Review Article

Potential Non-neoplastic Applications for Polyphenols in Stem Cell Utilization

Author(s): E. Paul Cherniack*, Sahithi Chekuri and Heather F. Lee

Volume 20, Issue 3, 2019

Page: [347 - 353] Pages: 7

DOI: 10.2174/1389450119666180731092453

Price: $65


While polyphenols may have important effects on pluripotential stem cells that make them noteworthy as potential antineoplastic agents, their action on stem cells may portend other health benefits, such as treatments for cardiovascular and neurocognitive disorders. Resveratrol, the beststudied polyphenol, has been found to enable stem cells to differentiate into cardiomyocytes, neurons, osteocytes, and pancreatic beta cells, as well as facilitating augmentation of stem cell populations and protecting them from toxic injury. Curcumin protects mesenchymal stem cells from toxicity, and prevents them from facilitating chondrocytic hypertrophy. Quercetin enabled osteocytic and pancreatic beta cell differentiation, and protected neuronal stem cells from injury. Epigallocatechin gallate prevented damage to osteocyte precursors and averted differentiation into undesirable adipocytes. Genistein facilitated osteogenesis while preventing adipogenesis. Several other polyphenols, daidzein, caffeic and chlorogenic acid, kaempferol, and piceatannol, protect stems cells from reactive oxygen species and foster stem cells differentiation away from adipocytic and toward osteocytic lineages. Further research should better elucidate the pharmacokinetic profiles of each polyphenol, explore novel delivery systems, and expand investigation beyond rodent models to additional species.

Keywords: Polyphenol stem cell, resveratrol, quercetin, genistein, epigallocatechin gallate, osteocytic lineages.

Graphical Abstract
Schilling T, Ebert R, Raaijmakers N, et al. Effects of phytoestrogens and other plant-derived compounds on mesenchymal stem cells, bone maintenance and regeneration. J Steroid Biochem Mol Biol 2014; 139: 252-61.
Mitterberger MC, Zwerschke W. Mechanisms of resveratrol-induced inhibition of clonal expansion and terminal adipogenic differentiation in 3T3-L1 preadipocytes. J Gerontol A Biol Sci Med Sci 2013; 68: 1356-76.
Kumazoe M, Takai M, Hiroi S, et al. PDE3 inhibitor and EGCG combination treatment suppress cancer stem cell properties in pancreatic ductal adenocarcinoma. Sci Rep 2017; May 15. 7(1): 1917.
Lin CH, Li NT, Cheng HS, et al. Oxidative stress induces imbalance of adipogenic/osteoblastic lineage commitment in mesenchymal stem cells through decreasing SIRT1 functions. J Cell Mol Med 2018; 22(2): 786-96.
Yao H, Rahman I. Perspectives on translational and therapeutic aspects of SIRT1 in inflammaging and senescence. Biochem Pharmacol 2012; 84(10): 1332-9.
Shin JH, Jeon HJ, Park J, et al. Epigallocatechin-3-gallate prevents oxidative stress-induced cellular senescence in human mesenchymal stem cells via Nrf2. Int J Mol Med 2016; 38(4): 1075-82.
Mizuguchi Y, Hatakeyama H, Sueoka K, et al. Low dose resveratrol ameliorates mitochondrial respiratory dysfunction and enhances cellular reprogramming. Mitochondrion 2017; 34: 43-8.
Ornstrup MJ, Harslof T, Sorensen L, et al. Resveratrol increases osteoblast differentiation in vitro independently of inflammation. Calcif Tissue Int 2016; 99: 155-63.
Caldarelli I, Speranza MC, Bencivenga D, et al. Resveratrol mimics insulin activity in the adipogenic commitment of human bone marrow mesenchymal stromal cells. Int J Biochem Cell Biol 2015; 60: 60-72.
Ding H, Xu X, Qin X, et al. Resveratrol promotes differentiation of mouse embryonic stem cells to cardiomyocytes. Cardiovasc Ther 2016; 34: 283-9.
Liu H, Zhang S, Zhao L, et al. Resveratrol Enhances Cardiomyocyte Differentiation of Human Induced Pluripotent Stem Cells through Inhibiting Canonical WNT Signal Pathway and Enhancing Serum Response Factor-miR-1 Axis. Stem Cells Int 2016; 2016: 2524092.
Campagnolo P, Hong X, di Bernardini E, et al. Resveratrol-induced vascular progenitor differentiation towards endothelial lineage via mir-21/akt/beta-catenin is protective in vessel graft models. PLoS One 2015; 10: e0125122.
Ling L, Gu S, Cheng Y. Resveratrol activates endogenous cardiac stem cells and improves myocardial regeneration following acute myocardial infarction. Mol Med Rep 2017; 15: 1188-94.
Huang JG, Shen CB, Wu WB, et al. Primary cilia mediate sonic hedgehog signaling to regulate neuronal-like differentiation of bone mesenchymal stem cells for resveratrol induction in vitro. J Neurosci Res 2014; 92: 587-96.
Wang X, Ma S, Meng N, et al. resveratrol exerts dosage-dependent effects on the self-renewal and neural differentiation of huc-mscs. Mol Cells 2016; 39: 418-25.
Guo L, Wang L, Wang L, et al. resveratrol induces differentiation of human umbilical cord mesenchymal stem cells into neuron-like cells. Stem Cells Int 2017; 2017: 1651325.
Jahan S, Singh S, Srivastava A, et al. PKA-GSK3beta and beta-catenin signaling play a critical role in trans-resveratrol mediated neuronal differentiation in human cord blood stem Cells. Mol Neurobiol 2017.
Geng YW, Zhang Z, Liu MY, et al. Differentiation of human dental pulp stem cells into neuronal by resveratrol. Cell Biol Int 2017; 41: 1391-8.
Joe IS, Jeong SG, Cho GW. Resveratrol-induced SIRT1 activation promotes neuronal differentiation of human bone marrow mesenchymal stem cells. Neurosci Lett 2015; 584: 97-102.
Prager I, Patties I, Himmelbach K, et al. Dose-dependent short- and long-term effects of ionizing irradiation on neural stem cells in murine hippocampal tissue cultures: neuroprotective potential of resveratrol. Brain Behav 2016; 6: e00548.
Konyalioglu S, Armagan G, Yalcin A, et al. Effects of resveratrol on hydrogen peroxide-induced oxidative stress in embryonic neural stem cells. Neural Regen Res 2013; 8: 485-95.
Shen C, Cheng W, Yu P, et al. Resveratrol pretreatment attenuates injury and promotes proliferation of neural stem cells following oxygen-glucose deprivation/reoxygenation by upregulating the expression of Nrf2, HO-1 and NQO1 in vitro. Mol Med Rep 201; 14: 3646-54
Cheng W, Yu P, Wang L, et al. Sonic hedgehog signaling mediates resveratrol to increase proliferation of neural stem cells after oxygen-glucose deprivation/reoxygenation injury in vitro. Cell Physiol Biochem 2015; 35: 2019-32.
Fu Y, Wang Y, Du L, et al. Resveratrol inhibits ionising irradiation-induced inflammation in MSCs by activating SIRT1 and limiting NLRP-3 inflammasome activation. Int J Mol Sci 2013; 14: 14105-18.
Wang D, Li SP, Fu JS, et al. Resveratrol augments therapeutic efficiency of mouse bone marrow mesenchymal stem cell-based therapy in experimental autoimmune encephalomyelitis. Int J Dev Neurosci 2016; 49: 60-6.
Park HR, Kong KH, Yu BP, et al. Resveratrol inhibits the proliferation of neural progenitor cells and hippocampal neurogenesis. J Biol Chem 2012; 287: 42588-600.
Pezzolla D, Lopez-Beas J, Lachaud CC, et al. Resveratrol ameliorates the maturation process of beta-cell-like cells obtained from an optimized differentiation protocol of human embryonic stem cells. PLoS One 2015; 10: e0119904.
Lei LT, Chen JB, Zhao YL, et al. Resveratrol attenuates senescence of adipose-derived mesenchymal stem cells and restores their paracrine effects on promoting insulin secretion of INS-1 cells through Pim-1. Eur Rev Med Pharmacol Sci 2016; 20: 1203-13.
Okay E, Simsek T, Subasi C, et al. Cross effects of resveratrol and mesenchymal stem cells on liver regeneration and homing in partially hepatectomized rats. Stem Cell Rev 2015; 11: 322-31.
Zhang QB, Cao W, Liu YR, et al. Effects of Sirtuin 1 on the proliferation and osteoblastic differentiation of periodontal ligament stem cells and stem cells from apical papilla. Genet Mol Res 2016; 15
Montesano A, Luzi L, Senesi P, et al. Resveratrol promotes myogenesis and hypertrophy in murine myoblasts. J Transl Med 2013; 11: 310.
Chen YB, Lan YW, Chen LG, et al. Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol alleviates elastase-induced emphysema in a mouse model. Cell Stress Chaperones 2015; 20: 979-89.
Heinz N, Ehrnstrom B, Schambach A, et al. Comparison of different cytokine conditions reveals resveratrol as a new molecule for ex vivo cultivation of cord blood-derived hematopoietic stem cells. Stem Cells Transl Med 2015; 4: 1064-72.
Li N, Du Z, Shen Q, Lei Q, et al. Resveratrol enhances self-renewal of mouse embryonic stem cells. J Cell Biochem 2017; 118: 1928-35.
Wang H, Yang YJ, Qian HY, et al. Zhang Q, Gao LJ, Li P, Wang TJ, Wang SD: Statin administration does not improve the mobilization of very small embryonic-like stem cells (VSELs) in contrast to resveratrol treatment in a murine model of acute myocardial infarction. Physiol Res 2012; 61: 543-9.
Zhang H, Zhai Z, Wang Y, et al. Resveratrol ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice. Free Radic Biol Med 2013; 54: 40-50.
Lee YL, Peng Q, Fong SW, et al. Sirtuin 1 facilitates generation of induced pluripotent stem cells from mouse embryonic fibroblasts through the miR-34a and p53 pathways. PLoS One 2012; 7: e45633.
Cremers NA, Lundvig DM, van Dalen SC, et al. Curcumin-induced heme oxygenase-1 expression prevents H2O2-induced cell death in wild type and heme oxygenase-2 knockout adipose-derived mesenchymal stem cells. Int J Mol Sci 2014; 15: 17974-99.
Wang N, Wang F, Gao Y, et al. Curcumin protects human adipose-derived mesenchymal stem cells against oxidative stress-induced inhibition of osteogenesis. J Pharmacol Sci 2016; 132: 192-200.
Yagi H, Tan J, Tuan RS. Polyphenols suppress hydrogen peroxide-induced oxidative stress in human bone-marrow derived mesenchymal stem cells. J Cell Biochem 2013; 114: 1163-73.
Gu Q, Cai Y, Huang C, et al. Curcumin increases rat mesenchymal stem cell osteoblast differentiation but inhibits adipocyte differentiation. Pharmacogn Mag 2012; 8: 202-8.
You J, Sun J, Ma T, et al. Curcumin induces therapeutic angiogenesis in a diabetic mouse hindlimb ischemia model via modulating the function of endothelial progenitor cells. Stem Cell Res Ther 2017; 8: 182.
Cao Z, Dou C, Dong S. Curcumin inhibits chondrocyte hypertrophy of mesenchymal stem cells through ihh and notch signaling pathways. Chem Pharm Bull (Tokyo) 2017; 65: 762-7.
Ormond DR, Shannon C, Oppenheim J, et al. Stem cell therapy and curcumin synergistically enhance recovery from spinal cord injury. PLoS One 2014; 9: e88916.
Li Y, Wang J, Chen G, et al. Quercetin promotes the osteogenic differentiation of rat mesenchymal stem cells via mitogen-activated protein kinase signaling. Exp Ther Med 2015; 9: 2072-80.
Tang X, Zhang C, Zeng W, et al. Proliferating effects of the flavonoids daidzein and quercetin on cultured chicken primordial germ cells through antioxidant action. Cell Biol Int 2006; 30: 445-51.
Zhou Y, Wu Y, Jiang X, et al. The Effect of quercetin on the osteogenesic differentiation and angiogenic factor expression of bone marrow-derived mesenchymal stem cells. PLoS One 2015; 10: e0129605.
Casado-Diaz A, Anter J, Dorado G, et al. Effects of quercetin, a natural phenolic compound, in the differentiation of human mesenchymal stem cells (MSC) into adipocytes and osteoblasts. J Nutr Biochem 2016; 32: 151-62.
Miladpour B, Rasti M, Owji AA, et al. Quercetin potentiates transdifferentiation of bone marrow mesenchymal stem cells into the beta cells in vitro. J Endocrinol Invest 2017; 40: 513-21.
Zhou C, Lin Y. Osteogenic differentiation of adipose-derived stem cells promoted by quercetin. Cell Prolif 2014; 47: 124-32.
Kim YJ, Bae YC, Suh KT, et al. Quercetin, a flavonoid, inhibits proliferation and increases osteogenic differentiation in human adipose stromal cells. Biochem Pharmacol 2006; 72: 1268-78.
Wu X, Qu X, Zhang Q, et al. Quercetin promotes proliferation and differentiation of oligodendrocyte precursor cells after oxygen/glucose deprivation-induced injury. Cell Mol Neurobiol 2014; 34: 463-71.
Sajad M, Zargan J, Zargar MA, et al. Quercetin prevents protein nitration and glycolytic block of proliferation in hydrogen peroxide insulted cultured neuronal precursor cells (NPCs): Implications on CNS regeneration. Neurotoxicology 2013; 36: 24-33.
Bhagwat S, Haytowitz DB, Holden JM. USDA database for the flavonoid content of selected foods, release 3 agricultural research service, U.S. Department of Agriculture 2011; 2, 98-103. https: // _R03.pdf [Accessed July 11, 2018]
Kaida K, Honda Y, Hashimoto Y, et al. Application of green tea catechin for inducing the osteogenic differentiation of human dedifferentiated fat cells in Vitro. Int J Mol Sci 2015; 16: 27988-8000.
Jin P, Wu H, Xu G, et al. Epigallocatechin-3-gallate (EGCG) as a pro-osteogenic agent to enhance osteogenic differentiation of mesenchymal stem cells from human bone marrow: An in vitro study. Cell Tissue Res 2014; 356: 381-90.
Qiu Y, Chen Y, Zeng T, et al. EGCG ameliorates the hypoxia-induced apoptosis and osteogenic differentiation reduction of mesenchymal stem cells via upregulating miR-210. Mol Biol Rep 2016; 43: 183-93.
Liu W, Fan JB, Xu DW, et al. Epigallocatechin-3-gallate protects against tumor necrosis factor alpha induced inhibition of osteogenesis of mesenchymal stem cells. Exp Biol Med (Maywood) 2016; 241: 658-66.
Jung IH, Lee DE, Yun JH, et al. Anti-inflammatory effect of (-)-epigallocatechin-3-gallate on Porphyromonas gingivalis lipopolysaccharide-stimulated fibroblasts and stem cells derived from human periodontal ligament. J Periodontal Implant Sci 2012; 42: 185-95.
Zeng X, Tan X. Epigallocatechin-3-gallate and zinc provide anti-apoptotic protection against hypoxia/reoxygenation injury in H9c2 rat cardiac myoblast cells. Mol Med Rep 2015; 12: 1850-6.
Monzen S, Mori T, Takahashi K, et al. The effects of (-)-epigallocatechin-3-gallate on the proliferation and differentiation of human megakaryocytic progenitor cells. J Radiat Res 2006; 47: 213-20.
Barenys M, Gassmann K, Baksmeier C, et al. Epigallocatechin gallate (EGCG) inhibits adhesion and migration of neural progenitor cells in vitro. Arch Toxicol 2017; 91: 827-37.
Jeong JY, Park MN, Cho ES, et al. Epigallocatechin-3-gallate-induced free-radical production upon adipogenic differentiation in bovine bone-marrow mesenchymal stem cells. Cell Tissue Res 2015; 362: 87-96.
Okumura N, Yoshikawa T, Iida J, et al. Bone formation-promoting effect of genistein on marrow mesenchymal cell culture. Biomed Mater Eng 2006; 16: 23-32.
Dai J, Li Y, Zhou H, Chen J, et al. Genistein promotion of osteogenic differentiation through BMP2/SMAD5/RUNX2 signaling. Int J Biol Sci 2013; 9: 1089-98.
Liao QC, Xiao ZS, Qin YF, et al. Genistein stimulates osteoblastic differentiation via p38 MAPK-Cbfa1 pathway in bone marrow culture. Acta Pharmacol Sin 2007; 28: 1597-602.
Heim M, Frank O, Kampmann G, et al. The phytoestrogen genistein enhances osteogenesis and represses adipogenic differentiation of human primary bone marrow stromal cells. Endocrinology 2004; 145: 848-59.
Kim MH, Park JS, Seo MS, et al. Genistein and daidzein repress adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells via Wnt/beta-catenin signalling or lipolysis. Cell Prolif 2010; 43: 594-605.
Liao QC, Li YL, Qin YF, et al. Inhibition of adipocyte differentiation by phytoestrogen genistein through a potential downregulation of extracellular signal-regulated kinases 1/2 activity. J Cell Biochem 2008; 104: 1853-64.
Benvenuti S, Cellai I, Luciani P, et al. Androgens and estrogens prevent rosiglitazone-induced adipogenesis in human mesenchymal stem cells. J Endocrinol Invest 2012; 35: 365-71.
Zhang LY, Xue HG, Chen JY, et al. Genistein induces adipogenic differentiation in human bone marrow mesenchymal stem cells and suppresses their osteogenic potential by upregulating PPARgamma. Exp Ther Med 2016; 11: 1853-8.
Lee SH, Lee JH, Asahara T, et al. Genistein promotes endothelial colony-forming cell (ECFC) bioactivities and cardiac regeneration in myocardial infarction. PLoS One 2014; 9: e96155.
Kwon DJ, Hwang IS, Kwak TU, et al. Effects of cell cycle regulators on the cell cycle synchronization of porcine induced pluripotent stem cells. Dev Reprod 2017; 21: 47-54.
Chen X, Han Y, Zhang B, et al. Caffeic acid phenethyl ester promotes haematopoietic stem/progenitor cell homing and engraftment. Stem Cell Res Ther 2017; 8: 255.
Liu Y, Zhang B, Zhang J, et al. CAPE promotes the expansion of human umbilical cord blood-derived hematopoietic stem and progenitor cells in vitro. Sci China Life Sci 2014; 57: 188-94.
Zhou RP, Deng MT, Chen LY, et al. Shp2 regulates chlorogenic acid-induced proliferation and adipogenic differentiation of bone marrow-derived mesenchymal stem cells in adipogenesis. Mol Med Rep 2015; 11: 4489-95.
Li S, Bian H, Liu Z, Wang Y, et al. Chlorogenic acid protects MSCs against oxidative stress by altering FOXO family genes and activating intrinsic pathway. Eur J Pharmacol 2012; 674: 65-72.
Zhu J, Tang H, Zhang Z, et al. Kaempferol slows intervertebral disc degeneration by modifying LPS-induced osteogenesis/adipogenesis imbalance and inflammation response in BMSCs. Int Immunopharmacol 2017; 43: 236-42.
Correia M, Sousa MI, Rodrigues AS, et al. Data on the potential impact of food supplements on the growth of mouse embryonic stem cells. Data Brief 2016; 7: 1190-5.
Correia M, Rodrigues AS, Perestrelo T, et al. Different concentrations of kaempferol distinctly modulate murine embryonic stem cell function. Food Chem Toxicol 2016; 87: 148-56.
Arai D, Kataoka R, Otsuka S, et al. Piceatannol is superior to resveratrol in promoting neural stem cell differentiation into astrocytes. Food Funct 2016; 7: 4432-41.
Clough BH, Ylostalo J, Browder E, et al. Theobromine upregulates osteogenesis by human mesenchymal stem cells in vitro and accelerates bone development in rats. Calcif Tissue Int 2017; 100: 298-310.
Gomez-Florit M, Monjo M, Ramis JM. Quercitrin for periodontal regeneration: effects on human gingival fibroblasts and mesenchymal stem cells. Sci Rep 2015; 5: 16593.
Wu G, Wang L, Li H, et al. Function of sustained released resveratrol on IL-1beta-induced hBMSC MMP13 secretion inhibition and chondrogenic differentiation promotion. J Biomater Appl 2016; 30: 930-9.
Felice F, Zambito Y, Belardinelli E, et al. Delivery of natural polyphenols by polymeric nanoparticles improves the resistance of endothelial progenitor cells to oxidative stress. Eur J Pharm Sci 2013; 50: 393-9.
Cordoba A, Monjo M, Hierro-Oliva M, et al. Bioinspired quercitrin nanocoatings: A fluorescence-based method for their surface quantification, and their effect on stem cell adhesion and differentiation to the osteoblastic lineage. ACS Appl Mater Interfaces 2015; 7: 16857-64.
Yang L, Zheng Z, Qian C, et al. Curcumin-functionalized silk biomaterials for anti-aging utility. J Colloid Interface Sci 2017; 496: 66-77.
Li C, Luo T, Zheng Z, et al. Curcumin-functionalized silk materials for enhancing adipogenic differentiation of bone marrow-derived human mesenchymal stem cells. Acta Biomater 2015; 11: 222-32.
Perteghella S, Crivelli B, Catenacci L, et al. Stem cell-extracellular vesicles as drug delivery systems: New frontiers for silk/curcumin nanoparticles. Int J Pharm 2017; 520: 86-97.
Kalani A, Chaturvedi P, Kamat PK, et al. Curcumin-loaded embryonic stem cell exosomes restored neurovascular unit following ischemia-reperfusion injury. Int J Biochem Cell Biol 2016; 79: 360-9.
Requejo-Aguilar R, Alastrue-Agudo A, Cases-Villar M, et al. Combined polymer-curcumin conjugate and ependymal progenitor/stem cell treatment enhances spinal cord injury functional recovery. Biomaterials 2017; 113: 18-30.

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy