10.59987/ads/2011.1-2.3-8
Aim. Stem cell research in recent years have been considered the most advanced sort of medical-scientific research and early results have aroused great expectations. Also in dentistry many studies were performed with the final aim of obtaining new bone and new teeth. In this work we describe the state of the art in dental science stem cell research. Methods. We have performed a web-based research on MEDLINE within (www.pubmed.gov). We have used “stem cells from human exfoliated deciduous teeth” (24 paper found), “periodontal ligament stem cells” (32 paper found), “stem cell apical papilla” (16 paper found), “dental pulp stem cells” (136 paper found) as keywords for research. For each keyword we have performed a complete review focusing on knowledge upgrade.
Results. For each topic was created a selection of papers in chronological order of publication date so to give a timetable of the development of the research for each niche.
Conclusion. Research about stem cell from oral niches began in 2000 and every year papers publicated were more than the precedent. This review analysed about 180 articles most of which in the last 5 years. Dentla pulp from adult as from deciduous teeth seems to be the most valuable font of stem cells due to the pluripotential type of cells.
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1971-1441
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Annali di stomatologia
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Stem cells from oral niches: a review
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Literature review
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L. Ottolenghi
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Stem cells from oral niches: a review
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                                                                                                         Literature review



    Stem cells from oral niches: a review




                                                                                                         li
                                                                                                      na
    Guido Giordano, DDS, PhD                                   Introduction
    Gerardo La Monaca, DDS, PhD
    Susanna Annibali, MD                                       Stem cells are cells with the ability to divide, generating




                                                                                                   io
    Andrea Cicconetti, MD                                      a cell identical to itself plus another one capable of generate
    Livia Ottolenghi, DDS                                      different kind of tissues (1). Stem cells can be recognized
                                                               by potency: totipotent cells can differentiate into any type




                                                                           az
                                                               of progenitor cell; pluripotent cells can differentiate into any
    "Sapienza" University of Rome, Rome, Italy                 type of progenitor cell except those totipotent; multipotent
    Department of Oral and Maxillofacial Sciences              cells can differentiate only into certain kinds of tissues; uni-
                                                               potent cells can differentiate only in one tissue type (Fig.
                                                               1). Stem cell research in recent years have been considered




                                                                         rn
                                                               the most advanced sort of medical-scientific research and
                                                               early results have aroused great expectations.
    Corresponding author:                                      In dentistry the term “bone regeneration” is often impro-
    Guido Giordano                                             perly used by clinicians, since it doesn’t distinguish the dif-




                                                               te
    Viale Colli Portuensi, 501                                 ference between the processes of “regeneration” and “re-
    00151 Rome, Italy                                          pair”. The first term shows the complete structural recon-
    E-mail: guido.giordano@uniroma1.it                         struction of the tissue to rebuild with the same biological
                                                      In       capacities and integration with surrounding tissues, whi-
                                                               le the term “repair “ describes the process that is curren-
                                                               tly achieved with the reconstruction with biomaterials that
                                                               never reaches complete biological and functional integration
                                                               with surrounding tissues. It should be instead regarded as
                                                 ni
    Summary
                                                               a “scar” to connect and fill the gap, with limited biofunctional
    Stem cells from oral niches: a review.
                                                               capacities. Even in dentistry, authors have been carried out
    Aim. Stem cell research in recent years have been con-
                                                               numerous studies on stem cells with the ultimate goal of
                                       io


    sidered the most advanced sort of medical-scientific       obtaining bone regeneration (e.g. pre-implant) or new te-
    research and early results have aroused great expec-       eth. The enormous strides made by molecular biology re-
    tations. Also in dentistry many studies were performed     search have made possible to speculate the creation of
                             iz



    with the final aim of obtaining new bone and new teeth.    in vitro oral hard tissues. Currently, literature is divided bet-
    In this work we describe the state of the art in dental    ween clinicians, which tests methods to form single tissues
    science stem cell research.                                (bone, dentin, pulp, etc.) and biochemists that investiga-
                                                               te the biochemical mechanisms that leads to cell diffe-
             Ed




    Methods. We have performed a web-based research on
    MEDLINE within (www.pubmed.gov). We have used              rentiation. Therefore, this paper describes the state of the
    “stem cells from human exfoliated deciduous teeth” (24     art of stem cell research in dentistry.
    paper found), “periodontal ligament stem cells” (32
    paper found), “stem cell apical papilla” (16 paper
    found), “dental pulp stem cells” (136 paper found) as      Stem cells
    keywords for research. For each keyword we have per-
 IC




    formed a complete review focusing on knowledge up-         Stem cells can be found in any region of human body, into
    grade.                                                     three-dimensional anatomical regions called “niches” that
    Results. For each topic was created a selection of pa-     contain elements that are involved in the proliferative re-
    pers in chronological order of publication date so to      gulation of stem cells, can control the destiny of the “dau-
    give a timetable of the development of the research for
C




                                                               ghter” cells and are concerned to prevent exhaustion and
    each niche.
                                                               death of stem cells themselves (1,2). If it is easy to de-
    Conclusion. Research about stem cell from oral niches
                                                               monstrate their presence in tissues that obviously under-
    began in 2000 and every year papers publicated were
    more than the precedent. This review analysed about        go reparation and regeneration as skin, bone and muscle,
©




    180 articles most of which in the last 5 years. Dentla     it is more difficult to think of their presence in other ana-
    pulp from adult as from deciduous teeth seems to be        tomical regions. In fact, only in the 90s stem cells niches
    the most valuable font of stem cells due to the pluripo-   were found in human brain (3,4,5).. Earliest studies in den-
    tential type of cells.                                     tistry were concentrated about finding niches in order to
                                                               draw multi or unipotent stem cells. Currently, niches have
    Key words: stem cells, tissue engineering, osteogene-      been identified in the dental pulp of permanent teeth (Den-
    sis, oral niches, review.                                  tal Pulp Stem Cells - DPSCs) (6), in naturally exfoliated de-
                                                               ciduous teeth (Stem cells from Human Esfoliated Deci-

    Annali di Stomatologia 2011; II (1-2): 3-8                                                                                3
    G. Giordano et al.


    cuous teeth - SHED) (7), in the periodontal ligament (Pe-
    riodontal Ligament Stem Cells - PDLSC) (8), in the api-
    cal papilla (Stem Cells from Apical Papilla)(9), in the den-
    tal follicle (Dental Follicular PCs) (10), and in the periosteum
    of the maxillary tuberosity (Oral Periostium Stem Cells) (11).
    In each of these studies a multipotent mesenchymal stem




                                                                                                                    li
    cell was isolated, capable of differentiating in vitro into at
    least three lines: osteo/odontogenic, adipogenic and




                                                                                                                 na
    neurogenic. For the evaluation of the potentiality of stem
    cells from oral niches, Bone Marrow Mesenchymal Stem
    Cells (BMMSCs) was used as a gold standard, as they are
    the most tested stem cells and the point of reference for




                                                                                                              io
    each new line of stem cells.


    Dental pulp stem cells




                                                                                    az
    Dental Pulp Stem Cells (DPSCs) were isolated at first in
    2000 by Gronthos et al (6). Cells can differentiate in pulp-
    like cells. Under appropriate growth factors, DPSCs also




                                                                                  rn
    differentiated in adipocytes and neural-like cells. Sub-
    sequent studies (12,13,14) were made to understand the
    differentiative capacity of DPSCs, especially compared
    with BMMSC. Particularly, Gronthos et al in 2002 have




                                                                       te
    established the ability of self-duplication in vivo. The same
    group in 2003 (15) showed that BMMSC and DPSCs can
    be traced in perivascular tissue of their respective origin
    tissue assumpting that this discovery could have impli-
                                                              In
    cations for the tissue stem cells populations identification
    in other districts. Even in 2005, Shi et al (16) questioned
    whether stem cells could be helpful in dental tissue re-           Figure 1 - The figure shows how totipotent cell can divide in
    generation, raising doubts on the potential of stem cell           totipotent cell and a pluripotent cell and following pluripotent cell
    research, since not much was achieved beyond the mere
                                                ni
                                                                       can divide in a pluripotent cell and a unipotent cell. Finally, unipo-
    observation of their presence at five years from first ob-         tent cell can generate only one kind of tissue.
    servation. Moreover in 2005 Laino et al (17) showed how
    DPSCs are still detectable in patients over 30 and that
                                      io


    there were no substantial differences with younger cells.          Besides, PLGA is a well known osteoconductive bioma-
    In 2005 and 2006 the influence of various molecules in             terial, but mechanisms that underlie its operation are still
    DPSCs differentiation as DMP1 and MEPE was deeply                  unknown.
                                                                       Between 2008 and 2010, two main lines of research have
                            iz



    discussed (18, 19). Genetic map of DPSCs and BMSC
    was compared in order to better understanding of                   been developed: (i) therapeutic applications of DPSCs and
    DPSCs differentiation mechanisms (20). A 2006 study                (ii) bone regeneration comparing different types of scaf-
                                                                       fold added with growth factors (as BMP).
            Ed




    compared different types of scaffolds (three-dimensional
    material) which are necessary to obtain bone tissue (21).          Due to their proved versatility, DPSCs were used for the
    The authors have tested a specially prepared collagen              treatment of myocardial infarction (29), for the regenera-
    matrix based on bovine collagen, a matrix of hydroxya-             tion of nervous tissue, particularly in the treatment of mu-
    patite/beta-tricalcium phosphate (HA/TCP) in 60/40 ra-             scular dystrophy (31), for the cerebral ischemia (32), ex-
    tio and a web of titanium with different texture spaces bet-       ploiting the angiogenetic capabilities, and finally in corneal
    ween fibers (45 or 20 microns). Results showed bone ge-            regeneration (33,34). As regard to scaffold a 2009 paper
 IC




    neration though significantly inferior to the BMSC gene-           (35) studied polylactic acid, bovine collagen and calcium
    rated tissue. Of course DPSCs, since their discovery, have         phosphate bioceramics. A higher number of survived cells
    been studied from transcription factors, growth factors and        was observed only for the first two materials, despite cal-
    molecular matrices that follows stem cell differentiation          cium phosphate bioceramics have proved to be an excellent
C




    points of view (20, 22, 23, 24, 25,26, 27). However, in-           scaffold for BMMSC. The reason why this type of scaffold
    ternational literature seems to have found since 2008 gre-         did not have the same results with DPSCs as with
    at interest in testing various types of scaffold used for new      BMMSC, is unknown. Authors have made assumptions
    bone regeneration.                                                 about an inappropriate pH or surface characteristics and
©




    Graziano et al (28) have compared poly-lactide-co-                 they suggest more specific studies. In mid-2009 (36)
    glycoide (PLGA) (as concave substrate), HA 150 micron              DPSCs were used with a different type of scaffold, poly (ep-
    diameter (as convex substrate), and machined titanium              silon-caprolactone) (PCL) in association with nanohydro-
    disks (as flat substrate) and showed the best results data         xyapatite (nHA) showing that nHA can promote DPCS dif-
    from the PLGA sample in terms of osteodifferentiation, in-         ferentiation in odontoblasts-like cells. Huang et al (37) in
    cluding cellular maturation and the profile of specific pro-       2010 published a study on DPSCs cultured with low dose
    teins, resulting in a significant thickness of newly formed        glucosamine (0.005 mg/ml) to obtain confirmation of
    bone tissue.                                                       their assumptions of better DPSCs osteodifferentiation.

    4                                                                                            Annali di Stomatologia 2011; II (1-2): 3-8
    Stem cells from oral niches: a review


    Stem cells from human esfoliated deciduous                        and obtaining a good bone regeneration at 24 weeks and
                                                                      showing how it is possible to obtain bone regeneration in
    In 2003, Miura et al (7) published an article announcing          an animal model of large size. It was also proposed by Aro-
    the detection of multipotent stem cells among physiolo-           ra et al in 2009 to create a SHED bank for future use by
    gically exfoliated deciduous teeth pulp cells (SHED).             the same donors.
    Comparing SHED with BMSCs, they show a higher degree              In 2009, several reviews have been published (45, 46) .




                                                                                                             li
    of proliferation and a higher number of population doubling.      Particularly, it is to quote the work of Nakamura et al who
    The cells ex-vivo studies have shown markers STRO-1 and           have compared SHED, BMSC and DPSCs (47). He em-




                                                                                                          na
    CD146 that have been demonstrated even in BMSSCs and              phasize SHED having a greater proliferative capacity by
    DPSCs. These two markers were located around blood ves-           assigning this characteristics to higher expression of FGF2
    sels of the pulp, suggesting that SHED may originate from         and TGF-ß2 and presenting SHED as the best candida-
    the perivascular microenvironment. To study a cell ability        te to play a leading role in tissue engineering and rege-




                                                                                                       io
    to differentiate into new line rather than into another one       nerative medicine.
    author examined the expression of surface markers, and            In 2010 was published the first clinical application of SHED
    in particular have been found bone markers CBFA1, ALP,            in the treatment of Parkinson’s disease, and preliminary
    MEPE, and bone sialoprotein.                                      results were very encouraging (48).




                                                                                 az
    It has also been demonstrated, both in vitro and ex vivo,
    SHED capacity to differentiate into odontoblasts-like
    cells, producing dentin reactive antibody DSPP after              Periodontal ligament stem cell
    growing on a scaffold of HA / TCP. Finally, SHED also sho-




                                                                               rn
    wed markers related to neural cells such as nestin, III-tu-       Seo et al. in 2004 published “Investigation of multipotent
    bulin, GAD, NeuN, GFAP, NFM, and the possibility of de-           postnatal stem cells from human Periodontal ligament” (8)
    veloping fat cells full of lipids and Oil-red-O+. In this stu-    announcing the isolation of stem cells from the periodontal
    dy, SHED have not been shown to be able to differentia-           ligament, funding confirmed by Gay et al. in 2007 (49). De-




                                                                      te
    te (in vivo) in osteoblasts, but to induce the new bone esta-     spite the identification of this new oral cavity niche, other
    blishment composing a supporting osteoinductive network           authors have grappled with the isolation of stem cells from
    to murine osteogenic cells. In a 2005 article the same re-        this niche (50, 51, 52) but until 2007 there has been no new
    searchers focuses on the higher growth potential of stem          addition to the simple cell type isolation.
    cell niches of the oral cavity, compared to those derived
                                                             In       In the same year Leon et al. (53) and Gay et al.(54) de-
    from bone marrow (38). In fact, they report CFU-F refer-          veloped various topics adding news to the research on
    red to 10-12 days are 14 for the BMSC, 400 for DPSCs,             PDLSCs. The work of Leon et al. focuses on a cytokine,
    200 and 170 for the SHED for PLDSC each 105 cells pla-            interleukin-11 (IL-11), currently used by patients receiving
    ted. Even in the cloning experiments, the population dou-
                                                 ni
                                                                      chemotherapy for its ability to stimulate the production of
    bling of BMSC hardly exceeds 50, while DPSCs, SHED                platelets. Authors use the IL-11 following some new
    and PDLSC can reach a value of 100, but the mechanism             scientific findings that demonstrate its osteogenic activi-
    of these differences is not yet known.                            ty and then adding the drug to the culture of PDLSC re-
                                       io


    A practical application of SHEDs was published on                 sulting in a osteoblast differentiation demonstrated through
    JADA in 2008 (39). Authors tested on 105 premolar with            the production of collagen type 1.
    a single root canal the possibility of pulp tissue regene-        Gay et al. instead developed an interesting study that com-
                             iz



    ration by implanting SHED seeded on two different scaf-           pares PDLSC and BMSC in terms of the ability of diffe-
    fold (open-cell polylactic acid and collagen from cow hide),      rentiation in osteogenic cultures, emphasizing that the ex-
    added with different types of growth factors (BMP2, TGF           pression of alkaline phosphatase (ALP) can be noted in
             Ed




    beta 1, beta-Glycerol-phosphate). They thus demonstra-            the first case after 14 days and after 7 days in the second,
    ted that the scaffold is essential for the generation of pulp-    while the bone sialoprotein (BSP) are visible after 7 days
    like tissue, while growth factors did not improve the amount      in both cell types. Authors also make condrogenetic adi-
    of newly formed tissue. Also in 2008, Seo et al (40) stu-         pogenetic crops, noting that the surface antigens can be
    died the use of SHED in bone regeneration associating             found in both PDLSC than in BMSC after the same num-
    them with HA/TCP and obtaining good results in filling cri-       ber of days, showing that PDLSC are cells with the same
    tical size defects in mice calvaria. These results are in con-    differentiation potential of BMSC.
 IC




    trast with those of Miura in 2003 (7) but agree with Ko-          The following year Lindroos et al (55) with a study focu-
    yamain 2009 (41), emphasizing that SHED are capable               sed on surface antigens related to the bone - alkaline pho-
    of osteoblast-like cells differentiatiation, thus having an ac-   sphatase, Runx2, type I collagen, osteocalcin and osteo-
    tive role in new bone development and not just a passi-           pontin - stress that dental stem cells shows the same sur-
C




    ve role, as stated previously. In 2008, Cordeiro et al (42)       face antigens of stem cells derived from bone marrow and
    studied SHED in order to get more results and better un-          then are as valid to continue the search for bone rege-
    derstanding of the mechanisms underlying the formation            neration.
    of the pulp to obtain a tissue architecture and cellularity       In 2008 an article was published that tries to take a step
©




    similar to those of physiologic dental pulp. At well as stu-      forward in PDLSC research (56) demonstrating the rege-
    dies on cellularity, studies on scaffolds were also carried       neration of the periodontal ligament on pig model and la-
    out, as Galler et al in 2008 that used an hydrogel scaffold       ying the foundation for stem cell therapy of periodontitis.
    for SHED and DPSCs proliferation, resulting in resorption         Even Ma and colleagues presented a paper on regene-
    of the scaffold and a collagen production by SHED and             ration of the periodontal ligament demonstrating formation
    phenotypically osteoblastic cells from DPSCs (43). Zheng          of cement-like cells from PDLSC cells stimulated with Non-
    et al in 2009 (44) reconstructed critical-size defects (2,5       collagenous Dentin Proteins (DNCPs) (57).
    x1, 5x1, 5cm) in minipig mandibles using SHED / ß-TCP             Thus in 2007 and in 2008 research on PDLSC has found

    Annali di Stomatologia 2011; II (1-2): 3-8                                                                                   5
    G. Giordano et al.


    a new impetus thanks to the fact that these cells were used        Acknowledgement
    in the regeneration of the periodontal ligament, a cellular
    type so difficult to regain once lost. Some authors tried other    This study was supported by grants from “Fondazione
    less traditional ways for PDLSC cultivation in order to have       Roma” n. 10.2.3.1.
    a greater resemblance to the situation in vivo using three-
    dimensional methods, such as pellets on crops,or in three-




                                                                                                                   li
    dimensional rotational systems, the results are controversial      References
    (58, 59).




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 IC




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©




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    6                                                                                           Annali di Stomatologia 2011; II (1-2): 3-8
    Stem cells from oral niches: a review


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                                                                                                                        li
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                                                                                                                     na
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