Abstract
Dental pulp stem cells (DPSCs) are a new population of mesenchymal stem cells (MSCs) located in the oral cavity with potential capacities for tissue regeneration and immunomodulation. The purpose from this study was to determine effects of curcumin nanoparticle into phytosomal formulation (PC) on the relative expression of DSPP, VEGF-A, HLA-G5, VCAM1, RelA and STAT3 genes which are among the most important factors influencing processes of immunomodulatory and tissue regenerative by DPSCs. After isolation and culture of DPSCs, these cells were characterized according to predetermined criteria including flow cytometric analysis for detection of the most important cell surface markers and also evaluation of multilineage differentiation potential. Then, the MTT method was employed to check the cell viability in treatment with different concentrations of PC. Following DPSCs’ treatment with an optimal-non-toxic dose of this nanoparticle, quantification of expression of target genes was performed using real-time PCR procedure. According to results of immunophenotyping analysis and cell differentiation experiments, the isolated cells were confirmed as MSCs as more than 99% of them expressed specific mesenchymal markers while only about 0.5% of them were positive for hematopoietic marker. The real-time PCR results indicated that PC significantly reduced the expression of RelA, STAT3, VCAM1 and HLA-G5 genes up to many times over while optimally enhanced the expression of DSPP and VEGF-A genes, although this enhance was statistically significant only for VEGF-A (all P < 0.001). The study suggests that PC affects the stemness capabilities of DPSCs and it may facilitate the development of MSCs-based therapeutics in regenerative dentistry.
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Data availability
Data are available from the corresponding author upon reasonable request.
Abbreviations
- DPSC:
-
Dental pulp stem cell
- DP-MSCs:
-
Dental pulp mesenchymal stem cells
- PC:
-
Phytosomal curcumin
- DSPP:
-
Dentin sialophosphoprotein
- VEGF:
-
Vascular endothelial growth factor
- HLA-G5:
-
Human leukocyte antigen-G5
- STAT:
-
Signal transducer and activator of transcription
- VCAM:
-
Vascular cell adhesion molecule
References
Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci. 2000;97(25):13625–30.
Lin C-S, Xin Z-C, Dai J, Lue TF. Commonly used mesenchymal stem cell markers and tracking labels: limitations and challenges. Histol Histopathol. 2013;28(9):1109.
Dominici ML, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS, Deans RJ, Keating A, Prockop DJ, Horwitz EM. Minimal criteria for defining multipotent mesenchymal stromal cells. Int Soc Cell Therapy Position Statement. 2006;8(4):315–7.
Siew Ching H, Luddin N, Ab Rahman I, Thirumulu PK. Expression of odontogenic and osteogenic markers in DPSCs and SHED: a review. Curr Stem Cell Res Ther. 2017;12(1):71–9.
Sui B, Wu D, Xiang L, Fu Y, Kou X, Shi S. Dental pulp stem cells: from discovery to clinical application. J Endod. 2020;46(9):S46-55.
Ishizaka R, Iohara K, Murakami M, Fukuta O, Nakashima MJB. Regeneration of dental pulp following pulpectomy by fractionated stem/progenitor cells from bone marrow and adipose tissue. Biomaterials. 2012;33(7):2109–18.
Iohara K, Utsunomiya S, Kohara S, Nakashima M. Allogeneic transplantation of mobilized dental pulp stem cells with the mismatched dog leukocyte antigen type is safe and efficacious for total pulp regeneration. Stem Cell Res Therapy. 2018;9(1):1–6.
Pierdomenico L, Bonsi L, Calvitti M, Rondelli D, Arpinati M, Chirumbolo G, Becchetti E, Marchionni C, Alviano F, Fossati V, Staffolani N. Multipotent mesenchymal stem cells with immunosuppressive activity can be easily isolated from dental pulp. Transplantation. 2005;80(6):836–42.
Hossein-Khannazer N, Hashemi SM, Namaki S, Ghanbarian H, Sattari M, Khojasteh A. Study of the immunomodulatory effects of osteogenic differentiated human dental pulp stem cells. Life Sci. 2019;216:111–8.
Andrukhov CB, Blufstein A, Rausch-Fan X. Immunomodulatory properties of dental tissue-derived mesenchymal stem cells: implication in disease and tissue regeneration. World J Stem Cells. 2019;11(9):604.
Li Y, Zhang D, Xu L, Dong L, Zheng J, Lin Y, Huang J, Zhang Y, Tao Y, Zang X, Li D. Cell–cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models. Cell Mol Immunol. 2019;16(12):908–20.
Nakashima M, Iohara K, Sugiyama M. Human dental pulp stem cells with highly angiogenic and neurogenic potential for possible use in pulp regeneration. Cytokine Growth Factor Rev. 2009;20(5–6):435–40.
Zhu Q, Gibson MP, Liu Q, Liu Y, Lu Y, Wang X, Feng JQ, Qin C. Proteolytic processing of dentin sialophosphoprotein (DSPP) is essential to dentinogenesis. J Biol Chem. 2012;287(36):30426–35.
Jin Q, Yuan K, Lin W, Niu C, Ma R, Huang Z. Comparative characterization of mesenchymal stem cells from human dental pulp and adipose tissue for bone regeneration potential. Artif Cells Nanomed Biotechnol. 2019;47(1):1577–84.
Dissanayaka WL, Hargreaves KM, Jin L, Samaranayake LP, Zhang C. The interplay of dental pulp stem cells and endothelial cells in an injectable peptide hydrogel on angiogenesis and pulp regeneration in vivo. Tissue Eng Part A. 2015;21(3–4):550–63.
Yu J, He H, Tang C, Zhang G, Li Y, Wang R, Shi J, Jin Y. Differentiation potential of STRO-1+ dental pulp stem cells changes during cell passaging. BMC Cell Biol. 2010;11(1):1–7.
Yang X, Zhang W, van den Dolder J, Walboomers XF, Bian Z, Fan M, Jansen JA. Multilineage potential of STRO-1+ rat dental pulp cells in vitro. J Tissue Eng Regen Med. 2007;1(2):128–35.
Yang X, Walboomers XF, van den Beucken JJ, Bian Z, Fan M, Jansen JA. Hard tissue formation of STRO-1–selected rat dental pulp stem cells in vivo. Tissue Eng Part A. 2009;15(2):367–75.
Yang X, Van der Kraan PM, Dolder JV, Walboomers XF, Bian Z, Fan M, Jansen JA. STRO-1 selected rat dental pulp stem cells transfected with adenoviral-mediated human bone morphogenetic protein 2 gene show enhanced odontogenic differentiation. Tissue Eng. 2007;13(11):2803–12.
Fukiage K, Aoyama T, Shibata KR, Otsuka S, Furu M, Kohno Y, Ito K, Jin Y, Fujita S, Fujibayashi S, Neo M. Expression of vascular cell adhesion molecule-1 indicates the differentiation potential of human bone marrow stromal cells. Biochem Biophys Res Commun. 2008;365(3):406–12.
Mabuchi Y, Morikawa S, Harada S, Niibe K, Suzuki S, Renault-Mihara F, Houlihan DD, Akazawa C, Okano H, Matsuzaki Y. LNGFR+ THY-1+ VCAM-1hi+ cells reveal functionally distinct subpopulations in mesenchymal stem cells. Stem Cell Rep. 2013;1(2):152–65.
Hollands P, Aboyeji D, Orcharton M. Dental pulp stem cells in regenerative medicine. Br Dent J. 2018;224(9):747.
Yu S, Li P, Li B, Miao D, Deng Q. RelA promotes proliferation but inhibits osteogenic and chondrogenic differentiation of mesenchymal stem cells. FEBS Lett. 2020;594(9):1368–78.
Demircan PC, Sariboyaci AE, Unal ZS, Gacar G, Subasi C, Karaoz E. Immunoregulatory effects of human dental pulp-derived stem cells on T cells: comparison of transwell co-culture and mixed lymphocyte reaction systems. Cytotherapy. 2011;13(10):1205–20.
Xu K, Xiao J, Zheng K, Feng X, Zhang J, Song D, Wang C, Shen X, Zhao X, Wei C, Huang D. MiR-21/STAT3 signal is involved in odontoblast differentiation of human dental pulp stem cells mediated by TNF-α. Cell Reprogram. 2018;20(2):107–16.
Vigo T, La Rocca C, Faicchia D, Procaccini C, Ruggieri M, Salvetti M, Centonze D, Matarese G, Uccelli A. IFNβ enhances mesenchymal stromal (Stem) cells immunomodulatory function through STAT1-3 activation and mTOR-associated promotion of glucose metabolism. Cell Death Dis. 2019;10(2):1–8.
Kornicka K, Kocherova I, Marycz K. The effects of chosen plant extracts and compounds on mesenchymal stem cells—a bridge between molecular nutrition and regenerative medicine-concise review. Phytother Res. 2017;31(7):947–58.
Das U, Behera SS, Pramanik K. Ethno-herbal-medico in wound repair: an incisive review. Phytotherapy Res. 2017;31(4):579–90.
Mohammadi A, Blesso CN, Barreto GE, Banach M, Majeed M, Sahebkar A. Macrophage plasticity, polarization and function in response to curcumin, a diet-derived polyphenol, as an immunomodulatory agent. J Nutr Biochem. 2019;1(66):1–6.
Kahkhaie KR, Mirhosseini A, Aliabadi A, Mohammadi A, Mousavi MJ, Haftcheshmeh SM, Sathyapalan T, Sahebkar A. Curcumin: a modulator of inflammatory signaling pathways in the immune system. Inflammopharmacology. 2019;27(5):885–900.
Hassan FU, Rehman MS, Khan MS, Ali MA, Javed A, Nawaz A, Yang C. Curcumin as an alternative epigenetic modulator: mechanism of action and potential effects. Front Genet. 2019;4(10):514.
Ahangari N, Kargozar S, Ghayour-Mobarhan M, Baino F, Pasdar A, Sahebkar A, Ferns GA, Kim HW, Mozafari M. Curcumin in tissue engineering: a traditional remedy for modern medicine. BioFactors. 2019;45(2):135–51.
Tuyaerts S, Rombauts K, Everaert T, Van Nuffel AM, Amant F. A phase 2 study to assess the immunomodulatory capacity of a lecithin-based delivery system of curcumin in endometrial cancer. Front Nutr. 2019;11(5):138.
Pastorelli D, Fabricio AS, Giovanis P, D’Ippolito S, Fiduccia P, Soldà C, Buda A, Sperti C, Bardini R, Da Dalt G, Rainato G. Phytosome complex of curcumin as complementary therapy of advanced pancreatic cancer improves safety and efficacy of gemcitabine: results of a prospective phase II trial. Pharmacol Res. 2018;1(132):72–9.
Marjaneh RM, Rahmani F, Hassanian SM, Rezaei N, Hashemzehi M, Bahrami A, Ariakia F, Fiuji H, Sahebkar A, Avan A, Khazaei M. Phytosomal curcumin inhibits tumor growth in colitis-associated colorectal cancer. J Cell Physiol. 2018;233(10):6785–98.
Mirzaei H, Shakeri A, Rashidi B, Jalili A, Banikazemi Z, Sahebkar A. Phytosomal curcumin: a review of pharmacokinetic, experimental and clinical studies. Biomed Pharmacother. 2017;1(85):102–12.
Gronthos S, Arthur A, Bartold PM, Shi SA. method to isolate and culture expand human dental pulp stem cells. In: Mesenchymal stem cell assays and applications. Totowa: Humana Press; 2011. p. 107–21.
Al-Habib M, Huang GT. Dental mesenchymal stem cells: dental pulp stem cells, periodontal ligament stem cells, apical papilla stem cells, and primary teeth stem cells—isolation, characterization, and expansion for tissue engineering. Odontogenesis. 2019;1922:59–76.
Ayadilord M, Nasseri S, Emadian Razavi F, Saharkhiz M, Rostami Z, Naseri M. Immunomodulatory effects of phytosomal curcumin on related-micro RNAs, CD200 expression and inflammatory pathways in dental pulp stem cells. Cell Biochem Funct. 2021. https://doi.org/10.1002/cbf.3659.
Zhu L, Dissanayaka WL, Zhang C. Dental pulp stem cells overexpressing stromal-derived factor-1α and vascular endothelial growth factor in dental pulp regeneration. Clin Oral Invest. 2019;23(5):2497–509.
Dissanayaka WL, Zhu L, Hargreaves KM, Jin L, Zhang C. Scaffold-free prevascularized microtissue spheroids for pulp regeneration. J Dent Res. 2014;93(12):1296–303.
Nakashima M, Iohara K, Murakami M, Nakamura H, Sato Y, Ariji Y, Matsushita K. Pulp regeneration by transplantation of dental pulp stem cells in pulpitis: a pilot clinical study. Stem Cell Res Therapy. 2017;8(1):1–3.
Fierro FA, Kalomoiris S, Sondergaard CS, Nolta JA. Effects on proliferation and differentiation of multipotent bone marrow stromal cells engineered to express growth factors for combined cell and gene therapy. Stem Cells. 2011;29(11):1727–37.
Zimta AA, Baru O, Badea M, Buduru SD, Berindan-Neagoe I. The role of angiogenesis and pro-angiogenic exosomes in regenerative dentistry. Int J Mol Sci. 2019;20(2):406.
Hirata-Tsuchiya S, Fukushima H, Katagiri T, Ohte S, Shin M, Nagano K, Aoki K, Morotomi T, Sugiyama G, Nakatomi C, Kokabu S. Inhibition of BMP2-induced bone formation by the p65 subunit of NF-κB via an interaction with Smad4. Mol Endocrinol. 2014;28(9):1460–70.
Tarapore RS, Lim J, Tian C, Pacios S, Xiao W, Reid D, Guan H, Mattos M, Yu B, Wang CY, Graves DT. NF-κB has a direct role in inhibiting Bmp-and Wnt-induced matrix protein expression. J Bone Miner Res. 2016;31(1):52–64.
Wang N, Zhou Z, Wu T, Liu W, Yin P, Pan C, Yu X. TNF-α-induced NF-κB activation upregulates microRNA-150–3p and inhibits osteogenesis of mesenchymal stem cells by targeting β-catenin. Open Biol. 2016;6(3): 150258.
Ma XX, Liu J, Wang CM, Zhou JP, He ZZ, Lin H. Low-dose curcumin stimulates proliferation of rat embryonic neural stem cells through glucocorticoid receptor and STAT 3. CNS Neurosci Ther. 2018;24(10):940–6.
Cao F, Hata R, Zhu P, Nakashiro KI, Sakanaka M. Conditional deletion of Stat3 promotes neurogenesis and inhibits astrogliogenesis in neural stem cells. Biochem Biophys Res Commun. 2010;394(3):843–7.
Zhang DM, Li YC, Xu D, Ding XQ, Kong LD. Protection of curcumin against fructose-induced hyperuricaemia and renal endothelial dysfunction involves NO-mediated JAK–STAT signalling in rats. Food Chem. 2012;134(4):2184–93.
Liu L, Liu YL, Liu GX, Chen X, Yang K, Yang YX, Xie Q, Gan HK, Huang XL, Gan HT. Curcumin ameliorates dextran sulfate sodium-induced experimental colitis by blocking STAT3 signaling pathway. Int Immunopharmacol. 2013;17(2):314–20.
Sinjari B, Pizzicannella J, D’Aurora M, Zappacosta R, Gatta V, Fontana A, Trubiani O, Diomede F. Curcumin/liposome nanotechnology as delivery platform for anti-inflammatory activities via NFkB/ERK/pERK pathway in human dental pulp treated with 2-hydroxyethyl methacrylate (HEMA). Front Physiol. 2019;11(10):633.
Wang N, Wang F, Gao Y, Yin P, Pan C, Liu W, Zhou Z, Wang J. Curcumin protects human adipose-derived mesenchymal stem cells against oxidative stress-induced inhibition of osteogenesis. J Pharmacol Sci. 2016;132(3):192–200.
Acknowledgements
The writers appreciate Birjand University of Medical Sciences for supporting this research and also Dr. Seyed Mohammad Riahi, Cardiovascular Diseases Research Center, Department of Epidemiology and Biostatistics, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran, for providing assistance in the statistical analysis.
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This research was financed by Birjand University of Medical Sciences, Iran (Grant no.456182).
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MS study design, executor of plan, analysis and interpretation of data and drafting of the manuscript. MA study design, executor of plan, analysis and interpretation of data and drafting of the manuscript. FER study design, edit and critical revision of the manuscript for important intellectual content. MN material support, study design, executor of plan, supervision and interpretation and analysis of data and edit of the manuscript.
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Saharkhiz, M., Ayadilord, M., Emadian Razavi, F. et al. Effects of phytosomal curcumin treatment on modulation of immunomodulatory and pulp regeneration genes in dental pulp mesenchymal stem cells. Odontology 110, 287–295 (2022). https://doi.org/10.1007/s10266-021-00659-4
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DOI: https://doi.org/10.1007/s10266-021-00659-4