Nrf2: Redox and Metabolic Regulator of Stem Cell State and Function

As a cellular metabolic and stress sensor, the transcription factor Nrf2 is a pivotal regulator of stem cell self-renewal, proliferation, and differentiation.Nrf2 displays cell type-specific and/or stage-dependent impact on stem cell biology in response to various environmental cues.Nrf2 modulates PSCs through the regulation of pluripotency factors, metabolism, redox homeostasis, and cellular stress responses.Nrf2 maintain ASCs self-renewal, quiescence, and regenerative capacity while protecting against ASC depletion in response to stress and aging. Nuclear factor erythroid 2-related factor 2 (Nrf2) is ubiquitously expressed in most eukaryotic cells and functions to induce a broad range of cellular defenses against exogenous and endogenous stresses, including oxidants, xenobiotics, and excessive nutrient/metabolite supply. Because the production and fate of stem cells are often modulated by cellular redox and metabolic homeostasis, important roles of Nrf2 have emerged in the regulation of stem cell quiescence, survival, self-renewal, proliferation, senescence, and differentiation. In a rapidly advancing field, this review summarizes Nrf2 signaling in the context of stem cell state and function and provides a rationale for Nrf2 as a therapeutic target in stem cell-based regenerative medicine. Nuclear factor erythroid 2-related factor 2 (Nrf2) is ubiquitously expressed in most eukaryotic cells and functions to induce a broad range of cellular defenses against exogenous and endogenous stresses, including oxidants, xenobiotics, and excessive nutrient/metabolite supply. Because the production and fate of stem cells are often modulated by cellular redox and metabolic homeostasis, important roles of Nrf2 have emerged in the regulation of stem cell quiescence, survival, self-renewal, proliferation, senescence, and differentiation. In a rapidly advancing field, this review summarizes Nrf2 signaling in the context of stem cell state and function and provides a rationale for Nrf2 as a therapeutic target in stem cell-based regenerative medicine. Nrf2 is a stress-responsive transcription factor encoded by the NFE2L2 gene in humans [1Moi P. et al.Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region.Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9926-9930Crossref PubMed Scopus (931) Google Scholar]. Although previously considered to function primarily as an antioxidative transcription factor, Nrf2 is now recognized to be involved in the cellular response to multiple stressors including xenobiotics, excessive nutrient/metabolite supply, inflammation, and the accumulation of misfolded proteins (Box 1) [2Swamy S.M. et al.Nuclear factor-erythroid-2-related factor 2 in aging and lung fibrosis.Am. J. Pathol. 2016; 186: 1712-1723Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 3Niture S.K. et al.Regulation of Nrf2-an update.Free Radic. Biol. Med. 2014; 66: 36-44Crossref PubMed Scopus (403) Google Scholar, 4Matzinger M. et al.Activation of Nrf2 signaling by natural products—can it alleviate diabetes?.Biotechnol. Adv. 2018; 36: 1738-1767Crossref PubMed Scopus (19) Google Scholar]. Although Nrf2 regulation in cancer, diabetes, and aging is well studied [2Swamy S.M. et al.Nuclear factor-erythroid-2-related factor 2 in aging and lung fibrosis.Am. J. Pathol. 2016; 186: 1712-1723Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 4Matzinger M. et al.Activation of Nrf2 signaling by natural products—can it alleviate diabetes?.Biotechnol. Adv. 2018; 36: 1738-1767Crossref PubMed Scopus (19) Google Scholar, 5Menegon S. et al.The dual roles of NRF2 in cancer.Trends Mol. Med. 2016; 22: 578-593Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 6Moon E.J. Giaccia A. Dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment.Free Radic. Biol. Med. 2015; 79: 292-299Crossref PubMed Scopus (69) Google Scholar, 7David J.A. et al.The Nrf2/Keap1/ARE pathway and oxidative stress as a therapeutic target in type II diabetes mellitus.J. Diabetes Res. 2017; 2017: 4826724Crossref PubMed Scopus (25) Google Scholar, 8Cloer E.W. et al.NRF2 activation in cancer: from DNA to protein.Cancer Res. 2019; 79: 889-898Crossref PubMed Scopus (7) Google Scholar, 9Rojo de la Vega M. et al.NRF2 and the hallmarks of cancer.Cancer Cell. 2018; 34: 21-43Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar], the role of Nrf2 signaling in stem cells is not clear.Box 1Nrf2 Structure and FunctionNrf2 belongs to the cap ‘n’ collar transcription factor family. Human Nrf2 possesses a conserved basic leucine zipper structure and seven functional Nrf2-ECH homology (Neh) domains, Neh1–7 [98Tonelli C. et al.Transcriptional regulation by Nrf2.Antioxid Redox Signal. 2018; 29: 1727-1745Crossref PubMed Scopus (73) Google Scholar]: Neh1 interacts with small musculoaponeurotic fibrosarcoma (Maf) and binds to antioxidant response element (ARE)-DNA; Neh2 binds to Keap1; Neh3–5 are required for transactivation of Nrf2; Neh6 regulates stability of Nrf2; and Neh7 is involved in activation of transcription, retinoid X receptor α binds to the Neh7 domain and downregulates Nrf2, suggesting a mechanism for Nrf2 repression independent of Neh2-Keap1.Nrf2 activity can be regulated at multiple levels, including Nrf2 transcription, post-transcriptional regulation, and post-translational modification. At the transcription level, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [99Rushworth S.A. et al.The high Nrf2 expression in human acute myeloid leukemia is driven by NF-kappaB and underlies its chemo-resistance.Blood. 2012; 120: 5188-5198Crossref PubMed Scopus (107) Google Scholar], aryl hydrocarbon receptor [100Miao W. et al.Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes.J. Biol. Chem. 2005; 280: 20340-20348Crossref PubMed Scopus (293) Google Scholar], Kras, Braf, Myc, and Jun [101DeNicola G.M. et al.Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis.Nature. 2011; 475: 106-109Crossref PubMed Scopus (990) Google Scholar] can bind to the Nrf2 promoter to enhance Nrf2 transcription. The phosphoinositide-3-kinase–protein kinase B (PI3K–Akt) [102Mitsuishi Y. et al.Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming.Cancer Cell. 2012; 22: 66-79Abstract Full Text Full Text PDF PubMed Scopus (562) Google Scholar] and Notch signaling pathways [103Wakabayashi N. et al.Notch-Nrf2 axis: regulation of Nrf2 gene expression and cytoprotection by notch signaling.Mol. Cell. Biol. 2014; 34: 653-663Crossref PubMed Scopus (55) Google Scholar] have also been reported to augment Nrf2 transcription. Nrf2 also appears to autoregulate its own expression through an ARE-like element located in the proximal promoter region, leading to persistent nuclear accumulation of Nrf2 and protracted induction of phase 2 genes in response to chemopreventative agents [104Kwak M.K. et al.Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter.Mol. Cell. Biol. 2002; 22: 2883-2892Crossref PubMed Scopus (0) Google Scholar]. Nrf2 can also be transcriptionally repressed. For example, Nrf2 promoter modifications, including hypermethylation or single nucleotide polymorphisms result in decreased Nrf2 expression [105Li W. et al.Curcumin derivative epigenetically reactivates Nrf2 antioxidative stress signaling in mouse prostate cancer TRAMP C1 cells.Chem. Res. Toxicol. 2018; 31: 88-96Crossref PubMed Scopus (8) Google Scholar]. Nrf2 post-transcriptional regulation occurs mainly via miRNA. Several miRNAs, including miR-27a, miR-144, and miR-93 have been identified to reduce Nrf2 mRNA expression [106Wang P. et al.MicroRNA-93 downregulation ameliorates cerebral ischemic injury through the Nrf2/HO-1 defense pathway.Neurochem. Res. 2016; 41: 2627-2635Crossref PubMed Scopus (17) Google Scholar, 107Zhou S. et al.miR-144 reverses chemoresistance of hepatocellular carcinoma cell lines by targeting Nrf2-dependent antioxidant pathway.Am. J. Transl. Res. 2016; 8: 2992-3002PubMed Google Scholar, 108Xue W.L. et al.rhTNFR:Fc increases Nrf2 expression via miR-27a mediation to protect myocardium against sepsis injury.Biochem. Biophys. Res. Commun. 2015; 464: 855-861Crossref PubMed Google Scholar]. In addition, Nrf2 can be regulated through post-transcriptional alternative splicing, and Nrf2 mRNA splice variants lack the Keap1 interaction domain resulting in Nrf2 stabilization [109Goldstein L.D. et al.Recurrent loss of NFE2L2 exon 2 is a mechanism for Nrf2 pathway activation in human cancers.Cell Rep. 2016; 16: 2605-2617Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. Nrf2 is also subject to post-translational modifications including phosphorylation, acetylation, ubiquitination, sumoylation, and distinct chaperon interactions that may finely tune degradation, nuclear translocation, nuclear residence, nuclear export, or transactivation capacity [4Matzinger M. et al.Activation of Nrf2 signaling by natural products—can it alleviate diabetes?.Biotechnol. Adv. 2018; 36: 1738-1767Crossref PubMed Scopus (19) Google Scholar].Nrf2 is ubiquitously expressed in most eukaryotic cells and serves as a primary regulator of numerous inducible cell defense systems through the regulated expression of more than 200 downstream cytoprotective genes, including antioxidant proteins, detoxification and metabolism enzymes, transport proteins, proteasome subunits, chaperones, growth factors and their receptors, and transcription factors [90Hayes J.D. Dinkova-Kostova A.T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism.Trends Biochem. Sci. 2014; 39: 199-218Abstract Full Text Full Text PDF PubMed Scopus (651) Google Scholar, 110Al-Sawaf O. et al.Nrf2 in health and disease: current and future clinical implications.Clin. Sci. (Lond). 2015; 129: 989-999Crossref PubMed Scopus (60) Google Scholar]. Extensive research has deciphered the signaling pathways regulated by Nrf2 that are involved in regulating redox homeostasis, detoxification, autophagy, mitochondrial bioenergetics, lipid synthesis, transport and degradation, fatty acid oxidation, gluconeogenesis, and metabolic reprogramming. Nrf2 belongs to the cap ‘n’ collar transcription factor family. Human Nrf2 possesses a conserved basic leucine zipper structure and seven functional Nrf2-ECH homology (Neh) domains, Neh1–7 [98Tonelli C. et al.Transcriptional regulation by Nrf2.Antioxid Redox Signal. 2018; 29: 1727-1745Crossref PubMed Scopus (73) Google Scholar]: Neh1 interacts with small musculoaponeurotic fibrosarcoma (Maf) and binds to antioxidant response element (ARE)-DNA; Neh2 binds to Keap1; Neh3–5 are required for transactivation of Nrf2; Neh6 regulates stability of Nrf2; and Neh7 is involved in activation of transcription, retinoid X receptor α binds to the Neh7 domain and downregulates Nrf2, suggesting a mechanism for Nrf2 repression independent of Neh2-Keap1. Nrf2 activity can be regulated at multiple levels, including Nrf2 transcription, post-transcriptional regulation, and post-translational modification. At the transcription level, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [99Rushworth S.A. et al.The high Nrf2 expression in human acute myeloid leukemia is driven by NF-kappaB and underlies its chemo-resistance.Blood. 2012; 120: 5188-5198Crossref PubMed Scopus (107) Google Scholar], aryl hydrocarbon receptor [100Miao W. et al.Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes.J. Biol. Chem. 2005; 280: 20340-20348Crossref PubMed Scopus (293) Google Scholar], Kras, Braf, Myc, and Jun [101DeNicola G.M. et al.Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis.Nature. 2011; 475: 106-109Crossref PubMed Scopus (990) Google Scholar] can bind to the Nrf2 promoter to enhance Nrf2 transcription. The phosphoinositide-3-kinase–protein kinase B (PI3K–Akt) [102Mitsuishi Y. et al.Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming.Cancer Cell. 2012; 22: 66-79Abstract Full Text Full Text PDF PubMed Scopus (562) Google Scholar] and Notch signaling pathways [103Wakabayashi N. et al.Notch-Nrf2 axis: regulation of Nrf2 gene expression and cytoprotection by notch signaling.Mol. Cell. Biol. 2014; 34: 653-663Crossref PubMed Scopus (55) Google Scholar] have also been reported to augment Nrf2 transcription. Nrf2 also appears to autoregulate its own expression through an ARE-like element located in the proximal promoter region, leading to persistent nuclear accumulation of Nrf2 and protracted induction of phase 2 genes in response to chemopreventative agents [104Kwak M.K. et al.Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter.Mol. Cell. Biol. 2002; 22: 2883-2892Crossref PubMed Scopus (0) Google Scholar]. Nrf2 can also be transcriptionally repressed. For example, Nrf2 promoter modifications, including hypermethylation or single nucleotide polymorphisms result in decreased Nrf2 expression [105Li W. et al.Curcumin derivative epigenetically reactivates Nrf2 antioxidative stress signaling in mouse prostate cancer TRAMP C1 cells.Chem. Res. Toxicol. 2018; 31: 88-96Crossref PubMed Scopus (8) Google Scholar]. Nrf2 post-transcriptional regulation occurs mainly via miRNA. Several miRNAs, including miR-27a, miR-144, and miR-93 have been identified to reduce Nrf2 mRNA expression [106Wang P. et al.MicroRNA-93 downregulation ameliorates cerebral ischemic injury through the Nrf2/HO-1 defense pathway.Neurochem. Res. 2016; 41: 2627-2635Crossref PubMed Scopus (17) Google Scholar, 107Zhou S. et al.miR-144 reverses chemoresistance of hepatocellular carcinoma cell lines by targeting Nrf2-dependent antioxidant pathway.Am. J. Transl. Res. 2016; 8: 2992-3002PubMed Google Scholar, 108Xue W.L. et al.rhTNFR:Fc increases Nrf2 expression via miR-27a mediation to protect myocardium against sepsis injury.Biochem. Biophys. Res. Commun. 2015; 464: 855-861Crossref PubMed Google Scholar]. In addition, Nrf2 can be regulated through post-transcriptional alternative splicing, and Nrf2 mRNA splice variants lack the Keap1 interaction domain resulting in Nrf2 stabilization [109Goldstein L.D. et al.Recurrent loss of NFE2L2 exon 2 is a mechanism for Nrf2 pathway activation in human cancers.Cell Rep. 2016; 16: 2605-2617Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. Nrf2 is also subject to post-translational modifications including phosphorylation, acetylation, ubiquitination, sumoylation, and distinct chaperon interactions that may finely tune degradation, nuclear translocation, nuclear residence, nuclear export, or transactivation capacity [4Matzinger M. et al.Activation of Nrf2 signaling by natural products—can it alleviate diabetes?.Biotechnol. Adv. 2018; 36: 1738-1767Crossref PubMed Scopus (19) Google Scholar]. Nrf2 is ubiquitously expressed in most eukaryotic cells and serves as a primary regulator of numerous inducible cell defense systems through the regulated expression of more than 200 downstream cytoprotective genes, including antioxidant proteins, detoxification and metabolism enzymes, transport proteins, proteasome subunits, chaperones, growth factors and their receptors, and transcription factors [90Hayes J.D. Dinkova-Kostova A.T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism.Trends Biochem. Sci. 2014; 39: 199-218Abstract Full Text Full Text PDF PubMed Scopus (651) Google Scholar, 110Al-Sawaf O. et al.Nrf2 in health and disease: current and future clinical implications.Clin. Sci. (Lond). 2015; 129: 989-999Crossref PubMed Scopus (60) Google Scholar]. Extensive research has deciphered the signaling pathways regulated by Nrf2 that are involved in regulating redox homeostasis, detoxification, autophagy, mitochondrial bioenergetics, lipid synthesis, transport and degradation, fatty acid oxidation, gluconeogenesis, and metabolic reprogramming. Stem cells, including pluripotent stem cells (PSCs) and adult tissue stem cells (ASCs) (Box 2), possess unique metabolic programs and reduction–oxidation (redox) states to sustain proliferation while maintaining pluripotency (see Glossary) or multipotency and/or specified differentiation [10Zhang J. et al.Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal.Cell Stem Cell. 2012; 11: 589-595Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 11Zhong X. et al.Mitochondrial dynamics is critical for the full pluripotency and embryonic developmental potential of pluripotent stem cells.Cell Metab. 2019; 29: 979-992.e4Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 12Ito K. Suda T. Metabolic requirements for the maintenance of self-renewing stem cells.Nat. Rev. Mol. Cell Biol. 2014; 15: 243-256Crossref PubMed Scopus (431) Google Scholar]. In stem cells, ATP is mainly produced by glycolysis and oxidative phosphorylation (OXPHOS) during self-renewal and differentiation [13Shyh-Chang N. Ng H.H. The metabolic programming of stem cells.Genes Dev. 2017; 31: 336-346Crossref PubMed Scopus (0) Google Scholar]. Quiescent PSCs rely primarily on glycolysis for energy with lower respiration rates, reduced reactive oxygen species (ROS) production, and elevated antioxidant enzyme expression [10Zhang J. et al.Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal.Cell Stem Cell. 2012; 11: 589-595Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar]. PSC differentiation results in a metabolic shift from glycolysis to OXPHOS, which has been shown to revert back to glycolysis after reprogramming to pluripotency [10Zhang J. et al.Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal.Cell Stem Cell. 2012; 11: 589-595Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 14Mathieu J. et al.Hypoxia-inducible factors have distinct and stage-specific roles during reprogramming of human cells to pluripotency.Cell Stem Cell. 2014; 14: 592-605Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar]. Most quiescent ASCs in their niches tend to prefer glycolysis and fatty acid oxidation with high levels of transcription factors, such as Nrf2, driven antioxidant enzyme expression to suppress ROS signaling [13Shyh-Chang N. Ng H.H. The metabolic programming of stem cells.Genes Dev. 2017; 31: 336-346Crossref PubMed Scopus (0) Google Scholar]. Upon activation by stress or injury, proliferating ASCs increase their oxygen use via the influence of growth factor kinase signaling, alter cell metabolite levels and redox states, lower their expression of antioxidant enzymes, and activate ROS signaling [10Zhang J. et al.Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal.Cell Stem Cell. 2012; 11: 589-595Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 13Shyh-Chang N. Ng H.H. The metabolic programming of stem cells.Genes Dev. 2017; 31: 336-346Crossref PubMed Scopus (0) Google Scholar]. Therefore, the stem cell metabolic state and redox profile can be used as an index of stem cell self-renewal, pluripotency or multipotency, and differentiation. Consistent with an essential role for energy regulation in stem cell survival and function, redox biology and metabolic programming-related genes are among the most enriched transcripts and proteins present in stem cells [13Shyh-Chang N. Ng H.H. The metabolic programming of stem cells.Genes Dev. 2017; 31: 336-346Crossref PubMed Scopus (0) Google Scholar, 15Ramalho-Santos M. et al.“Stemness”: transcriptional profiling of embryonic and adult stem cells.Science. 2002; 298: 597-600Crossref PubMed Scopus (1349) Google Scholar, 16Munoz J. et al.The quantitative proteomes of human-induced pluripotent stem cells and embryonic stem cells.Mol. Syst. Biol. 2011; 7: 550Crossref PubMed Scopus (91) Google Scholar, 17Konze S.A. et al.Proteomic analysis of human pluripotent stem cell cardiomyogenesis revealed altered expression of metabolic enzymes and PDLIM5 isoforms.J. Proteome Res. 2017; 16: 1133-1149Crossref PubMed Scopus (12) Google Scholar]. Nrf2 is a common upstream regulator of many of these genes suggesting that Nrf2 can serve as a master regulator of stem cell redox and metabolic homeostasis [13Shyh-Chang N. Ng H.H. The metabolic programming of stem cells.Genes Dev. 2017; 31: 336-346Crossref PubMed Scopus (0) Google Scholar, 18Jang J. et al.Nrf2, a regulator of the proteasome, controls self-renewal and pluripotency in human embryonic stem cells.Stem Cells. 2014; 32: 2616-2625Crossref PubMed Google Scholar, 19Tsai J.J. et al.Nrf2 regulates haematopoietic stem cell function.Nat. Cell Biol. 2013; 15: 309-316Crossref PubMed Scopus (108) Google Scholar]. In this review, we summarize and discuss recent progress in understanding Nrf2 regulatory signaling in stem cells, and highlight the role of Nrf2 in controlling stem cell redox states, metabolic homeostasis, survival, self-renewal, pluripotency, proliferation, differentiation, and reprogramming (Table 1).Box 2Stem Cells and Progenitor CellsIn mammals, there are two basic types of stem cells: PSCs and ASCs. PSCs can be subcategorized into germline or ESCs and iPSCs. ESCs are derived from the inner cell mass of preimplantation embryos. iPSCs are reprogrammed from adult somatic cells in vitro through simultaneous overexpression of four core pluripotent factors: Oct4, Sox2, Klf4, and c-Myc. Both ESCs and iPSCs can be indefinitely maintained and expanded in a pluripotent state in vitro and are capable of differentiating into the derivatives of all three germ layers.ASCs are characterized by their ability to self-renew and differentiate to generate all the cell types in a tissue. Based on their locations and turnover rates in various tissues/organs, ASCs can be subcategorized into HSCs, MSCs, EPCs, and NSCs.During embryonic development, stem cells differentiate into organ- and tissue-specialized cells but are also maintained in stem cell niches capable of regenerative repair for most organs, including the BM, most solid organs, and skin, but not the postnatal heart. Stem and progenitor cells support the repair and replenishment of most adult tissues, though this capacity declines with age.Table 1Function of Nrf2 in Stem Cells and Progenitor CellsStem cells/progenitor cellsSpecies originNrf2 functionManipulating approachMechanismRefsESCsHuman embryoSelf-renewal ↑Re-establishment of pluripotency ↑Differentiation ↓Nrf2 siRNA or shRNA knockdown or Keap1 overexpression or pharmacological activationNrf2 maintains and regulates proteasome activity through POMP18Jang J. et al.Nrf2, a regulator of the proteasome, controls self-renewal and pluripotency in human embryonic stem cells.Stem Cells. 2014; 32: 2616-2625Crossref PubMed Google ScholarNeuroectoderm differentiation ↓Nrf2 shRNA or siRNA knockdownNrf2 binds directly to upstream regions of pluripotency genes OCT4 and NANOG to promote their expression and repress neuroectoderm derivation20Jang J. et al.Primary cilium-autophagy-Nrf2 (PAN) axis activation commits human embryonic stem cells to a neuroectoderm fate.Cell. 2016; 165: 410-420Abstract Full Text Full Text PDF PubMed Google ScholarOsteogenic differentiation ↑Nrf2 siRNA knockdownNrf2 increases the expression of Runx2 to facilitates the mineralization of ESCs21Sim H.J. et al.Glucose oxidase facilitates osteogenic differentiation and mineralization of embryonic stem cells through the activation of Nrf2 and ERK signal transduction pathways.Mol. Cell Biochem. 2016; 419: 157-163Crossref PubMed Scopus (4) Google ScholarNeuronal differentiation ↓Nrf2 siRNA knockdownNrf2 decreases ROS level to inhibit neuronal differentiation22Hu Q. et al.Oxidative stress promotes exit from the stem cell state and spontaneous neuronal differentiation.Oncotarget. 2018; 9: 4223-4238Crossref PubMed Scopus (6) Google ScholariPSCsHuman fibroblastsReprograming ↑Keap1 overexpressionNrf2 promotes metabolic reprogramming of iPSCs via HIF-1α26Hawkins K.E. et al.NRF2 orchestrates the metabolic shift during induced pluripotent stem cell reprogramming.Cell Rep. 2016; 14: 1883-1891Abstract Full Text Full Text PDF PubMed Scopus (91) Google ScholarHuman or chimpanzee skin fibroblastNeuroectoderm differentiation ↓Mesendoderm differentiation ↑Nrf2 shRNA knockdownNrf2 represses neuroectoderm differentiation and promotes mesendoderm differentiation by regulating pluripotency genes20Jang J. et al.Primary cilium-autophagy-Nrf2 (PAN) axis activation commits human embryonic stem cells to a neuroectoderm fate.Cell. 2016; 165: 410-420Abstract Full Text Full Text PDF PubMed Google ScholarHSCsMouse BMSurvival ↑Nrf2 knockoutNrf2 promotes HSC survival via enhancing prosurvival cytokine (such as G-CSF) signaling levels34Merchant A.A. et al.The redox-sensitive transcription factor Nrf2 regulates murine hematopoietic stem cell survival independently of ROS levels.Blood. 2011; 118: 6572-6579Crossref PubMed Scopus (62) Google ScholarProliferation ↓Expansion ↓Differentiation ↓Self-renewal ↑Quiescence ↑Migration ↑Nrf2 knockoutNrf2 regulates cell quiescence, differentiation, and migration partially via regulating CXCR4 transcription19Tsai J.J. et al.Nrf2 regulates haematopoietic stem cell function.Nat. Cell Biol. 2013; 15: 309-316Crossref PubMed Scopus (108) Google ScholarQuiescence and Maintenance ↓Differentiation ↑Keap1 knockout or pharmacological activation of Nrf2Nrf2 drives cell cycle entry and differentiation possibly via activation of JAK–STAT3 pathway36Murakami S. et al.NRF2 activation impairs quiescence and bone marrow reconstitution capacity of hematopoietic stem cells.Mol. Cell. Biol. 2017; 37 (e00086-17)Crossref Scopus (6) Google ScholarFunction↑Survival ↑Expansion ↑Keap1 knockout or pharmacological activations of Nrf2 or Nrf2 knockoutNrf2-mediated Notch signaling improves HSC function following ionizing radiation exposure; Nrf2 increases the expression of antioxidative proteins under stress conditions41Kim J.H. et al.NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation.J. Clin. Invest. 2014; 124: 730-741Crossref PubMed Scopus (55) Google Scholar, 43Xue X.L. et al.Astaxanthin attenuates total body irradiation-induced hematopoietic system injury in mice via inhibition of oxidative stress and apoptosis.Stem Cell Res. Ther. 2017; 8: 7Crossref PubMed Scopus (12) Google ScholarMSCsHuman BMApoptosis ↓Oxidative stress ↓Nrf2 overexpressionNrf2 upregulates SOD and HO-1 expression52Mohammadzadeh M. et al.Nrf-2 overexpression in mesenchymal stem cells reduces oxidative stress-induced apoptosis and cytotoxicity.Cell Stress Chaperones. 2012; 17: 553-565Crossref PubMed Scopus (0) Google ScholarHuman umbilical cordProliferation ↑Stemness ↑Osteogenesis ↑Apoptosis ↓Nrf2 overexpression or shRNA knockdownNrf2 might lead alterations in MSC genome sequences53Yuan Z. et al.NRF2 overexpression in mesenchymal stem cells induces stem-cell marker expression and enhances osteoblastic differentiation.Biochem. Biophys. Res. Commun. 2017; 491: 228-235Crossref PubMed Scopus (6) Google ScholarHuman amnionHoming ↑Differentiation↑Apoptosis ↓Nrf2 overexpressionUpregulation of Nrf2 DNA binding activity increases the cytoprotective genes expression54Zhang S. et al.Nrf2 transfection enhances the efficacy of human amniotic mesenchymal stem cells to repair lung injury induced by lipopolysaccharide.J. Cell Biochem. 2018; 119: 1627-1636Crossref PubMed Scopus (9) Google ScholarHuman BMSelf-renewal ↑Osteogenic Differentiation ↑Nrf2 shRNA knockdown or pharmacological activationNrf2 maintains self-renewal and osteogenic differentiation of MSCs via p53-SIRT1 signaling61Yoon D.S. et al.Cellular localization of NRF2 determines the self-renewal and osteogenic differentiation potential of human MSCs via the P53-SIRT1 axis.Cell Death Dis. 2016; 7: e2093Crossref PubMed Scopus (9) Google ScholarRat adiposeOsteoblastic Differentiation ↓Nrf2 siRNA knockdownNrf2 inhibits ROS-induced osteogenic differentiation of adipose derived MSCs by downregulating the expression of BMP2 and Runx262Tao J. et al.Downregulation of Nrf2 promotes autophagy-dependent osteoblastic differentiation of adipose-derived mesenchymal stem cells.Exp. Cell Res. 2016; 349: 221-229Crossref PubMed Scopus (13) Google ScholarNSCsRat/mouse subventricular zoneSurvival ↑Proliferation ↑Differentiation ↑Regeneration ↑Nrf2 overexpression or Nrf2 knockout or shRNA knockdownThe mechanism is not clear64Corenblum M.J. et al.Reduced Nrf2 expression mediates the decline in neural stem cell function during a critical middle-age period.Aging Cell. 2016; 15: 725-736Crossref PubMed Scopus (26) Google ScholarRat/mouse dentate gyrus of the hippocampusProliferation ↑Neuronal differentiation ↑Regeneration ↑Nrf2 overexpression or Nrf2 knockout or siRNA knockdownThe mechanism is not clear70Ray S. et al.A role for Nrf2 expression in defining the aging of hippocampal neural stem cells.Cell Transplant. 2018; 27: 589-606Crossref PubMed Scopus (9) Google ScholarMouse subgranular zoneProliferation ↑Differentiation ↑Nrf2 shRNA knockdownNrf2-knockout or pharmacological activationThe mechanism is not clear65Robledinos-Anton N. et al.Transcription factor NRF2 controls