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. Author manuscript; available in PMC: 2014 Jul 28.
Published in final edited form as: Dent Clin North Am. 2012 Jul;56(3):563–575. doi: 10.1016/j.cden.2012.05.001

Effects of Growth Factors on Dental Stem/ProgenitorCells

Sahng G Kim 1,2, Charles Solomon 2, Ying Zheng 1, Takahiro Suzuki 1, Chen Mo 1, Songhee Song 1, Nan Jiang 1, Shoko Cho 1, Jian Zhou 1, Jeremy J Mao *
PMCID: PMC4112411  NIHMSID: NIHMS390106  PMID: 22835538

Synopsis

The primary goal of regenerative endodontics is to restore the vitality and functions of the dentin-pulp complex, as opposed to filing of the root canal with bioinert materials. Structural restoration is also important but is likely secondary to vitality and functions. Myriads growth factors regulate multiple cellular functions including migration, proliferation, differentiation and apoptosis of several cell types that are intimately involved in dentin-pulp regeneration: odontoblasts, interstitial fibroblasts, vascular-endothelial cells and sprouting nerve fibers. Recent work showing that growth factor delivery, without cell transplantation, can yield pulp-dentin like tissues in vivo provides one of the tangible pathways for regenerative endodontics. This review synthesizes our knowledge on a multitude of growth factors that are known or anticipated to be efficacious in dental pulp-dentin regeneration.

Keywords: growth factors, dentin, dental pulp, dental pulp cells, regeneration, repair

1. Introduction

Regenerative endodontics aims to restore the vitality and functions of the pulp-dentin complex that has been lost to trauma or infections. Several recent reports have shown that dental pulp-like tissues can regenerate in vivo following the delivery of dental or non-dental stem cells.1-3 An alternative approach to orchestrate dental pulp-dentin regeneration by the homing of host endogenous cells relies on growth factor delivery, instead of cell delivery.4 Regardless of cell transplantation or cell homing approaches in dental pulp regeneration, a multitude of growth factors have been shown to have effects on dental pulp cells.5-7

The dental pulp is a unique, specialized loose connective tissue that contains mainly interstitial fibroblasts in cell-rich zone in the center of the pulp8 and odontoblasts that align dentin surface in the periphery (the odontoblast layer).9 Stem/progenitor cells reside among interstitial fibroblasts and perhaps adjacent to blood vessels.10 When dental pulp are isolated and studied in vitro, some of mononucleated and adherent cells, but certainly not all or not even the majority, have stem/progenitor cell properties including clonogenicity, self-renewal and multipotentiality.11 Clonogenicity refers to the ability of a single cell to yield a progeny. Self-renewal refers to the ability of cells to multiply themselves, with the offspring cells possessing the same properties as the parent cells. Multipotentiality is the capacity of a cell to differentiate into multiple, dissimilar cell lineages.12,13

Fundamental to our understanding of regenerative endodontics is the knowledge of growth factors that effect on a broad range of cellular activities including migration, proliferation, differentiation and apoptosis of all dental pulp cells, including stem/progenitor cells. Growth factors and cytokines may act as signaling molecules that modulate cell behavior by mediating intracellular communication. Growth factors are polypeptides or proteins that bind to specific receptors on the surface of target cells.14 They can initiate a cascade of intracellular signaling and act in either an autocrine or paracrine manner.15 Cytokines are typically referred to as immunomodulatory proteins or polypeptides.16 Cytokines are often used interchangeably with growth factors because many cytokines share similar actions as growth factors. As opposed to systemic effects by hormones on target cells, growth factors or cytokines typically act locally on target cells. This review first discusses the effects of various growth factors on dental pulp cells, and then explores how some of the growth factors may participate in dental pulp-dentin regeneration.

2. Platelet-Derived Growth Factor (PDGF)

PDGF is released by platelets, and has potency in promoting angiogenesis and cell proliferation.17-22 PDGF has 4 isoform homodimers: AA, BB, CC, and DD in addition to a heterodimer, PDGF-AB. PDGF dimers bind to two cell surface receptors known as PDGFRα and PDGFRβ.23 The receptors form dimers before binding to different isoforms of PDGF. PDGF-AA, -BB, and -CC bind to PDGFR α/α, whereas PDGF-AB, -BB, -CC, and -DD bind to PDGFR α/β.23 PDGF-BB and DD bind to PDGFR β/β.23 Therefore, the biological effect of PDGF depends on the expression level of PDGFR dimer on target cells.

The chemotaxis and proliferation of mesenchymal stem/progenitor cells can be induced by PDGF in the injury site. In trauma, hemorrhage is followed by blood clot formation in dental pulp. Platelets in the blood clot releaseα-granules containing PDGFs and attract neutrophils and macrophages.18 These cells play key roles in early wound healing by producing other signaling molecules for the formation of granulation tissues. However, PDGFs appear to have little effects on the formation of the dentin-like nodule in dental pulp cells isolated from rat lower incisors although PDGF-AB and -BB isoforms stimulate the expression of dentin sialoprotein (DSP).24 PDGFs stimulate cell proliferation and dentin matrix protein synthesis but appear to inhibit alkaline phosphatase (ALP) activity in dental pulp cells in culture.22,25,26 DSP expression is inhibited by PDGF-AA, but enhanced by PDGF-AB and PDGF-BB although the mineralized tissue formation is inhibited, suggesting diverging effects of PDGFs on odontoblastic differentiation depending on dimeric form.24 PDGF senhance the proliferation of fibroblasts in human dental pulp.22 PDGF-BB may increase the expression of VEGF in osteoblasts and promotes angiogenesis at the site of dental pulp injury.20 In vivo, PDGF promotes de novo formation of dental-pulp-like tissues in endodontically treated human teeth that are implanted in rats.4

3. Transforming growth factor-β (TGFβ)

The TGFβ family comprises a group of diverse growth factors including TGFβ, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), Anti-Mullerian hormone (AMH), activin and nodal.27-30 TGFβ is composed of ~390 amino acids, which are released mainly from platelets, macrophages, and bone.30 This inactive polypeptide undergoes proteolytic cleavage to create the active C-terminal 112-amino acid form. The active form of TGFβ dimerizes to form 25 kD homodimers.31 The three isoforms present in mammals, which are TGFβ1, TGFβ2, TGFβ3, are detected in human dentin.32 Inactive TGFβ exists as a large latent complex.33 After proteolytic cleavage, the active TGFβ binds to the Type II receptor (TGFβRII) and recruits Type I receptor (TGFβRI) to dimerize. TGFβRI, in turn, phosphorylates the intracellular proteins SMAD (homologs of drosophila proteins including Caenorhabditis elegans protein, SMA, and mothers against decapentaplegic, MAD), in particular, SMAD2 and SMAD3.34,35 The activated SMAD complex translocates to the nucleus and activates downstream TGFβ gene transcription.

The effect of TGFβ is highly variable and dependent on the type of cells and tissues. TGFβ1 regulates a wide range of cellular activities, such as cell migration, cell proliferation, cell differentiation, and extracellular matrix synthesis.36-40 TGFβ1 has been shown to increase cell proliferation and production of the extracellular matrix in dental pulp tissue culture,40 and promotes odontoblastic differentiation of dental pulp cells.41 The effect of TGFβ1 can be synergistically upregulated by fibroblast growth fatocr-2 (FGF2), as evidenced by the increased ALP activity, the formation of mineralized nodule, and the expression of DSP and dentin matrix protein-1.41 The dentinogenic ability of dental pulp cells in the mechanically exposed dental pulp of dog teeth is shown to be induced by exogenous TGFβ1.42 TGFβ is chemotactic on dental pulp cells in vitro43 TGFβ1 also plays an important role in the immune response during the dental pulp injury.44,45

4. Bone Morphogenetic Protein (BMP)

BMPs comprise a subgroup of the TGFβ superfamily and are involved in many biological activities including cell proliferation, differentiation, and apoptosis.46 BMPs have strong osteoinductive and chondrogenic effects. BMP2 was discovered by Urist et al.47 showing ectopic bone formation in connective tissues by transplanted dimineralized bone. Later, some of BMPs were identified, purified and sequenced from proteins extracted from bone.48 To date, more than 20 BMPs have been identified and characterized, among which growth differentiation factors (GDFs) were included.46 Unlike TGFβ, BMPs are secreted as an active form of 30-38 kDa homodimers after proteolytic cleavage of a synthesized form composed of 400 to 525 amino acids.46 Two TGFβ receptors (Type I and Type II) are known to be involved in the BMP signaling pathway.46 The activity of BMPs is regulated by the antagonists of BMPs such as noggin and chordin.49 This modulation of BMP activity by the BMP antagonists may have a critical role in tooth development.50

BMP2, BMP4, BMP7 and BMP11 are of clinical significance due to their role in inducing mineralization.5,51-62 Human recombinant BMP2 stimulates the differentiation of dental pulp cells into odontoblasts,51 inducing mRNA expression of dentin sailophosphoproteins (DSPPs) and higher ALP activity upon BMP2 application, but no effect on cell proliferation. DSPP expression and odontoblastic differentiation are regulated likely via BMP2-induced nuclear transcription factor Y signaling.52 BMP2 also stimulates the differentiation of dental pulp stem/progenitor cells into odontoblasts in vivo and in vitro.53 Human recombinant BMP2 or BMP4 induces dentin formation when used in capping materials over amputated canine pulp.54,55 Osteodentin formation occurs in amputated canine pulps treated with BMPs in collagen matrix.56 Bovine dental pulp cells treated with BMP2 and BMP4 differentiate into preodontoblasts.55 BMP7, also known as osteogenic protein-1, promotes dentin formation when placed over amputated dental pulp in macaque teeth.57,58 The dentinogenic effect of BMP7 on amputated dental pulp has been shown in several animal models including rats,59 ferrets,5 and miniature swine.60 Dental pulp cells transfected with BMP11, also known as GDF11, yields mineralization.61 Dentin matrix protein 1, ALP, DSPP, enamelysin, and phosphate-regulating gene are highly expressed in BMP11-tranfected cells.61 Transplantation of BMP11-transfected cell pellets induces formation of dentin-like tissue on amputated dental pulp in dogs.61 Ultrasound-mediated gene delivery of BMP11 stimulates odontoblastic differentiation of dental pulp stem/progenitor cells in vitro and reparative dentin formation in vivo.62

5. Vascular Endothelial Growth Factor (VEGF)

VEGF is a heparin-binding protein with specific affinity to endothelial cells and plays a keyrole in angiogenesis.63 The functions of VEGF involve the proliferation of endothelial cells and their enhanced survival,64 stimulating neovascularization in the area of injury. The VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D and placenta growth factor.65 Among these isoforms, VEGF-A is the most versatile in function. VEGF-A, also known as vascular permeability factor, and promotes cell migration, cell proliferation, vasodilatation and vascular permeability by binding to two tyrosine kinases receptors, VEGFR1 and VEGFR2.65 VEGF increases microvessel density of the dental pulp when tooth slices containing severed dental pulp were treated with VEGF and implanted into subcutaneous tissues of severely combined immunodeficiency (SCID) mice.66

VEGF appears to induce the differentiation of human dental pulp cells into endothelial cells.67 Dental pulp cells become positive for CD29, CD44, CD73, CD105, CD166 but negative for CD14, CD34, CD45 after VEGF treatment.67 VEGF increases the expression of VEGFR1 (fms-like tyrosine kinase, Flt-1) and VEGFR2 (kinase-insert domain containing receptor, KDR) and microvessel formation in a three-dimensional fibrin mesh seeded with dental pulp cells.67 However, VEGF treatment does not appear to promote CD31, CD34, and CD144 positivity in dental pulp cells that are positive for CD29, CD90, CD105, CD166, CD146, and STRO-1.68 Interestingly, VEGF increases the proliferation and osteogenic differentiation of dental pulp cells under osteogenic conditions, suggesting a possible stimulatory role of VEGF in osteogenesis.68

6. Fibroblast Growth Factor (FGF)

FGF plays key roles in cell migration, proliferation and differentiation during embryonic development69 and wound healing.70 Currently 22 members have been identified in humans,71 of which FGF2 appears to be significant in regeneration of the pulp-dentin complex. Four FGF receptors, FGFR1 through FGFR4 are expressed in humans.72 Signal transduction is mediated by interaction between FGFs with the ability to bind to haparan sulfate and heparan sulfate proteoglycans on cell surface.73 FGF2 is a basic FGF, while FGF1 is acidic. FGF2 regulates tooth morphogenesis by controlling cell proliferation and differentiation.74 FGF2 is a potent angiogenic factor stimulating new blood vessel formation in the dental pulp75 along with PDGF19,20 and VEGF.66 Given its role in cell proliferation and angiogenesis, FGF2 acts as an early stimulating factor in granulation tissue formation during wound healing.75

FGF2 induces the migration of dental pulp cells.7 Using a transwell migration assay, significantly more dental pulp cells are recruited by bFGF (FGF2) into a 3D collagen gel than controls without cytokines and BMP7.7 FGF2 also stimulates the proliferation of dental pulp cells without differentiation, whereas FGF2 combined with TGFβ1 induces differentiation of dental pulp cells into odotoblast-like cells, and synergistically upregulates the effect of TGFβ1 on odontoblast differentiation.41 The FGF2 on exposed dental pulp in rat molars induces vascular invasion and cell proliferation early in wound healing.76-78 Also, FGF2 stimulates reparative dentin formation or dentin-particles in the exposed pulp.76-78

7. Insulin-like Growth Factor (IGF)

IGFs are single chain polypeptides that have high sequence similarity to proinsulin.79 IGFs, comprising IGF-1 and IGF-2, contribute to odontogenesis and dental tissue repair by cell proliferation and differentiation.80 There are two known IGF receptors, of which IGF-1R has tyrosine kinase activity that phosphorylates the insulin receptor substrates and activates MAP kinase and the phosphatidylinositol 3-kinase (PI3K) cascades.81 However, IGF-2R has no intrinsic kinase activity. IGF-1R binds to both isoforms of IGFs, but IGF-2R only binds to IGF-2.82,83

Of the two isoforms, IGF-1, also known as somatomedin C, has potency in growth and differentiation of dental pulp cells.84 IGF-1 induces proliferation and differentiation of dog dental pulp cells into odontoblast-like cells in serum-free medium.84 IGF-1 with PDGF-BB has a synergistic effect on the proliferation of dental pulp cells in vitro.25 IGF-1 and IGF-1R have a higher level of expression in dental pulp tissue from teeth with complete root development than teeth with incomplete root formation, suggesting that IGF-1 stimulates mineralization and cell differentiation.85-87

8. Nerve Growth Factor (NGF)

NGFs, also known as neutrophins, promote the survival and maintenance of sympathetic and sensory neurons. NGFs bind to two receptors, a p75 low-affinity neutrophin receptor (p75 LANR) and a high-affinity tyrosine kinase receptor (trk).88 NGFs are involved in the survival and differentiation of neuronal and non-neuronal cells through high-affinity trkA, but NGFs regulates apoptosis through p75 LANR.89 The expression of NGF and p75 LANR increases in dental pulp cells at the injury site.90 NGFs play a role in regulating tooth morphogenesis and tooth innervation in rat tooth development.91 NGFs induce the differentiation of immortalized dental papilla cells into odontoblasts in vitro, suggesting that NGF acts as a stimulant for mineralization.92

9. Stromal Cell-Derived Factor-1 (SDF-1)

SDF-1, also known as chemokine (C-X-C motif) ligand 12 (CXCL12), is a chemoattractant involved in cell mobilization and homing by binding to the chemokine receptor CXCR4.93 SDF-1 functions as a chemokine for hematopoietic stem cells,94 mesenchymal stromal cells,95 and immune cells.96 SDF-1 stimulates the migration and proliferation of CD31-/CD146- side population (SP) cells isolated from porcine tooth germ that are positive for CXCR4 and negative for hematopoietic markers.97 Furthermore, the CD31-/CD146- SP cells have strong migration and proliferation activity with localized SDF-1 expression in amputated canine dental pulp.98 Dental pulp-like tissue with capillaries and nerves regenerate in dog teeth following pulp extirpation and autologous transplantation of the CD31-/CD146- SP cells or CD105+ cells with SDF-1 into root canals.99

10. Dental Pulp/Dentin Regeneration by Cell Homing

Previous work on dental pulp-dentin regeneration has followed typical approaches of tissue engineering by delivering cells in biomaterial scaffolds. Also previous work has typically relied on ectopic models of tooth slices or fragments.100-102 In a recent study, a cell homing approach was used to regenerate the pulp-dentin complex by the delivery of growth factors rather than cells in entire human teeth following root canal treatment.4 Several growth factors, including bFGF, VEGF, NGF, PDGF, and BMP7, were delivered singularly or in combination into root canal spaces of endodontically treated human teeth (without gutta percha filling).4 bFGF was chosen for chemotaxis and angiogenesis; VEGF for chemotaxis, mitogenesis, and angiogenesis; PDGF for angiogenesis; NGF for survival and growth of nerve fibers; and BMP-7 for mineralized tissue formation. Dental pulp/dentin-like tissues regenerated with new blood vessels, representing the first study showing dental pulp-dentin-like tissues can regenerate without cell transplantation.4 Cell homing approach for dental pulp/dentin regeneration by using multiple growth factors may accelerate clinical translation. Examples of the signaling molecule or chemical cue that play a role in cell mobilization and homing are PDGF,17,18 TGFβ,43 bFGF,7 and SDF-1.94-98 The recruited stem/progenitor cells proliferate in the area of injury and differentiate into a specific cell phenotype to replace the damaged cells. The replacement cells are stimulated to produce extracellular matrix that is essential for tissue to function biologically. These events of repair and regeneration can be coordinated and modulated by growth factors such as PDGF,22,24-26 TGF,40,41 BMP,5,51-62 VEGF,68 FGF,41,76-78 and IGF.84-87 Angiogenesis and neuronal growth also can be stimulated by growth factors such as FGF2, PDGF, VEGF and NGF. Angiogenesis is stimulated by growth factors such as FGF2,75 PDGF,19,20 VEGF,66 and the survival and growth of neuron is regulated by NGF.91

Summary

The goal of regenerative endodontics is to regain the vitality and functions of dental pulp-dentin complex. Dental pulp is the only vascularized tissue in mature, functional teeth in humans, and maintains homeostasis of the dentin. Current root canal therapy ends up with a de-vitalized tooth, therefore predisposing endodontically treated teeth to re-infections and fractures. Recent work showing regeneration of dental pulp-dentin-like tissues by cell homing that is orchestrated by growth factor delivery, without cell transplantation, provides one of the tangible pathways towards clinical translation. Growth factors regulate either transplanted cells or endogenously homed cells in dental pulp-dentin regeneration. Further understanding of the actions of growth factors is pivotal for dental pulp-dentin regeneration.

Fig 1.

Fig 1

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Key Points.

  1. The goal of regenerative endodontics is to regain the vitality and functions of dental pulp-dentin complex. Dental pulp is the only vascularized tissue in mature, functional teeth in humans, and maintains homeostasis of the dentin.

  2. Current root canal therapy ends up with a de-vitalized tooth, therefore predisposing endodontically treated teeth to re-infections and fractures. Recent work showing regeneration of dental pulp-dentin-like tissues by cell homing that is orchestrated by growth factor delivery, without cell transplantation, provides one of the tangible pathways towards clinical translation.

  3. Growth factors regulate either transplanted cells or endogenously homed cells in dental pulp-dentin regeneration. Further understanding of the actions of growth factors is pivotal for dental pulp-dentin regeneration.

Acknowledgments

We thank F. Guo and J. Melendez for technical and administrative assistance. The work for composition of this manuscript is supported by NIH grants R01DE018248, R01EB009663 and RC2DE020767 (to J. J. M.).

Footnotes

Conflict of Interest

Columbia University is the owner of patents for several regenerative endodontic agents and methods on behalf of Dr. Jeremy Mao’s laboratory.

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