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Table of Contents   
REVIEW ARTICLE  
Year : 2011  |  Volume : 22  |  Issue : 1  |  Page : 132-139
Stem cell therapy: A challenge to periodontist


Department of Periodontics, H.K.E Society's S. N. Institute of Dental Sciences and Research, Gulbarga, Karnataka, India

Click here for correspondence address and email

Date of Submission11-Dec-2009
Date of Decision04-Mar-2010
Date of Acceptance19-Aug-2010
Date of Web Publication25-Apr-2011
 

   Abstract 

Periodontitis is an inflammatory disease which manifests clinically as loss of supporting periodontal tissues including periodontal ligament, cementum, and alveolar bone, and periodontal therapy is aimed at achieving complete regeneration of these structures. To date, this goal has been tried to accomplish using various bone grafts, growth factors, and barrier membranes. Stem cells are the most fascinating area of biology today and have been used clinically in the field of medicine to treat many incurable diseases. Various human and animal studies have confirmed the presence of stem cells in dental tissues including periodontal ligament. This has opened new avenues aiming toward complete periodontal regeneration using cell-based therapies. This review provides an overview of various types of stem cells in medicine and dentistry and their potential uses especially pertaining to periodontal regeneration.

Keywords: Adult stem cells, periodontal regeneration, stem cells

How to cite this article:
Mudda JA, Bajaj M. Stem cell therapy: A challenge to periodontist. Indian J Dent Res 2011;22:132-9

How to cite this URL:
Mudda JA, Bajaj M. Stem cell therapy: A challenge to periodontist. Indian J Dent Res [serial online] 2011 [cited 2020 Jul 10];22:132-9. Available from: http://www.ijdr.in/text.asp?2011/22/1/132/79978
Improved understanding of disease process and methods to prevent and cure them has led to increased lifespan of human beings. [1] This increased life expectancy has thus shifted the paradigm from replacement of lost or injured tissues to regeneration of the same. [2] Research on stem cells is advancing knowledge of development and repair process in an organism. Stem cells are one of the most fascinating areas of biology today. Stem cell plasticity has resulted in a new field of medicine entitled regenerative medicine. [3] Especially intriguing is the possibility of offering therapy for a number of incurable diseases and providing an innovative approach to treatment of chronic diseases. Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases including Parkinson's disease, [4] Alzheimer's disease, [5] spinal cord injury, stroke, [6] heart diseases, [7] diabetes, [8] arthritis, [9] and many more to be listed.

Though dental tissues are hard and rigid, they are vulnerable to damage caused by mechanical trauma, chemicals, congenital defects, cancer, and bacterial infections. [10] Adult teeth demonstrate only limited reparative/regenerative ability as the formation of reparative or tertiary dentin. [11] Similarly, periodontium also has limited capacity for regeneration in early phases of the disease. [12] Despite our extensive knowledge concerning the pathology of diseases of teeth, restoration of damaged or diseased dental tissues has relied primarily on the use of synthetic implants and structural substitutions comprising inert compounds. Attempts to regenerate periodontal tissues have focused exclusively on regenerating lost alveolar bone with the help of autografts and alloplastic materials. [10] More recently, several novel tissue-engineering approaches have emerged as perspective alternatives to conventional treatments including gene therapy and local administration of biocompatible scaffolds, with or without the presence of various growth factors. [13],[14] Most recent in the quest is the identification of putative dental stem cell populations and their potential use in stem cell based therapies to treat the damage caused by trauma, cancer, caries, and periodontal disease. [15],[16],[17]


   Definition and Various Types Top


The term stem cell first appeared in the literature during 19th century. [18] Birth of stem cell research took place way back in 1953 when Leroy Stevens identified teratoma like cells in testicles of inbred mice. However, the age of regenerative medicine started in 1998 with the discovery of human embryonic stem cells (ES cells). [19]

Stem cells are defined as cells that have clonogenic and self-renewing capabilities and differentiate into multiple cell lineages. [20] All stem cells regardless of their source have three general properties: they are capable of dividing and renewing themselves for long periods, they are unspecialized, and they can give rise to specialized cell types. Depending upon the intrinsic signals modulated by extrinsic factors in the stem cell niche, these cells may either undergo prolonged self-renewal or differentiation. [21] To date, six types of stem cells have been isolated in humans, mainly categorized into embryonic stem cells (ES cells) and adult stem cells. [22],[23],[24]

Embryonic stem cells

The identification and isolation of ES cells from mice was a major step in biology. [25],[26] Mammalian ES cells were first derived from mouse embryos independently by Evans and Kaufman in 1981. [19] In the 1990s, ES cell lines from two non-human primates, the rhesus monkey [27] and the common marmoset, [28] were derived. In 1998, Thomson and co-workers derived the first human ES cell line from the inner cell mass of 4-7 day old blastocyst stage embryo. [23]

ES cells are easier to propagate and manipulate in vitro than adult or somatic stem cells and have a greater differentiation potential, being totipotent as opposed to multipotent or unipotent. [29] These cells exhibit a morphology relatively flat and compact and are characterized by expression of stage-specific embryonic antigens 3 and 4 (SSEA-3 and SSEA-4), high molecular weight proteins (TRA-1-60 and TRA-1-81), alkaline phosphatases, octa-binding factor ¾ (Oct-4) [30] and high expression of telomerase, thereby maintaining their chromosomal length. [30] The remarkable discovery of four transcription factors to re-program fully differentiated cells to an ES-like state - so called induced pluripotent stem (iPS) cells - has opened up new hopes in the near future. [31] These cells have opened up the possibility of "fixing" a particular genotype (either normal or diseased) in pluripotent stem cells and allowing serious attempts at developing robust in vitro disease models [Figure 1]. [32]
Figure 1: Source of embryonic stem cells

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Fetal stem cells

Although many stem cell populations are present in the fetus during gestation and their roles in normal development have been widely studied, their possible clinical usefulness has barely been explored, owing to the ethical issues of using cells from fetuses in treating disease and the risks to pregnancy associated with intrauterine procedures. [33] These cells not only can differentiate into mesenchymal lineages including bone and cartilage but also have the ability to form oligodendrocytes and hematopoietic cells. [34] These cells, which can be found circulating only during the first trimester, are similar to hematopoietic populations in liver and bone marrow; they engraft into many organs and undergo site-specific tissue differentiation when transplanted into a xenogenic sheep model. [34] Recent studies investigating the self-renewal and differentiation of human fetal mesenchymal stem cells (MSCs) after transduction with oncoretroviral and lentiviral vectors have suggested that these cells could be suitable targets for ex vivo genetic manipulation with these vectors without effects on their stem cell properties. [35]

Adult stem cells

The ability of some tissues in the adult (e.g. skin, hematopoietic system, bone, and liver) to repair or renew indicates the presence of stem or progenitor cells. [1] Compared to the pluripotent and almost immortal nature of embryonic stem cells, adult stem cells appear more mature with a finite lifespan and only multipotent differentiation capacity. [18]

Hematopoietic stem cells from bone marrow were the first type of adult stem cells to be identified. [36] These cells have been extensively studied and are currently used therapeutically in patients with hematological disorders or who are undergoing chemotherapy or radiotherapy for malignant diseases. [1]

Another population of adult non-hematopoietic stem cells also resides in the bone marrow microenvironment. [37],[38],[39] These are termed bone marrow stromal stem cells (BMSSCs) or mesenchymal stem cells (MSCs). Friedenstein and co-workers [40] in 1976 first identified colony-forming unit fibroblasts (CFU-F), which are now known as MSCs or marrow stromal cells. Pittenger and colleagues [41] showed that they can be purified and propagated clonally in vitro and they give rise to several mesoderm derived cell types, including osteoblasts, chondrocytes, and adipocytes; neurons; and astrocytes in vivo and in vitro, depending on the growth factors used to stimulate them. This stem cell compartment is heterogeneous in terms of morphology, physiology, and expression of surface antigens [42] and is characterized by expression of: CD44, CD105 (SH2; endoglin), CD106 (vascular cell adhesion molecule; VCAM-1), CD166, CD29, CD73 (SH3 and SH4), CD90 (Thy-1), CD117, STRO-1, and Sca-1. [43],[44],[45],[46],[47] They also express a set of receptors associated with matrix- and cell-to-cell adhesive interactions, like integrins αVβ3 and αVβ5, ICAM-1, ICAM-2, and LFA-3 and L-selectin,[46],[47] and lack typical hematopoietic antigens and endothelial cell lineages, namely, CD11b, CD14, CD31, CD33, CD34, CD133, and CD45. [43] The main source of MSCs is the bone marrow. Apart from the bone marrow, MSCs are also located in other tissues like adipose tissue, [48] umbilical cord blood, chorionic villi of the placenta, [49] amniotic fluid, [50] peripheral blood, [51] fetal liver, [33] lung, [33] and even in exfoliated deciduous teeth, dental pulp, and periodontal ligament [Figure 2] and [Figure 3] [52]
Figure 2: Various tissues that demonstrate the presence of adult stem cells

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Figure 3: Differentiation potential of mesenchymal stem cells

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Human dental derived mesenchymal stem cells

Based on the findings obtained in medical fields, new studies in dentistry have been designed to identify and characterize dental derived stem cell populations, aiming at developing more predictable regenerative approaches for lost tissues as a consequence of disease and/or trauma. Recently, MSC population derived from dental pulp (DPSCs), exfoliated human deciduous teeth (SHED), and adult periodontal ligament stem cells (PDLSCs) have been isolated and identified by their ability to generate clonogenic adherent cell clusters such as BMSSCs. [15],[16],[17] Cloning experiments showed that DPSC, SHED, and PDLSC have a frequency of colony forming cells significantly higher than that of bone marrow. Besides, proliferation studies demonstrated that multi-colony-derived DPSC, SHED, and PDLSC cell cultures exhibited higher rates of proliferation, approximately 30%, 50%, and 30%, respectively, when compared to BMSCCs. [15],[16],[17],[45]

Dental pulp derived stem cells

The identification and isolation of an odontogenic progenitor population in adult dental pulp were first reported by Gronthos and co-workers [17],[53] in 2000 by virtue of their clonogenic abilities, rapid proliferative rates, and capacity to form mineralized tissues both and in vivo. The most striking feature of DPSCs is their ability to regenerate a dentin-pulp-like complex that is composed of mineralized matrix with tubules lined with odontoblasts, and fibrous tissue containing blood vessels in an arrangement similar to the dentin-pulp complex found in normal human teeth. [17] Like osteoblasts, pulp cells express bone markers such as bone sialoprotein, alkaline phosphatase, type I collagen, and osteocalcin. There is a great potential for isolation of a large number of DPSCs from a single tooth that could be used for dentinal repair of a number of teeth. Further development of carriers with appropriate shape and composition to be used in conjunction with ex vivo expanded DPSCs makes the fabrication of a viable dental implant a real possibility in the near future. [17]

Stem cells derived from exfoliated human deciduous teeth

The transition from deciduous teeth to adult permanent teeth is a very unique and dynamic process in which the development and eruption of permanent teeth coordinate with the resorption of the roots of deciduous teeth. [54] There is evidence indicating that a naturally occurring exfoliated deciduous tooth is similar in some ways to an umbilical cord, containing stem cells, which may offer a unique stem-cell resource for potential clinical applications. [48] SHED represent a population of post-natal stem cells capable of extensive proliferation and multipotential differentiation. These cells can be isolated and expanded ex vivo, thereby providing a unique and accessible population of stem cells from an unexpected tissue resource. [54] Ex vivo expanded SHED were found to express the cell surface molecules STRO-1 and CD146 (MUC18), two early mesenchymal stem-cell markers previously found to be present in BMSSCs and DPSCs. However, SHED was unable to regenerate a complete dentin-pulp-like complex as done by DPSCs in vivo. Thus, it indicates that SHED are distinctively different from DPSCs with respect to the odontogenic differentiation, osteogenic induction, higher proliferation rate, and perhaps, more immature than previously examined postnatal stromal stem-cell populations. The data from the same study also imply that deciduous teeth may not only provide guidance for eruption of permanent teeth but also be involved in inducing bone formation during the eruption of permanent teeth by acting as an osteoinductive template. [54] Deciduous teeth, therefore, may be an ideal resource of stem cells to repair damaged tooth structures, induce bone regeneration, and possibly to treat neural tissue injury or degenerative diseases. [54]

Adult periodontal ligament stem cells

The PDL cell population is heterogeneous, consisting of two major mesenchymal lineages, fibroblastic and mineralizing tissues, further divided into osteoblastic and cementoblastic subsets. The concept that the stem cells may reside in the periodontal tissues was proposed approximately 20 years ago by Melcher, [55] who queried whether the three cell populations of the periodontium (cementoblasts, osteoblasts, and periodontal ligament fibroblasts) were derived from a single population of ancestral cells or stem cells. The most compelling evidence that these cells are present within the periodontal tissues has been provided by the studies of McCulloch et al.[56],[57],[58] in 1987, who identified a small population of progenitor cells adjacent to blood vessels within periodontal ligament. These cells demonstrated some classical cytological features of stem cells, including small size, responsiveness to stimulating factors and slow cycle time. More recently, Seo et al.[15] isolated PDLSCs from normal impacted third molars, and using cloning techniques verified that only some of the progenitor cell strains of periodontal ligament can be considered stem cells. These periodontal adult stem cells have the morphological, phenotypic, and proliferative characteristics of adult MSCs. Only these cells are capable of promoting turnover and tissue homeostasis, serving as a source of renewable progenitor cells generating cementoblasts, osteoblasts, and fibroblast throughout the adult life. [59] The presence of MSCs in PDL is also supported by the findings of Trubiani et al [60] who isolated and characterized a population of MSCs from PDL, which expressed a variety of stromal cell markers (CD90, CD29, CD44, CD105, CD166, and CD13). These cells are found to express markers like STRO-1,CD146, α-smooth muscle actin and/or the pericyte-associated antigen, 3G5,[15] an array of cementoblastic/osteoblastic markers including alkaline phosphatase, matrix extracellular phospho-glycoprotein (MEPE), bone-sialoprotein, osteocalcin and TGFβ receptor type-1[32] and general soft tissue proteins such as type I and type III collagen. [15],[59],[61] Ex vivo expanded PDLSCs formed mineralized nodules, cementum-like tissue on the surface of the hydroxyapatite/tricalcium phosphate ceramic particle carrier, along with condensed collagen fibers resembling sharpey's fibers, in the presence of calcium in extracellular matrix. [32] In general, these cells require a suitable scaffold such as hydroxyapatite/tricalcium phosphate to induce the formation of bone, cementum, and bone in vivo. [17],[62] When ex vivo expanded PDLSCs are implanted in vivo with a suitable scaffold, atypical cementum/PDL like structure forms. [15]


   Stem Cell Therapy in Medicine Top


In the new field of medicine entitled regenerative medicine, [3] the plasticity of stem cells from a variety of sources offers therapy for a number of untreatable or incurable diseases and provides an innovative approach to treatment of chronic diseases. As of date, the only approved indication for stem cell therapy as a part of routine medical practice is Bone Marrow Transplantation (BMT). [63] However, MSCs have been also proposed to be an excellent potential tool for gene therapies. [42] One of the fields for MSC use in regenerative medicine is the treatment of bone defects [64] and cartilage lesions. [65] Promising results have been also obtained when using MSCs in neuronal lesion treatment such as in stroke or traumatic brain injury, [6] Parkinson's disease [4] and Alzheimer's disease. [5]


   Stem Cell Banking Top


In 2005, the National Academies [66] issued a report, Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program, which recommended that a national cord blood "bank" be established to harness the medical potential of this source of stem cells. Research in recent times indicates that umbilical cord blood is rich in "stem cells". [67] The umbilical cord stem cells have a number of important advantages compared to the bone marrow stem cells. The major advantage is that umbilical cord blood stem cells are easier to gather than stem cells from the bone marrow. They have the unique ability to regenerate/reproduce into over 200 types of tissues. Above all, such stem cells, collected from the umbilical cord of child, can be frozen and kept in a bank, which can be used later. [68] The first ever cord blood bank in the world was started in New York's Milstein National Cord Blood Center. Today, there are over 40 cord blood banks worldwide, both public and private. [67]

Licensed cord blood banks in India are the following: [67]

  • Reliance Life Sciences, Delhi,
  • Lifecell, Chennai,
  • Cordlife Sciences and Cryobanks International plan to establish cord blood banks in Kolkata and New Delhi, respectively,
  • Histostem, a South Korean biotech company plans to establish the world's largest cord blood bank is Mumbai.


A wealth of information can be obtained from the following links: [67]




   Periodontal Regeneration Top


Regeneration of the attachment apparatus destroyed because of periodontitis has long been the goal of periodontal therapy. [69] Periodontal regeneration can be defined as the complete restoration of the lost tissues to their original architecture and function by recapitulating the crucial wound healing events associated with their development. [70] The requirements for periodontal regeneration include the simultaneous regeneration of cementum, the periodontal ligament and alveolar bone. [71]

Conventional periodontal therapy, involving debridement of the root surface, leads to periodontal tissues healing by repair and migration of epithelium along the previously contaminated root surface, which prevents connective tissue attachment to the root surface. [71] Conventional regeneration therapies, such as guided tissue regeneration, topical application of enamel matrix derivative, and use of various growth factors, can partially regenerate periodontal tissues. [72],[73],[74],[75],[76] But the indications for such treatments are rather limited and the amounts of regenerated tissue are not predictable. [77]

Application of periodontal tissue engineering for improved periodontal regeneration can involve cell-based, protein-based, or genetic engineering approaches with advantages and drawbacks of their own. [78] Of these, the cell-based approach requires the ex vivo expansion of appropriate cells and their transplantation via different vehicles. [79]

Scaffolds and signaling molecules are already being used clinically in regenerative therapies; however, the cells have not yet been identified. In this context, use of suitable cells seeded into periodontal defects would appear to be a powerful strategy to promote regeneration of periodontal tissues. [12] The cells should be easy to harvest, non-immunogenic, highly proliferative, and with the ability to differentiate into various types of cells comprising periodontal tissue. [80]

In order to fulfill this requirement, applications of various cells have been considered. [70] Bone marrow-derived MSCs have a significant, but highly variable, self-renewal potential during in vitro experiments and this property has made them an attractive source for cell-based therapies aiming at the regeneration of orofacial tissues, especially when the size of the lost tissue is large and the body can no longer repair this defect. [81],[82] Yamada et al.[77] reported a novel approach to periodontal regeneration with MSCs and platelet-rich plasma (PRP).

It is likely that the transplanted PDLSCs generated some of the new tissues and helped remodel the local microenvironment, which prevented epithelial down growth to optimize recovery of the periodontal defects. [83]

Nakahara et al.[84] reported that autologous periodontal ligament derived cells were required for the regeneration of periodontal tissues with collagen sponge scaffold in dogs. Mizuno et al.[85] attempted to regenerate periodontal tissue defects by grafting autologous cultured membrane derived from the periosteum. Findings of Lin et al.[86] provide the first evidence that stem cells participate in the healing of regenerating periodontal defects in humans and offer support for the use of stem-cell based tissue engineering in regenerative periodontal therapy. Gomez et al.[70] demonstrated the use of human periodontal ligament cell sheet technique which can be applied for regeneration of periodontal ligament-cementum complex in clinical settings.

PDL tissues are clinically accessible in routine clinical practice like tooth extraction, possibly providing a readily available source of stem cells for clinical periodontal regenerative therapy. [15] However, little is known about the characteristics of PDL progenitor/stem cells because PDL is composed of heterogeneous cell populations, and thus far, no highly purified PDLSC clone has yet been established from human PDL tissue. [87]

Various in vitro and in vitro studies have suggested that FGF (fibroblast growth factor), PDGF (platelet derived growth factor) and PDGF with IGF (insulin growth factor) strongly stimulate periodontal regeneration when applied in periodontal defects. [88],[89] Bone morphogenic protien (BMP) has also shown potential for bone and cementum regeneration. [90],[91] In future, MSCs transplantation with these growth factors will likely have even better beneficial effects on periodontal regeneration. [80]


   Challenges and Future Prospects Top


ES cells provide a source of medically useful differentiating tissues that lack the awesome potential of an intact embryo and offer an approach to study the earliest events in human development at the cellular and molecular levels in a way that is ethically acceptable. But before using cells therapeutically, they have to be differentiated enough to be incapable of spreading inappropriately or forming unwanted tissue. [92]

Despite the challenges of isolating, expanding, and defining stem cell populations, MSCs hold tremendous promise for tissue regeneration at a clinically useful level. There are dramatic examples of the potential use of stem cells in regenerative medicine, but much work remains to be done, particularly to characterize graft versus host stem cell immune interactions and to identify mechanisms enabling the delivery or homing of the stem cells to the site of interest. [93]

Periodontal regeneration requires consideration of many features that parallel periodontal development, including the appropriate progenitor cells, signaling molecules, and matrix scaffold in an orderly temporal and spatial sequence. It is clear that the current regenerative procedures are less than ideal but the identification of stem cells in human dental tissues in recent years holds promise to the development of novel, more effective approaches to periodontal regeneration and reconstructive therapy. With the identification of adult human stem cell populations residing in the periodontal ligament, the next phase is to determine the clinical utility of these cells. Complete regeneration of periodontal complex is a big challenge to overcome, especially in a diseased state with inflammatory factors, including cytokines. Another challenge is to understand the interaction between various cell populations comprising the periodontium and to address the role played by mechanical stresses during regeneration. [94] It is expected that a multilevel approach involving cell biologists, matrix biologists, pharmacologists, biomaterials scientists/engineers, and nanotechnologists will be required to address many of these issues.

 
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Correspondence Address:
Jayashree A Mudda
Department of Periodontics, H.K.E Society's S. N. Institute of Dental Sciences and Research, Gulbarga, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9290.79978

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