate the expression of stem cells in PDL.  They discovered that the population of stem cells had increased at the compression site, but collagen-1 expression had reduced.  However, when orthodontic forces were withdrawn, the expression of collagen-1 was restored.  Hence, it can be hypothesized that it enhances orthodontic tooth movement via increasing the progenitor cells of osteoclasts and most importantly, stabilizes the achieved tooth movement by production and maturation of collagen via expression of collagen-1.20  An intriguing, if somewhat distant, prospect is the manipulation of PDL stem cell biology to speed up orthodontic tooth movement and, more crucially, to promote stability of tooth position.

 

External root resorption: One of the side effects of orthodontic tooth movement is external apical root resorption, which results in loss of cementum and dentine that may compromise the longevity of the tooth.  The orthodontic treatment is halted when the severe root resorption is found and there is no treatment modality available to manage the resorbed root.  However, now there is a hope where stem cells could be used as a potential solution to regenerate the cementum and there is reason to be hopeful that a viable source can be found, where the wide distribution and various anatomical locations of DMSCs are already discovered.  Despite the fact that the aforementioned idea is still in its infancy, it has recently been discovered that when PDL stem cells were isolated by outgrowth, they were able to produce cellular cementum-like hard tissue including embedded osteocalcin-embedded cells forming in vivo transplantation.21

 

Rapid maxillary expansion: Maxillary constriction causes numerous occlusal and functional complications. It may induce a constricted oropharyngeal airway, a decrease in nasal airflow, and a change in position of the tongue, which may lead to a narrowing of the retroglossal airway and mouth breathing.22-24  The treatment modalities to correct constricted maxilla consist of slow expansion of the maxilla, rapid expansion of the maxilla (RME), and surgical assisted expansion of maxilla.25,26  In children younger than 12 years age or patients with incompletely fused mid-palatal suture, RME is often advised.  By opening the midpalatal suture via RME, an orthodontist can effectively enhance maxillary width, restore jaw-to-face proportions, and alleviate jaw-to-face pain.27,28 In RME, the two bone segments are separated by force, and the resulting space is filled with granulation tissue and blood before active bone formation begins.  Without an adequate retention period, the maxillary arch widening achieved during orthodontics (RME) will revert to its original size. Accordingly, enhancing the rate at which bone forms in the void left by RME can reduce treatment and retention times and stabilize the treatment.  Injecting the stem cells, which have the potential to develop into osteogenic cells, appears to hasten bone formation.  Ekizer et al.29 conducted an experiment on animals showing that injecting stem cells into a fractured intermaxillary suture led to an increase in the number of new blood vessels and osteoblasts, which in turn led to more bone growth.  Thus patients undergoing RME may benefit from a shorter treatment and retention time if local DMSCs are applied to the expanded maxilla to stimulate new bone formation in the midpalatal suture.30

 

Envelope of discrepancy: The range of orthodontic tooth movement is limited by factors such as alveolar bone structure, soft tissue pressures, levels of periodontal attachment, neuromuscular forces, and tooth-lip relationships.31,32  The envelope of discrepancy refers to the millimetric range of tooth movement in the sagittal, transverse, and vertical planes that can be achieved without compromising stability and ensuing side effects i.e. if maxillary teeth are expanded beyond the envelope, bone dehiscence and gingival recession are possible outcomes.33  Defects like fenestration and dehiscence are inevitable at sites with thin buccal and lingual cortical plates and gingival biotype, especially in the case of lower incisors compensated with lingual inclinations and with prominent chin.34,35

Stem cell treatment is a potential technique for the regeneration of alveolar bone because stem cells may produce many tissues, including bone.  Human bone ridge augmentation by stem cell therapy has been attempted by some studies, with bone marrow cells being the primary source.36-38  The results of regenerating alveolar bone had an inclination to improve bone growth.39 As a result, bone regeneration techniques involving stem cells may offer a means of enlarging the potential range of error. 

Hypothetically, osteogenesis based on stem cells might be used to augment the ridge horizontally, enhancing the stability of tooth movement/envelope of discrepancy and allowing the patient to surpass some restrictions, based on the findings of investigations on alveolar bone augmentation.

 

Dentofacial anomalies: Difficult-to-correct defects are a frequent clinical challenge in craniofacial surgery, such as those caused by congenital and developmental deformity, trauma, tumour removal, and non-union of fractures.  In order to repair bone and soft tissue, modern surgical procedures have been used in conjunction with autogenous, allogeneic, and prosthetic materials.40  Stem cell-based tissue regeneration presents a promising way to deliver an advanced and reliable therapeutic technique for craniofacial tissue repair, which could help patients overcome the difficulties of donor site morbidity, irregularities of contour, cost and lengthy surgery times.41  Cleft lip and palate (CLP) and hemifacial microsomia are discussed in this article as two examples of dentofacial anomalies.

Failure of the nasal process and oro-palatal shelves to fuse during development causes CLP, a common congenital anomaly.  This anomaly  affects 0.36 to 0.83 of every 1,000 newborns.42  Repairing malformed alveolar bone corrects oronasal fistula, maxillary arch unification, tooth eruption, and alar base support.  Autogenous cancellous bone grafts are the standard of care for reconstructing alveolar bone defects.43  Grafts to the alveolar cleft have an 88% success rate with respect to bone resorption, and the most common site for extracting autogenous bone for transplantation is the anterior iliac crest.44  The development of tissue engineering has resulted in the availability of several bone grafts apart from the conventional iliac crest graft.  There is evidence that MSCs can generate new bone after being implanted in the cleft region.45-50 (Table: II)

 

 

Hemifacial microsomia is the second most common congenital syndrome, following cleft lip and palate, that results after aberration in first and second pharyngeal arches that leads to unilateral abnormality on the face.51  Congenital and posttraumatic soft tissue abnormalities can be repaired with grafting of autologous fat.52  Fat grafting results are uncertain and have a low survival rate, despite various novel initiatives and advancements of surgical techniques.53  Adipose derived stromal cells (ASCs) have recently gained popularity because of their potential to be used in tissue regeneration.  At six months, individuals with hemifacial microsomia whose grafts were augmented with ASCs had 88% fat volume survival, compared to 54% in the control group.54  In addition, ASC-enriched grafts had greater amounts of residual tissue following transplantation compared to the control group.55

The long-term effects of these kinds of therapies need to be investigated as additional data from studies become available. Angiogenesis, transplant survival, and atrophy can all be improved by using ASCs to repair soft tissue, according to the literature.54-56

 

Disorders of temporomandibular joint: The temporomandibular joint (TMJ) is the cartilaginous and osseous structure that connects the mandible to the skull.  It has two articular surfaces that can adjust to different environments and is protected by a capsule that is constantly being lubricated by synovial fluid, making it a crucial growth site for post-natal growth.57,58 Condyle-region progenitor/stem cells differentiate into chondrocytes that produce condylar matrix, which then differentiates into lamellar bone hence making up the condyle.59  Since stem cells can differentiate into both chondrogenic and osteogenic lineages, they may be effective for maintaining the altered position of the jaw and treating TMJ injuries.

Patients with mandibular deficit typically receive a functional appliance that positions the mandible forward.  This position causes an increase in stem cells in the TMJ fossa, culminating in the production of new bones.  In this context, the question will be that can injection of stem cells into the temporal fossa during functional appliance therapy or any destructive TMJ condition increase new bone formation in the temporal fossa?  This needs to be explored in further studies.

The TMJ is vulnerable to trauma, malignancy, osteoarthritis, rheumatoid arthritis, and congenital abnormalities.  Surgery to replace the mandibular condyle is often the first and only option for individuals with severe degenerative diseases.60  However, these approaches can lead to infection, immune-rejection, implant wear, insufficient biocompatibility, dislocation, donor site limits and morbidity, and even pathogen transfer.61,62 Engineering of osteochondral tissue have devised strategies to overcome them by developing medically and mechanically effective tissue.  Rebuilding joints with these cells has recently gained a great deal of attention.

Numerous studies have looked into the feasibility of engineering an osteochondral transplant with a TMJ-like structure.  The cultivation of human umbilical cord stem cells with chondrogenic stimuli revealed that human umbilical cord matrix stem cells can surpass TMJ cartilage cells.63  Mesenchymal stem cells isolated from rat bone marrow, cultured in a hydrogel composed of ethylene glycol, and moulded into the form of a human cadaver condyle showed a combination of cartilaginous and osseous morphologies.64,65

Though studies have revealed that TMJ bone and cartilage can regenerate, the TMJ disc is made of fibrocartilage, and there has been minimal success in making synthetic TMJ discs; thus, the focus has switched to engineering to repair the disc.66  Tissue-engineered TMJ discs were developed in one study by fusing polylactide acid discs and stem cells from adipose tissue.67  Human clinical trials have not yet been completed, however studies are now underway using animal models to reproduce the osteochondral interface and develop TMJ. In the light of these results, combining SCs with various scaffolds may be an effective method for repairing the osteochondral tissues of the TMJ and, ultimately, the joint disc.

 

Distraction osteogenesis: Endogenous bone tissue engineering, or "DO," is commonly utilized in orthopaedic surgery for the correction of various craniofacial deformities and the restoration of limb length.68  By accelerating osteogenesis in the distraction Gap and decreasing the consolidation phase, nonunion, infection, and fracture can be reduced.  Recent studies have shown that stem cells can stimulate bone formation and shorten the consolidation phase during DO, perhaps because of the engagement of MSCs in osteogenesis.  Human exfoliated deciduous teeth (SHED), bone marrow, and adipose tissue are just a few of the places where SCs have been used in research to promote DO.69-71

 

Conclusion and Future Perspectives

 

Oral mesenchymal stem cells are a valuable and easily accessible stem cell source with potential use in orthodontics and other regenerative dental therapy.  However, the use of these stem cells in clinical orthodontics is still a matter of debate due to lack of high quality of evidence.  Research in many fields, such as cell biology and tissue regeneration, will be required to improve our ability to regulate their behaviour in vivo.  However, it is also vital to understand how these cells may be recognized, collected, expanded, and, most significantly, maintain their in vitro characteristics. Almost certainly, the rate of development is at a rapid pace.

 

Disclaimer: None to declare.

 

Conflict of Interest: None to declare.

 

Funding Disclosure: None to declare.

 

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