Inflammatory Cytokines and Biodegradable Scaffolds in Dental Mesenchymal Stem Cells Priming

Author(s): Tatjana Kanjevac* , Collin Gustafson , Ana Ivanovska , Francesca Ravanetti , Antonio Cacchioli , Darko Bosnakovski* .

Journal Name: Current Stem Cell Research & Therapy

Volume 14 , Issue 4 , 2019

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Mesenchymal stem cells (MSCs) are multipotent stem cells with wide-ranging clinical applications due to their ability to regenerate tissue from mesenchymal origin and their capability of suppressing immune responses, thus reducing the likelihood of graft versus host disease after transplantation. MSCs can be isolated from a variety of sources including bone marrow, adipose tissue, umbilical cord blood, and immature teeth. Dental stem cells (DSCs) possess progenitor and immunomodulatory abilities as the other MSC types and because they can be easily isolated, are considered as attractive therapeutic agents in regenerative dentistry. Recently, it has been shown that DSCs seeded onto newly developed synthetic biomaterial scaffolds have retained their potential for proliferation and at the same time have enhanced capabilities for differentiation and immunosuppression. The scaffolds are becoming more efficient at MSC priming as researchers learn how short peptide sequences alter the adhesive and proliferative capabilities of the scaffolds by stimulating or inhibiting classical osteogenic pathways. New findings on how to modulate the inflammatory microenvironment, which can prime DSCs for differentiation, combined with the use of next generation scaffolds may significantly improve their therapeutic potential. In this review, we summarize current findings regarding DSCs as a potential regenerative therapy, including stem cell priming with inflammatory cytokines, types of scaffolds currently being explored and the modulation of scaffolds to regulate immune response and promote growth.

Keywords: Mesenchymal stem cells, dental stem cells, immunomodulation, scaffold, differentiation, cytokines.

Volarevic V, Ljujic B, Stojkovic P, et al. Human stem cell research and regenerative medicine--present and future. Br Med Bull 2011; 99: 155-68.
Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284(5411): 143-7.
Mendez-Ferrer S, Michurina TV, Ferraro F, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010; 466(7308): 829-34.
Bosnakovski D, Mizuno M, Kim G, et al. Isolation and multilineage differentiation of bovine bone marrow mesenchymal stem cells. Cell Tissue Res 2005; 319(2): 243-53.
Gang EJ, Bosnakovski D, Figueiredo CA, Visser JW, Perlingeiro RC. SSEA-4 identifies mesenchymal stem cells from bone marrow. Blood 2007; 109(4): 1743-51.
Cook D, Genever P. Regulation of mesenchymal stem cell differentiation. Adv Exp Med Biol 2013; 786: 213-29.
Gang EJ, Bosnakovski D, Simsek T, To K, Perlingeiro RC. Pax3 activation promotes the differentiation of mesenchymal stem cells toward the myogenic lineage. Exp Cell Res 2008; 314(8): 1721-33.
Bosnakovski D, Mizuno M, Kim G, et al. Chondrogenic differentiation of bovine bone marrow mesenchymal stem cells in pellet cultural system. Exp Hematol 2004; 32(5): 502-9.
Volarevic V, Arsenijevic N, Lukic ML, Stojkovic M. Concise review: Mesenchymal stem cell treatment of the complications of diabetes mellitus. Stem Cells 2011; 29(1): 5-10.
Isobe Y, Koyama N, Nakao K, et al. Comparison of human mesenchymal stem cells derived from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous tooth pulp. Int J Oral Maxillofac Surg 2016; 45(1): 124-31.
Tsai AI, Hong HH, Lin WR, et al. Isolation of mesenchymal stem cells from human deciduous teeth pulp. BioMed Res Int 2017; 2017: 2851906.
Mead B, Logan A, Berry M, Leadbeater W, Scheven BA. Concise review: Dental pulp stem cells: A novel cell therapy for retinal and central nervous system repair. Stem Cells 2017; 35(1): 61-7.
La Noce M, Paino F, Spina A, et al. Dental pulp stem cells: State of the art and suggestions for a true translation of research into therapy. J Dent 2014; 42(7): 761-8.
Kushnerev E, Shawcross SG, Hillarby MC, Yates JM. High-plasticity mesenchymal stem cells isolated from adult-retained primary teeth and autogenous adult tooth pulp-A potential source for regenerative therapies? Arch Oral Biol 2016; 62: 43-8.
Ballerini P, Diomede F, Petragnani N, et al. Conditioned medium from relapsing-remitting multiple sclerosis patients reduces the expression and release of inflammatory cytokines induced by LPS-gingivalis in THP-1 and MO3.13 cell lines. Cytokine 2017; 96: 261-72.
Glenn JD, Whartenby KA. Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy. World J Stem Cells 2014; 6(5): 526-39.
Pisciotta A, Carnevale G, Meloni S, et al. Human Dental Pulp Stem Cells (hDPSCs): Isolation, enrichment and comparative differentiation of two sub-populations. BMC Dev Biol 2015; 15: 14.
Bojic S, Volarevic V, Ljujic B, Stojkovic M. Dental stem cells-characteristics and potential. Histol Histopathol 2014; 29(6): 699-706.
Maxim MA, Soritau O, Baciut M, Bran S, Baciut G. The role of dental stem cells in regeneration. Clujul Med 2015; 88(4): 479-82.
Kang YH, Lee HJ, Jang SJ, et al. Immunomodulatory properties and in vivo osteogenesis of human dental stem cells from fresh and cryopreserved dental follicles. Differentiation 2015; 90(1-3): 48-58.
Liu J, Yu F, Sun Y, et al. Concise reviews: Characteristics and potential applications of human dental tissue-derived mesenchymal stem cells. Stem Cells 2015; 33(3): 627-38.
Li Z, Jiang CM, An S, et al. Immunomodulatory properties of dental tissue-derived mesenchymal stem cells. Oral Dis 2014; 20(1): 25-34.
Janebodin K, Horst OV, Ieronimakis N, et al. Isolation and characterization of neural crest-derived stem cells from dental pulp of neonatal mice. PLoS One 2011; 6(11): e27526.
Ibarretxe G, Crende O, Aurrekoetxea M, et al. Neural crest stem cells from dental tissues: A new hope for dental and neural regeneration. Stem Cells Int 2012; 2012: 103503.
Martens W, Bronckaers A, Politis C, Jacobs R, Lambrichts I. Dental stem cells and their promising role in neural regeneration: An update. Clin Oral Investig 2013; 17(9): 1969-83.
Ding G, Liu Y, An Y, et al. Suppression of T cell proliferation by root apical papilla stem cells in vitro. Cells Tissues Organs 2010; 191(5): 357-64.
Bright JJ, Kerr LD, Sriram S. TGF-beta inhibits IL-2-induced tyrosine phosphorylation and activation of Jak-1 and Stat 5 in T lymphocytes. J Immunol 1997; 159(1): 175-83.
Klincumhom NCD, Adulheem S, Pavasant P. Activation of TLR3 enhance stemness and immunomodulatory properties of Periodontal Ligament Stem Cells (PDLSCs) Interface Oral Health Science. 2017. In: Sasaki K, Suzuki O, Takahashi N, Ed.: 205-16
Ren G, Su J, Zhang L, et al. Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells 2009; 27(8): 1954-62.
Dazzi F, Krampera M. Mesenchymal stem cells and autoimmune diseases. Best Pract Res Clin Haematol 2011; 24(1): 49-57.
Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new Mesenchymal Stem Cell (MSC) paradigm: Polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One 2010; 5(4): e10088.
Vega-Letter AM, Kurte M, Fernandez-O’Ryan C, et al. Differential TLR activation of murine mesenchymal stem cells generates distinct immunomodulatory effects in EAE. Stem Cell Res Ther 2016; 7(1): 150.
Chen X, Zhang ZY, Zhou H, Zhou GW. Characterization of mesenchymal stem cells under the stimulation of toll-like receptor agonists. Dev Growth Differ 2014; 56(3): 233-44.
Bernardo ME, Fibbe WE. Mesenchymal stromal cells: Sensors and switchers of inflammation. Cell Stem Cell 2013; 13(4): 392-402.
Raffaghello L, Bianchi G, Bertolotto M, et al. Human mesenchymal stem cells inhibit neutrophil apoptosis: A model for neutrophil preservation in the bone marrow niche. Stem Cells 2008; 26(1): 151-62.
Cassatella MA, Mosna F, Micheletti A, et al. Toll-like receptor-3-activated human mesenchymal stromal cells significantly prolong the survival and function of neutrophils. Stem Cells 2011; 29(6): 1001-11.
Ghannam S, Bouffi C, Djouad F, Jorgensen C, Noel D. Immunosuppression by mesenchymal stem cells: Mechanisms and clinical applications. Stem Cell Res Ther 2010; 1(1): 2.
Brandau S, Jakob M, Hemeda H, et al. Tissue-resident mesenchymal stem cells attract peripheral blood neutrophils and enhance their inflammatory activity in response to microbial challenge. J Leukoc Biol 2010; 88(5): 1005-15.
Hall SR, Tsoyi K, Ith B, et al. Mesenchymal stromal cells improve survival during sepsis in the absence of heme oxygenase-1: The importance of neutrophils. Stem Cells 2013; 31(2): 397-407.
Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99(10): 3838-43.
Ackova DG, Kanjevac T, Rimondini L, Bosnakovski D. Perspectives in engineered mesenchymal stem/stromal cells based anti- cancer drug delivery systems. Recent Patents Anticancer Drug Discov 2016; 11(1): 98-111.
Nemeth K, Leelahavanichkul A, Yuen PS, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 2009; 15(1): 42-9.
Yildirim S, Zibandeh N, Genc D, et al. The Comparison of the immunologic properties of stem cells isolated from human exfoliated deciduous teeth, dental pulp, and dental follicles. Stem Cells Int 2016; 2016: 4682875.
Zhao Y, Wang L, Jin Y, Shi S. Fas ligand regulates the immunomodulatory properties of dental pulp stem cells. J Dent Res 2012; 91(10): 948-54.
Ding G, Niu J, Liu Y. Dental pulp stem cells suppress the proliferation of lymphocytes via transforming growth factor-beta1. Hum Cell 2015; 28(2): 81-90.
Del Papa B, Sportoletti P, Cecchini D, et al. Notch1 modulates mesenchymal stem cells mediated regulatory T-cell induction. Eur J Immunol 2013; 43(1): 182-7.
Ma S, Xie N, Li W, et al. Immunobiology of mesenchymal stem cells. Cell Death Differ 2014; 21(2): 216-25.
Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol 2012; 188(1): 21-8.
Sreeramkumar V, Fresno M, Cuesta N. Prostaglandin E2 and T cells: Friends or foes? Immunol Cell Biol 2012; 90(6): 579-86.
Luz-Crawford P, Djouad F, Toupet K, et al. Mesenchymal stem celL-derived interleukin 1 receptor antagonist promotes macrophage polarization and inhibits B Cell differentiation. Stem Cells 2016; 34(2): 483-92.
Safety and efficacy study of allogenic mesenchymal stem cells to treat extensive chronic graft versus host disease [Available from:.
Egusa H, Sonoyama W, Nishimura M, Atsuta I, Akiyama K. Stem cells in dentistry--Part II: Clinical applications. J Prosthodont Res 2012; 56(4): 229-48.
Meng X, Leslie P, Zhang Y, Dong J. Stem cells in a three-dimensional scaffold environment. Springerplus 2014; 3: 80.
Datta N, Holtorf HL, Sikavitsas VI, Jansen JA, Mikos AG. Effect of bone extracellular matrix synthesized in vitro on the osteoblastic differentiation of marrow stromal cells. Biomaterials 2005; 26(9): 971-7.
Puppi D, Chiellini F, Piras AM, Chiellini E. Polymeric materials for bone and cartilage repair. Prog Polym Sci 2010; 35(4): 403-40.
Bosnakovski D, Mizuno M, Kim G, et al. Chondrogenic differentiation of bovine bone marrow Mesenchymal Stem Cells (MSCs) in different hydrogels: Influence of collagen type II extracellular matrix on MSC chondrogenesis. Biotechnol Bioeng 2006; 93(6): 1152-63.
Chung C, Burdick JA. Influence of three-dimensional hyaluronic acid microenvironments on mesenchymal stem cell chondrogenesis. Tissue Eng Part A 2009; 15(2): 243-54.
Gassling V, Douglas T, Warnke PH, et al. Platelet-rich fibrin membranes as scaffolds for periosteal tissue engineering. Clin Oral Implants Res 2010; 21(5): 543-9.
Lei Y, Jeong D, Xiao J, Schaffer DV. Developing defined and scalable 3D culture systems for culturing human pluripotent stem cells at high densities. Cell Mol Bioeng 2014; 7(2): 172-83.
Wang F, Li Y, Shen Y, et al. The functions and applications of RGD in tumor therapy and tissue engineering. Int J Mol Sci 2013; 14(7): 13447-62.
Duan X, Sheardown H. Incorporation of cell-adhesion peptides into collagen scaffolds promotes corneal epithelial stratification. J Biomater Sci Polym Ed 2007; 18(6): 701-11.
Cacchioli A, Ravanetti F, Bagno A, Dettin M, Gabbi C. Human vitronectin-derived peptide covalently grafted onto titanium surface improves osteogenic activity: A pilot in vivo study on rabbits. Tissue Eng Part A 2009; 15(10): 2917-26.
Hennessy KM, Pollot BE, Clem WC, et al. The effect of collagen I mimetic peptides on mesenchymal stem cell adhesion and differentiation, and on bone formation at hydroxyapatite surfaces. Biomaterials 2009; 30(10): 1898-909.
Bellis SL. Advantages of RGD peptides for directing cell association with biomaterials. Biomaterials 2011; 32(18): 4205-10.
Culpepper BK, Phipps MC, Bonvallet PP, Bellis SL. Enhancement of peptide coupling to hydroxyapatite and implant osseointegration through collagen mimetic peptide modified with a polyglutamate domain. Biomaterials 2010; 31(36): 9586-94.
Sawyer AA, Hennessy KM, Bellis SL. Regulation of mesenchymal stem cell attachment and spreading on hydroxyapatite by RGD peptides and adsorbed serum proteins. Biomaterials 2005; 26(13): 1467-75.
Sawyer AA, Hennessy KM, Bellis SL. The effect of adsorbed serum proteins, RGD and proteoglycan-binding peptides on the adhesion of mesenchymal stem cells to hydroxyapatite. Biomaterials 2007; 28(3): 383-92.
Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 2014; 15(12): 786-801.
D’Alimonte I, Lannutti A, Pipino C, et al. Wnt signaling behaves as a “master regulator” in the osteogenic and adipogenic commitment of human amniotic fluid mesenchymal stem cells. Stem Cell Rev 2013; 9(5): 642-54.
James AW, Leucht P, Levi B, et al. Sonic Hedgehog influences the balance of osteogenesis and adipogenesis in mouse adipose-derived stromal cells. Tissue Eng Part A 2010; 16(8): 2605-16.
James AW, Pang S, Askarinam A, et al. Additive effects of sonic hedgehog and Nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells. Stem Cells Dev 2012; 21(12): 2170-8.
James AW. Review of signaling pathways governing MSC osteogenic and adipogenic differentiation. Scientifica (Cairo) 2013; 2013: 684736.
Lo KW, Ulery BD, Ashe KM, Laurencin CT. Studies of bone morphogenetic protein-based surgical repair. Adv Drug Deliv Rev 2012; 64(12): 1277-91.
Jung T, Lee JH, Park S, et al. Effect of BMP-2 delivery mode on osteogenic differentiation of stem cells. Stem Cells Int 2017; 2017: 7859184.
He X, Ma J, Jabbari E. Effect of grafting RGD and BMP-2 protein-derived peptides to a hydrogel substrate on osteogenic differentiation of marrow stromal cells. Langmuir 2008; 24(21): 12508-16.
He X, Yang X, Jabbari E. Combined effect of osteopontin and BMP-2 derived peptides grafted to an adhesive hydrogel on osteogenic and vasculogenic differentiation of marrow stromal cells. Langmuir 2012; 28(12): 5387-97.
Yang Z, Liu F. Wnt/β-catenin signaling for dental regeneration. Stem Cells Oral Med 2012; p. 1.
Qin Y, Guan J, Zhang C. Mesenchymal stem cells: Mechanisms and role in bone regeneration. Postgrad Med J 2014; 90(1069): 643-7.
Minear S, Leucht P, Jiang J, et al. Wnt proteins promote bone regeneration. Sci Transl Med 2010; 2(29): 29ra30.
Zhang DY, Wang HJ, Tan YZ. Wnt/beta-catenin signaling induces the aging of mesenchymal stem cells through the DNA damage response and the p53/p21 pathway. PLoS One 2011; 6(6): e21397.
Tatullo M, Marrelli M, Shakesheff KM, White LJ. Dental pulp stem cells: function, isolation and applications in regenerative medicine. J Tissue Eng Regen Med 2015; 9(11): 1205-16.
Jing W, Smith AA, Liu B, et al. Reengineering autologous bone grafts with the stem cell activator WNT3A. Biomaterials 2015; 47: 29-40.
Karadzic I, Vucic V, Jokanovic V, et al. Effects of novel hydroxyapatite-based 3D biomaterials on proliferation and osteoblastic differentiation of mesenchymal stem cells. J Biomed Mater Res A 2015; 103(1): 350-7.
Groeneveldt LC, Knuth C, Witte-Bouma J, et al. Enamel matrix derivative has no effect on the chondrogenic differentiation of mesenchymal stem cells. Front Bioeng Biotechnol 2014; 2: 29.
Yang W, Both SK, van Osch GJ, et al. Effects of in vitro chondrogenic priming time of bone-marrow-derived mesenchymal stromal cells on in vivo endochondral bone formation. Acta Biomater 2015; 13: 254-65.
Freeman FE, McNamara LM. Endochondral priming: A developmental engineering strategy for bone tissue regeneration. Tissue Eng Part B Rev 2017; 23(2): 128-41.
Yang W, Both SK, van Osch GJ, et al. Performance of different three-dimensional scaffolds for in vivo endochondral bone generation. Eur Cell Mater 2014; 27: 350-64.
Liao HT, Chen CT. Osteogenic potential: Comparison between bone marrow and adipose-derived mesenchymal stem cells. World J Stem Cells 2014; 6(3): 288-95.
Rai B, Lin JL, Lim ZX, et al. Differences between in vitro viability and differentiation and in vivo bone-forming efficacy of human mesenchymal stem cells cultured on PCL-TCP scaffolds. Biomaterials 2010; 31(31): 7960-70.

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Year: 2019
Page: [320 - 326]
Pages: 7
DOI: 10.2174/1574888X14666190103170109
Price: $58

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