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Annals of Medicine

Volume 49, 2017 - Issue 8
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Review Article

Dental stem cells: recent progresses in tissue engineering and regenerative medicine

João Botelho Egas Moniz Cooperativa de Ensino Superior CRL, Caparica, PortugalORCID Iconhttp://orcid.org/0000-0002-1019-8263
ORCID Icon,
Maria Alzira Cavacas Egas Moniz Cooperativa de Ensino Superior CRL, Caparica, PortugalCorrespondencemcavacas@egasmoniz.edu.pt
ORCID Iconhttp://orcid.org/0000-0002-1790-9646
ORCID Icon,
Vanessa Machado Egas Moniz Cooperativa de Ensino Superior CRL, Caparica, PortugalORCID Iconhttp://orcid.org/0000-0003-2503-260X
ORCID Icon &
José João Mendes Egas Moniz Cooperativa de Ensino Superior CRL, Caparica, PortugalORCID Iconhttp://orcid.org/0000-0003-0167-4077
ORCID Icon
Pages 644-651
Received 07 May 2017
Accepted 22 Jun 2017
Accepted author version posted online: 24 Jun 2017
Published online: 12 Jul 2017

Review Article

Dental stem cells: recent progresses in tissue engineering and regenerative medicine

Abstract

Abstract

Since the disclosure of adult mesenchymal stem cells (MSCs), there have been an intense investigation on the characteristics of these cells and their potentialities. Dental stem cells (DSCs) are MSC-like populations with self-renewal capacity and multidifferentiation potential. Currently, there are five main DSCs, dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SHED), stem cells from apical papilla (SCAP), periodontal ligament stem cells (PDLSCs) and dental follicle precursor cells (DFPCs). These cells are extremely accessible, prevail during all life and own an amazing multipotency. In the past decade, DPSCs and SHED have been thoroughly studied in regenerative medicine and tissue engineering as autologous stem cells therapies and have shown amazing therapeutic abilities in oro-facial, neurologic, corneal, cardiovascular, hepatic, diabetic, renal, muscular dystrophy and auto-immune conditions, in both animal and human models, and most recently some of them in human clinical trials. In this review, we focus the characteristics, the multiple roles of DSCs and its potential translation to clinical settings. These new insights of the apparently regenerative aptitude of these DSCs seems quite promising to investigate these cells abilities in a wide variety of pathologies.

  • Key messages

  • Dental stem cells (DSCs) have a remarkable self-renewal capacity and multidifferentiation potential;

  • DSCs are extremely accessible and prevail during all life;

  • DSCs, as stem cells therapies, have shown amazing therapeutic abilities in oro-facial, neurologic, corneal, cardiovascular, hepatic, diabetic, renal, muscular dystrophy and autoimmune conditions;

  • DSCs are becoming extremely relevant in tissue engineering and regenerative medicine.

Introduction

Regenerative medicine replaces or regenerates human cells, tissues or organs, to restore or establish normal function [1], and as stated by Klein and Nör [2] 'organ regeneration and repair is a holy grail of modern biomedical science'. According to Langer and Vacanti [3], tissue engineering involves the triad of stem/progenitor cells, scaffolds for cell growth and important growth factors. Clinical success of this engineering depends on understanding how to control unfavourable influences during regeneration, such as management of chronic inflammatory events, control of bacterial infection and reducing tissue injury during any restorative surgical intervention [4]. Moreover, Heil et al [5] described that stem cells can also act “as a software deliverer and not hardware”. Known as the paracrine effect, stem cells have the remarkable capacity of delivering cytokines locally, promoting regenerative processes and tip the balance between tissue degeneration and regeneration [5].

Almost three decades later [6], MSCs are the focus of intensive efforts worldwide towards to understand and study them and develop cell-based therapies for several diseases [7,8]. MSCs can be isolated from numerous tissues, for example bone marrow, peripheral blood, umbilical cord blood, adult connective tissue, placenta, amniotic membrane and dental tissues [9]. However, MSCs from dental tissues represents highly accessible multipotent cells [10], existing in the human body during all life.

This review aims to summarize and highlight the various roles played by the applications of DSCs known to date and its potential for future studies with clinical applications not only in dental pathologies, but in a broad multiplicity of diseases.

Dental stem cells

Dental stem cells (DSCs) are MSC-like populations with self-renewal capacity and multidifferentiation potential [11–14]. Dental pulp stem cells (DPSCs) were the first isolated and characterized DSCs [15]. Later, other types of DSCs were discovered: Stem cells from human exfoliated deciduous teeth (SHED) [16], periodontal ligament stem cells (PDLSCs) [17], dental follicle precursor cells (DFPCs) [18] and stem cells from apical papilla (SCAP) [19] (Figure 1). These five types of DSCs have an amazing multipotency of differentiation such as osteogenic, odontogenic, dentinogenic, cementogenic, adipogenic, chondrogenic, myogenic and neurogenic [16–18,20–34]. Further, DSCs seem to maintain multipotent properties after short- and long-term cryopreservation [35].

Figure 1. Schematic image of human DSCs. Abbreviations: DFPCs, dental follicle progenitor cells; DPSCs, dental pulp stem cells; PDLSCs, periodontal ligament stem cells; SCAP, stem cells from the apical papilla; SHED, stem cells from exfoliated deciduous teeth.

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DPSCs represent a diverse population, with individual isolated clones demonstrating differences in proliferative rates and their abilities to differentiate down specific lineages [11,15,36–38]. According to a recent study, this proliferative and regenerative heterogeneity is related to contrasting telomere lengths and CD271 expression between DPSCs populations [38]. Besides, it has been compared the DPSCs kinetics of third molar with premolar teeth and found that DPSCs from third molar teeth proliferated much faster [39].

Nakamura et al [40] compared the “stemness” of SHED with DPSCs and bone marrow-derived mesenchymal stem cells (BMMSCs) and noticed that SHED revealed higher proliferation rate than that of DPSCs and BMMSCs, and higher expression of genes of cell proliferation and extracellular matrix elements.

Applications of DSCs

Regenerative endodontics

In the last years, advances on dental pulp regeneration were made in research and clinical aspects. It has been proposed several strategies in regenerative endodontics, with different scaffolds, growth factors and stem cells [41–49], emphasizing important clinical aspects regarding disinfection [50] and dentin conditioning [51]. Nakashima et al [52] published, recently, a pilot study in which mobilized DPSCs showed to be safe and effective for complete pulp regeneration in humans’ pulpectomized definitive teeth. Despite the short sample, clinical and laboratory evaluations demonstrated no toxicity, with positive pulp responses. Currently, there is a single-centre, randomized, ongoing controlled study with the purpose of evaluate the revitalization of young immature necrotic permanent teeth using autologous SHEDs [53].

Periodontal regeneration

According to WHO [54], advanced periodontitis with deep periodontal pockets affects 10–15% of adults worldwide. Plenty surgical procedures with different methods and materials were extensively studied to regenerate periodontal defects with clinical successful outcomes [55]. Subsequently to the discovery of DSCs and according to Hynes et al [8], the use of these stem cells have the potential to considerably influence periodontal regeneration treatment strategies in the future. Although all five types of DSCs were studied as potential therapeutic in periodontal defects regeneration in animal models, DPSCs and PDLSCs showed promising clinical results in two human clinical studies [56,57].

Corneal epithelium regeneration

Anteriorly, it was discovered that SHED present similar characteristics with limbal stem cells [58]. Later, the same group transplanted a tissue-engineered SHED sheet into corneal epithelium in a rabbit’s limbal stem cell deficiency (LSCD) model with successful results [59]. Syed-Picard et al [60] injected DPSCs into mouse corneal stroma and found that it was formed a stromal extracellular matrix without immunological rejection. Recently, DPSCs were delivered onto debrided human cornea through contact lenses and confocal microscopy showed that DPSCs have migrated onto the cornea, establishing a barrier which prevented the conjunctivalization of the cornea [61]. These findings demonstrate a serious potential of DPSCs and SHED in cellular or tissue engineering therapies for corneal stromal degeneration.

Central nervous system (CNS) injuries

Kiraly et al [62] transplanted predifferentiated DPSCs into the cerebrospinal fluid of injured newborn rats’ brains. They showed that engrafted DPSCs expressed neuron-specific markers and exhibited voltage dependent sodium and potassium channels, being a potential useful source of neuro- and gliogenesis in vivo in brain injuries. Lately, it was studied if DPSCs, SHEDs, DFPCs and SCAP had the ability to regenerate rat’s spinal cord injuries (SCI) [63–66]. According to the results, these DSCs promoted recovery of spinal cord structures, with marked anti-inflammatory action and decreased myelin degeneration and specifically differentiated into neurons and oligondendrocytes, promoting locomotor recovery [63–66].

Craniofacial bone defects

De Mendonça Costa et al [67] and Chamieh et al [68] studied the potential of DPSCs loaded into a collagen gel scaffold to accelerate the craniofacial bone healing process in rats. Bone mineral density and bone microarchitectural parameters were significantly increased when DPSCs-seeded scaffolds were used [68]. The association of DPSCs with appropriate scaffold shows promising clinical relevance to regenerate large craniofacial bone defects [67]. Further, DPSCs were used with collagen scaffold to repair human mandible bone defects [69], and in the three-year follow-up presented as entirely compact, completely different from normal alveolar bone, creating a steadier mandible and with positive clinical results [70]. On the other hand, Zhang et al [71] examined that SHED from miniature pig were able to engraft and regenerate bone to repair critical-size mandibular defects in swine, with 6-month follow-up.

Brain ischaemia (stroke)

The potential of DSCs were studied as well in rat stroke models, after other published reports used different types of stem cell therapy for stroke recovery [72]. Several studies reported that both brain transplantation of DPSCs [73–75] and serum-free conditioned medium (CM) derived from SHED (SHED-CM) intranasal injection [76] ameliorated brain function, promoted the migration and differentiation of endogenous neuronal progenitor cells (NPC), induced vasculogenesis and improved brain injury. Subsequently, an enthusing phase-1 study protocol started to evaluate safety and feasibility of autologous human DPSCs therapy in patients with chronic disability after stroke, through brain transplantation of DPSCs [72].

Liver fibrosis

It has been proved that both DPSCs and SHED had the capacity to differentiate into hepatic cells [77,78]. Later, it was demonstrated that a single intravenous (IV) administration of SHED or SHED-CM improved liver fibrosis [79]. Hirata et al [79] showed that SHED-CM suppressed chronic inflammation, induced hepatic stellate cells’ apoptosis, protected hepatocytes from apoptosis and induced tissue repair. Furthermore, these authors noticed that hepatocyte growth factor played a key role in the SHED-CM-mediated amelioration of liver fibrosis.

Myocardial infarction (MI)

The therapeutic effect of DPSCs were also studied in the repair of MI in rats [80]. DPSCs were injected intramyocardially in rats, and 4 weeks later the animals showed cardiac function improvement, thickening of left ventricular anterior wall and decrease of the infarct size.

Duchene muscular dystrophy (DMD)

After Kerkis et al [20] tested SHED’s induction to several different lineages, namely smooth and skeletal muscles, the same group transplanted SHED by either IV and muscular injection in a dog model of DMD [81]. It was observed that systemic delivery of SHED was more effective than muscular injections, without immune response. Consequently, Pisciotta et al [82] explored the potential of DPSCs differentiated towards myogenic lineage in a DMD rat model and examined histological progresses, with angiogenesis and reduced fibrosis due to paracrine stimulus.

Acute renal failure (ARF)

Barros et al [83] explored the homing of cryopreserved DPSCs in an ARF rat model. DPSCs demonstrated renotropic and pericyte-like properties, after IV or intraperitoneal injection, and contributed to accelerate the regeneration of renal tubule structure [83]. Additionally, Hattori et al [84] verified that SHED attenuated the levels of inflammatory cytokines and improved kidney function in acute kidney injury induced by ischaemia-reperfusion injury.

Diabetes

For the first time, a group of investigators were capable of differentiate DPSCs into pancreatic cell lineage resembling islet-like cell aggregates (ICAs) with the ability to produce insulin [85,86]. Subsequently, Kanafi et al [87] transplanted subcutaneously ICAs from DPSCs and SHED into mice, and normoglycaemia was restored within 3 to 4 weeks, which persisted SHED about 60 days, with SHED showing to be superior to DPSCs. These results proved that SHED and DPSCs are potential sources for stem cell therapies in diabetes. Other researchers looked for the immunomodulatory outcomes of DPSCs transplantation on diabetic polyneuropathy, and have found that DPSCs stimulated macrophages polarization towards anti-inflammatory M2 phenotypes, and, therefore, presenting immunosuppressive effects on diabetic polyneuropathy [88].

Systemic lupus erythematosus (SLE)

Yamaza et al [28] investigated the immunomodulatory capacity of SHED as potential treatment in a murine SLE model. According to the results, SHED via IV administration resulted in a significant reduction in serum antibodies levels, trabecular bone reconstruction and regulation of Th17 cells [28].

Rheumatoid arthritis (RA)

Nevertheless, Ishikawa et al [89] showed that IV administration of SHED-CM in a rat RA model markedly improved the arthritis symptoms and joint destruction. The authors associated the therapeutic efficacy with the anti-inflammatory capacity of SHED-CM, by induction of M2 macrophage polarization, and inhibition of osteoclastogenesis [89], proving to be an encouraging novel therapy for RA.

Acute respiratory distress syndrome (ARDS)

Wakayama et al [90] assessed the effect of SHED and SHED-CM as potential treatment in rat ARDS model. The authors concluded that both SHED and SHED-CM attenuated the anti-inflammatory response by paracrine mechanisms, decreasing the lung injury and weight-loss, and improving the survival rate [90]. Also, the authors stand out the strong M2-inducing activity of SHED and SHED-CM on this inflammatory disorder.

Alzheimer’s disease (AD) and in Parkinson’s disease (PD)

Mita et al [91] investigated the therapeutic benefits of SHED-CM from human SHED in a mouse model of AD. The intranasal administration of SHED-CM in mice resulted in substantially improved cognitive function. The authors stated that SHED-CM generated an anti-inflammatory/tissue-regenerating environment, attenuating inflammation induced by β-amyloid plaques and inducing anti-inflammatory M2-like microglia [91]. In addition, SHED [27] and DPSCs [92] therapeutic usefulness were assessed in rat PD models. Both SHED and DPSCs could be in vitro differentiated into specific dopaminergic neuron-like cells, and their subsequent transplantation into the striatum of Parkinsonian rats resulted in the restoration of dopaminergic neurons and behavioral damage progress [27,92].

Autoimmune encephalomyelitis (AE)

Newly, Shimojima et al [93] assessed as well if SHED and SHED-CM had therapeutic effects on experimental autoimmune encephalomyelitis (EAE), in a mouse model of Multiple Sclerosis. The results showed that one injection of SHED-CM resulted in a reduction of demyelination and axonal injury, and decrease of inflammatory cell infiltration and pro-inflammatory cytokine expression in the spinal cord, which was associated with a shift in the microglia/macrophage phenotype from M1 to M2 [93].

Future prospects/conclusions

Recently, dental tissues were successfully reprogrammed into induced pluripotent stem cells (iPSCs) [94–100]. Then, iPSCs from DSCs (iPSCs-DSCs) were used in a mouse model as a therapeutic target for ischaemic vascular disease with competency for the generation of angiogenic and vasculogenic endothelial progenitor cells [101]. However, just two studies have investigated the role of iPSCs from MSCs (iPSCs-MSCs) in rat models of periodontitis and periodontal fenestration [102,103]. Therefore, iPSCs-DSCs’ potentials in tissue engineering and regenerative medicine remains unclear and further research is necessary.

The paracrine effect of transplanted DPSCs and mostly SHED seems to be important and promote consolidation of regenerative processes by helping and triggering tissue progenitor stem cells [33,63,76,79,89–91,93]. Also, the immunomodulatory properties of DSCs, mainly SHED, are noteworthy [28,88–91,93]. In spite of this immunomodulatory ability needs several studies to confirm the feasibility and safety of these cells as autologous stem cells therapy, the remarkable results of this studies could break new ground, perhaps leading to alternative therapies in other autoimmune diseases.

Nonetheless, in the future, it is necessary that the standardization and optimization of DSCs cryopreservation protocols should overcome some major challenges, such as culture-associated differences, patient-related variability and the effects of culture medium additives [31,35,104]. Only this way, we can expand and reinforce DSCs as possible stem cells therapies in patients with few or no therapeutic alternatives.

These stem cells are becoming extremely relevant not only in Dental Medicine, where their role might be important to regenerate and preserve teeth, but also in numerous fields of Medicine where they start to have a rising and remarkable prominence. In conclusion, further studies are needed to testify the apparently regenerative aptitude of these stem cells but it seems quite promising investigate their regenerative abilities in a wide variety of diseases, since they are highly reachable, prevail all life and own an amazing multipotency.

Disclosure statement

The authors report no declarations of interest.

References

 

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