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Regular Paper IDES Int. J. on Dental Science, Vol. 1, No.

1, October 2013

Cellular and Molecular Mechanisms of Multilineage Differentiation of Periodontal Ligament Stem/ Progenitor Cells: A Review
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B. Nayak, PhD, 2William Willtshire, BChD(Hons)(DentMat), MDent(Restor), MChD(Orth), DSc(Odont)(Pret), FRCD


(C). 3P.C. Lekic, DMD (Hons), MSc, PhD, FRCD(C). bnayak.204@gmail.com Department of Preventive Dental Science, Faculty of Dentistry, University of Manitoba, Winnipeg, Manitoba, Canada wa_wiltshire@umanitoba.ca, lekicpc@umanitoba.ca

Abstract-The present review deals with the cellular, molecular and functional organization of the periodontal ligament (PL) and the mechanisms of the multilineage differentiation of PL progenitor cells to different functional cell types such as osteoblasts, chondroblasts, cementoblasts and tissue specific fibroblasts. The PL is specialized matrix rich, mixed connective tissues, situated between the cementum and the alveolar bone, provides supportive, attachment and sensory functions to the tooth, and plays an important role in the repair and remodeling of the periodontium i.e. PL, cementum and alveolar bone. It is ectomesenchymal in origin from the inner layer of the dental follicle. Developmentally, PL arises from the cranial neural crest. The PL contains many specialized cell types including PL specific fibroblasts, osteoblasts, osteoclasts, macrophages, mast cells, and MHC II expressing antigen presenting cells (APC), undifferentiated mesenchymal stem/progenitor cells, endothelial and epithelial cells, including Epithelial cell rests of Malassez and neuronal elements such as Ruffini mechanoreceptors and cementoblasts. Index Terms- PL cells, stem/progenitor cells, differentiation, cytokines

The PL not only remodels itself but also remodels its surrounding structures including the cementum and the alveolar bone. The PL osteoblasts produce a number of signaling molecules such as bone morhogenetic proteins, fibroblast growth factor, platelet derived growth factor, insulin-like growth factor, transforming growth factor beta, platelet derived growth factor, macrophage colony stimulating factor, osteoprotegerin (OPG), RANKL and transcription factors osterix and Run x 2. The differentiation, function and activity of osteoclasts are regulated by osteoblasts derived factors such as receptor activator of NFKB ligand (RANKL) that stimulate osteoclasts formation. Osteoblasts derived osteoprotegerin (OPG) negatively regulates osteoclastogenesis[1].Generation, maturation and regulation of osteoclasts are also controlled by the macrophage colony stimulating factor, IL 1, TNF, TGF, IFN through RANKL and OPG [1]. A. The PL Matrix The main components of the extracellular matrix are collagen fibres, oxytalan fibres and ground substance. The PL contains primarily the Type I and Type III collagen fibers and the type 1 is the major type of collagen. The oxytalan fibers are the predominant elastic fiber, which provide elasticity to the ligament during the tension related force on the ligament [2]. The ground substance in the PL is highly viscous, but relatively lesss viscous compared to the gingiva and is made up of negatively charged branched glycoproteins with short oligosaccharide (glycans;chains of 1-20 sugars) and unbranched proteoglycans with disaccharide repeat units and various secretory products. The major proteoglycans in the PL are biglycans, decorin, fibromodulin, and fibronectin. These molecules readily respond to the mechanical forces such as orthodontic tooth movement and may perform multiple functions including cell migration and cell proliferation[1] Decorin is one of the major leucin rich proteoglycans in gingiva and plays a role in the organization of collagen fibrils [3] and in epithelial and mesenchymal interaction [4]. On the other hand, biglycans are mostly found in the matrix of the PL. These molecules are also known to occur on cell surface or pericellular matrix of mesenchymal cells of different tissues including skeletal muscle, bone, and cartilage as well as vascular endothelial and epithelial cells. MsX2 acts as a

I. INTRODUCTION: BIOLOGY OF THE PERIODONTAL LIGAMENT The periodontal ligament (PL) is ectomesenchymal in origin from the inner layer of the dental follicle; developmentally, it arises from the cranial neural crest. It is a specialized matrix rich cellular connective tissue with an unique neurovascular organization. The PL contains many specialized cell types which include PL specific fibroblasts, osteoblast, osteoclasts, cementoblasts and undifferentiated mesenchymal stem/progenitor cells. The stem/progenitor cells in the PL are localized around and within the walls of the PL blood vessels and under the sub capsular spaces of the periand endosteal and lacunar spaces of the alveolar bone, and in the junctional areas of the PL and the cementum, at the junction of PL, and the alveolar bone. The PL stem/progenitor cells show the properties of self-renewal and lineage specificity and respond to the external and internal factors such as mechanical stimuli, growth factors, cytokines, and hormones. The biomarkers commonly used to identify the various stages of development of PL cell types include smooth muscle actin ( SMA) osteopontin (OPN), bone sialoprotein (BSP), osteocalcin (OC) and alkaline phosphatase (ALP). 1 2013 AMDD DOI: 01.IJDS.1.1.1

Regular Paper IDES Int. J. on Dental Science, Vol. 1, No. 1, October 2013 molecular defense mechanism for preventing ossification in ligament fibroblasts [5]. B. Factors and Mechanisms Controlling PL Stem Cell/ Progenitor Cell Differentiation Factors such as basic fibroblast growth factor, tetracycline, oxycycline, mechanical stretching, TGF beta, platelet derived growth factor, ascorbic acid,epidermal growth factor, insulin-like growth factor induce differentiation of PL precurcells [6, 7,8] On the other hand, bisphosphonate causes both proliferation and differentiation. Nerve growth factor induces differentiation and mineralization [9]. On the other hand bone morphogenetic proteins can induce proliferation and mineralization of these cells. The stromal cell derived factors, transcription factors, and protein phosphorylation are the key factors, which control stem cell differentiation. The activation and de-activation of signaling mechanism is also a form of built-in mechanism that regulates stem cell differentiation. Type 1 collagen is a prerequisite for PL cells to differentiate to osteogenic cells. Matrix metalloproteinases are also essential to collagen remodeling and mineralization [10]. The stem cell factor SCFkit signal transduction pathway plays a role in the proliferation, differentiation and survival of stem cells and progenitor cell types [11] . Bone morphogenetic proteins are part of the transforming growth factor super family. BMP-2 is known to strongly promote osteogenesis when applied topically [12]. Similarly BMP-7 enhanced the proliferation and clonal growth of osteogenic precursor cells in the PL [12]. The WNT signaling system is operational for many different cell types including PL cells. Treatment with WNT molecules induced transcription of different skeletal muscle marker genes and evoked expression of cardiomyocytes markers. Induction of cardiomyocytes markers seems to require protein kinase dependant pathway [13]. The transcription factors and transcription factor associated proteins also play a major role in regulating the stem cell differentiation. The growth factors cytokines, hormones, cell-cell interaction particularly the interactions of the Epithelial Rests cells and mesenchymal cells at the root of the tooth may activate the resident stem/progenitor cell populations. Transforming growth factor beta, platelet derived growth factor, basic fibroblast growth factors play a significant role in the stem cell differentiation processes. The differentiation and functions of osteoblasts are regulated by osteoblasts derived factor such as receptor activator of NFKB ligand (RANKL) that stimulate osteoclast formation and osteoprotegerin that negatively regulates osteoclastogenesis. Bone marrow cells can give rise to muscle cells, bone cells, marrow stromal cells, adipocytes, chondrocytes, astrocytes neuronal/glial cells and possibly periodontal tissue cells [14]. Transcription factors are proteins that bind DNA at a specific promoter or enhance region or site where it regulates transcription. Transcription factors can be selectively activated or deactivated by other proteins. The different types of transcriptional factors include general transcription factors, upstream and inducible transcription factors. Some of the 2013 AMDD DOI: 01.IJDS.1.1.1 2 transcription factors include- i.helix-turn-helix: it binds to major groove of DNA ii. Zinc finger: it functions as structural platforms for DNA binding iii. Leucin Zipper: it functions in association with the transcription factor iv.basic- helix-loop helix: it binds DNA with two alpha-helices basic amino acids residues which are linked by a loop and are typically dimeric v.G-qudraplex: it functions by binding to RNA polymerase or another transcription factor or may bind to cis-acting DNA sequence. C. Growth Factors and PL Cell Differentiation Many adult tissues contain undifferentiated stem cells, which can differentiate to mature functional cell types under appropriate conditions[15]. However, the number of undifferentiated cells in any organ is too low to bring about effective tissue regeneration. Transplantation of ex-vivo expanded stem cells is a novel way of delivering partially differentiated cells which can give rise to tissue specific cell types and restore critical tissue mass and tissue integrity. Reports suggest that amplified adult differentiated cells may not differentiate or trans-differentiate to functional cell types due to the lack of cues. However, the published data are controversial. It has been shown that the cultured human PL cells produced nerve growth factor (NGF) and express mRNA for tyrosine kinase receptor (trkA), a high affinity receptor for NGF [9]. This suggests and proliferation of the periodontal ligament cells by paracrine and autocrine factors in vivo and these findings may further support the plasticity theory. Some reports also suggest that the differentiation of adult stem cells is incomplete (amplified) and lacks certain cues necessary to acquire a truly functional cell type. Frisen [16] has put forth several interesting hypotheses the way a cell switches lineages. Accordingly, fully differentiated cells take on another differentiated phenotype, often without cell division through a process of transdifferentiation. Alternatively, the lineage switch can be executed by transdetermination. Thirdly, a cell can switch lineage by first dedifferentiating to a common stem or progenitor cell and then redifferentiating to another distinct cell type. II. ORTHODONTIC T OOTH MOVEMENT AND CELL DIFFERENTIATION Orthodontic tooth movement is often needed to correct mandibular and maxillary tooth irregularities. Tooth movement causes cellular damage resulting in the production of many membr an e phospholipid derived messen ger mol ecul es such a s l i poxi ns, pr ost a gl a n di n s a nd leukotrienes. These molecules arise from the arachidonic acid (AA) pathway. AA is an unsaturated fatty acid, normal constituent of membrane phospholipids, and is released by action from phospholipase A2. Notably, prostaglandins arise from a cyclic endoperoxide generated by enzyme system PG synthesis (e.g. cyclooxygenase). Nitric oxide is produced in endothelial cells during tooth movement and is involved in vasorelaxation, platelet aggregation and cardiovascular homeostasis. Nitric oxide induces relaxation of smooth muscle cells in blood vessels in the PL and can stimulate guanylate

Regular Paper IDES Int. J. on Dental Science, Vol. 1, No. 1, October 2013 cyclase leading to the generation of second messengers. Wh en th e per i odon ta l l i ga m en t is st r et ch ed, bon e apposition occurs on the tension side due to the increased activity of osteoblasts along with other local and systemic hematopoietic cells [17] and bone resorption occurs on the compressed side by the multinucleated osteoclasts [18]. The osteoblasts are activated and induced to express BSP mRNA, wh i ch i s i n vol ved i n bon e r em odel i n g. Differentiation and functions of osteoclasts are regulated by osteoblast derived factors such as receptor activator of NFKB ligand (RANKL) that stimulates osteoclast formation and osteoprotegerin, a secretory product of osteoclasts that negatively regulates osteoclastogenesis [1]. Tooth movement actually remodels the PL, cementum, alveolar bone and the extracellular matrix through the interaction of PL cells and matrix [19]. The root apex is increased because of the increased thickness of apical cementum and the synthesis of Type I and Type III collagen and this may be a prerequisite for bone mineralization to occur. The expression of Type I collagen mRNA is also associated with bite force [20].The major inflammatory cytokines th at are produced during orthodontic tooth movement include interleukin-1 alpha, Il-6, Il-8, [21]. These proinflammatory cytokines play a role in bone remodeling, bone resorption and formation of new bone[21]. Orthodontic tooth movement also induces the proliferation of epithelial rests of Malassez at the root of the tooth and presence of a number of immune cytokines in the PL [22] including TGF, PDGF and insulin-like growth factor (IGF) [23]. Notably the internuclear transcription factors convert the mechanical force into a cellular response. Tooth movement also promotes remodeling of cementum, which covers the root of the tooth. Tooth movement may cause cell membrane damages resulting in the production of bioactive protein and lipid molecules, which act as second messengers in signal transduction. There are other specific cellular and molecular changes that also occur during tooth movement. For example there is an up regulation of c-fos mRNA after 30 min following mechanical stress on human PL, without any change in the mRNA of ALP or matrix proteins [24]). Tenascin, a matrix protein, has been reported to be upregula ted i n t he mechan ical ly str essed fi broblasts. Expression of metal proteinases such as MMP-8 and MMP13 genes in the PL during tooth movement in rats has also been reported. Parathyroid hormone (PTH) related proteins, may be produced, thyus inducing expression of receptor activator of NF (Kappa) B-ligand in the PL, via the cAMP/A protein Kinase A independent pathway. At the same time, or t h od on t i c t oot h movem en t i s k n own t o p r om ot e proliferation of mesenchymal cells in the PL thus activating basic fibroblast growth factor[25], capable of inducing PL cell proliferation [26]. Recently it has been reported that insulin-like growth factor-1(IGF-1), its receptor (IGF-IR) and receptor substrate (IRS1) are expressed as an early reaction of PDL cells to experimental tooth movement in the rat model [27]). Similarly, Wolf M et al., have shown a potential role for HMGB1 protein, originating from PDL cells, in regulating orthodontic tooth movement and the periodontal ligament 2013 AMDD DOI: 01.IJDS.1.1.1 3 remodeling process by modifying the local microenvironment [28]. A. PL Signaling Systems PL cells show multiple signaling systems. Some of these systems include: transmembrane protein with cytoplasmic protein tyrosine kinase, WNT, NOTCH signaling, BMP signaling system, NOGGIN and NO signaling systems. The stem cell factor (SCF)-kit signal transduction pathway plays a role in the proliferation, differentiation and survival of a range of stem and progenitor cell types [29]. Some of these signaling systems operate in a temporo-spatial manner [29, 30]. It is important to point out that the fibroblast growth factor signaling pathway is one of the most ubiquitous in biology. It has diverse role in development, differentiation and cancer. Fibroblast growth factor dependent signaling via phosphor-Erk activation may be a major mediator of transitions in lineage specification [31]. B. Transplantation and Tissue Regeneration in Periodontium The ex-vivo expanded Lac Z positive mouse mesenchymal PL and green fluorescent protein (GFP) and positive mouse embryonic stem (ES) cells transplanted at the periodontal wound-site in rats undergoing orthodontic tooth movement show enhanced capacity to differentiate to osteogenic and PL specific fibroblastic cell types with an increased number of BSP, OPN and -SMA labeled cells in the PL of treated animals that received orthodontic tooth movement, 24 hrs. followed with cell transplantation. We have shown Lekic et al. [14] that the transplanted cells migrate to alveolar marrow following a brief homing at the wound site; differentiate to OPN, BSP and SMA expressing cell types in the PL after undergoing proliferation and initial differentiation in the alveolar bone marrow spaces. These cells then migrate to the periodontal wound site to regenerate the wounded PL and alveolar bone [14]. PL cells differentiated to osteogenic and non-osteogenic cell types and also to other organ specific cell types such as kidney, lung, spleen, brain, heart and liver. However, the transplantation of PL cells had no significant effect on the heart and liver. Transplantation of PL and ES cells increased the density of cellular matrices in the PL significantly; the PL cells showed the maximum effect on the PL extracellular matrix protein. There was a significant increase in the fibronectin expression in the PL in treated animals. Fibronectin is a multidomain dimeric glycoprotein with multiple biological functions including cell adhesion, cell migration, embryonic cell differentiation and maintenance of cellular cytoskeleton [32]. Notably, no sign of rejection was found due to xenografting [14]. The main finding was that PL cells transplanted in vivo are capable of differentiating into specific organ cell types, other than the periodontal tissues. The ES cells differentiated into a broader range of organ specific cell types including PL, AB, CNS and cardiomyocytes and had a pronounced effect on the intercellular matrices in many organs compared to PL cells. However, the PL cells had pronounced effect on the extracellular matrix proteins in PL.

Regular Paper IDES Int. J. on Dental Science, Vol. 1, No. 1, October 2013 III. TISSUE SPECIFIC DIFFERENTIATION OF TRANSPLANTED PL CELLS Transplanted PL cells upon implantation migrate to alveolar marrow to home, proliferate and migrate Lekic et al., [14]. Interestingly the ES cells compared to the transplanted PL cells differentiated to a broader range of tissues and organ specific cell types that included cardiomyocytes, neuronal cell type, kidney tubular cells and Type II cells in the lung. Courax et al. [3399] have also reported the differentiating ability of ES cells to air way epithelial tissues. The PL cells showed a higher degree of differentiation in the PL tissue environment as determined by the expressions of the cell differentiation markers such as OPN, BSP and alpha smooth muscle actin. The possible explanation for this is that the PL cells are at a more advanced state of differentiation than the ES cells. The ES cells are found to be more primitive progenitor cells carrying lineage specific genetic blue print that result in larger number of organ specific cell types [33].The transplantation of ES cells resulted in a localized distribution of OPN, BSP and STRO-1 labeled cells in the PL. STRO-1 is a marker for stromal cell in bone marrow and STRO-1 positive cells which are capable of differentiating to functional osteoblasts [34]. Recently, Seo et. al. [35] have also reported that the PL stem cells express mesenchymal stem cell marker STRO-1 and CD 146 (MUC 18/s-endo). Collectively, results from our lab suggest that the PL or ES cells are capable of differentiating into osteogenic cell types as well as other tissue and organs specific cell types. Findings that mesenchymal cells are capable of differentiating into tissue/organ specific cell types in vivo make these cells very valuable in biotherapy of wounded tissues and organs. Overall, transplantation of undifferentiated PL progenitor/ stem cells may successfully be used to treat injured/damaged periodontal tissues periodontitis and other organ specific diseases. IV. CONCLUSIOINS AND FUTURE DIRECTIONS Although there has been significant research done to understand the effects of various growth factors, cytokines, hormones and transcription factors including mechanical force on the differentiation of stromal stem/progenitor cells, the information on the fate and differentiation of lineage committed transplanted cells and their ability to regenerate periodontal wounding is limited. Whether differentiated adult cells have the necessary cues to redifferentiate to other cell types require further research. If these cells can be induced in vitro in culture conditions to a state of stable differentiation, using a variety of growth and differentiatiation-promoting factors, and can lead to stable terminal differentiation in vivo, then they can be useful in cell therapy. There are a lot of fundamental questions with respect to the role of PL stromal stem/progenitor cells in the repair and remodeling of wounded periodontium. Recent reports that the transcription factors play a significant role in controlling the differentiation of periodontal stromal progenitor cells as well as maintaining the balance between the proliferation, apoptosis and 2013 AMDD DOI: 01.IJDS.1.1.1 4 differentiation also require further research. Critical research also needed to understand the convergence and divergence of signal pathways that are crucial in the differentiation of lineage decision making processes. Another important consideration is the proteonomic and genomic analyses of PL matrix and its role in adhesion, migration, proliferation and differentiation of PL fibroblasts as well as PL fibroblast precursors under physiological, pathological and experimental conditions including stem cell transplantation- based tissue regeneration. REFERENCES
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Regular Paper IDES Int. J. on Dental Science, Vol. 1, No. 1, October 2013
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2013 AMDD DOI: 01.IJDS.1.1.1

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