ERK信号通路在人多能干细胞的多能性状态调控中的作用

doi:10.3877/cma.j.issn.2095-1221.2023.01.004

人多能干细胞（hPSCs）具有无限自我更新和分化为体内所有种类细胞的潜能。研究者们发现hPSCs呈现不同的多能性状态，包括原始态（na?ve）、始发态（primed）以及介于两者之间的中间态（intermediate），分别对应体内胚胎发育早期不同阶段多能细胞的发育潜能，反映了多能性状态的连续性。胞外信号调节激酶（ERK）信号通路是真核细胞中经典的激酶级联途径，赋予细胞在各种胞外刺激下选择不同细胞命运的能力。对ERK信号通路依赖性的差异，被认为是区别hPSCs不同多能性状态的重要指标。本综述总结了hPSCs不同多能性状态的特征，以及ERK信号通路在这些不同状态hPSCs的维持和相互转化中的作用，旨在为优化不同多能性状态的hPSCs的培养条件和相互转化策略提供指导。

关键词: ERK信号通路, 人多能干细胞, 细胞命运决定, 多能性

Human pluripotent stem cells (hPSCs) can self-renew indefinitely and have the potential to differentiate into all cell types of the human body. Researchers have found that hPSCs display different pluripotency states (the na?ve state, primed state, and intermediate state) , which resemble the developmental potential of pluripotent cells at different stages of human early embryos, respectively, and exhibit a pluripotency continuum. Extracellular signal-regulated kinase (ERK) signaling pathway is a classical kinase cascade pathway in eukaryotic cells, which determines cell fates under various extracellular stimulation. The difference in the dependency on the ERK signaling pathway is considered to be a hallmark to distinguish different pluripotency states of hPSCs. In this review, we summarize the characteristics of hPSCs with different pluripotency states, and functions of the ERK signaling pathway in the maintenance and mutual conversion of these different states of hPSCs. This review could provide the guidance for optimizing culture conditions and mutual transition strategies of hPSCs with different pluripotency states.

Key words: ERK signaling pathway, Human pluripotent stem cells, Cell fate determination, Pluripotency

表1 利用非转基因方法将primed hPSCs转变为na?ve hPSCs的培养条件

参考文献以及配方名称^*	使用的小分子^**	使用的生长因子
Chan^[5]（3i/L）	MEKi（PD0325901），GSK3i（CHIR99021），AMPKi（dorsomorphin）	hLIF
Gafni^[6]（NHSM）	MEKi（PD0325901），GSK3i（CHIR99021），JNKi （SP600125），p38i（SB203580）	hLIF，FGF2，TGFβ1
Takashima^[9]（t2i/L/Gö）	MEKi（PD0325901），GSK3i（CHIR99021），PKCi（Gö 6983）	hLIF
Ware ^[11]	MEKi（PD0325901），GSK3i（CHIR99021），HDACi （sodium butyrate/SAHA）	FGF2
Theunissen^[7]（5i/L/A）	MEKi（PD0325901），GSK3βi（IM-12），BRAFi （SB590885），SRCi（WH4-023），ROCKi（Y-27632）	hLIF，Activin A
Theunissen^[8]（4i/L/A）	MEKi （PD0325901），BRAFi（SB590885），SRCi （WH4-023），ROCKi（Y-27632）	hLIF，Activin A
Duggal^[12]	MEKi（PD0325901），GSK3i（CHIR99021），Ascorbic acid	hLIF，FGF2，Forskolin
Park^[13]	MEKi（PD0325901），GSK3i（CHIR99021），tankyrasei（XAV939）	hLIF，Forsolin，sHH
Szczerbinska^[14]（FINE）	MEKi（PD0325901），GSK3i（CHIR99021），BRAFi （SB590885），SRCi（Dasatinib），ROCKi（Y-27632）	hLIF，FGF2，Activin A
N. Bredenkamp^[15]（PXGL）	MEKi（PD0325901），tankyrasei（XAV939），PKCi（Gö 6983）	hLIF
Alejandro^[16]（PGCX）	MEKi（PD0325901），GSK3i（CHIR99021），tankyrasei（XAV939），PKCi（Gö 6983）	hLIF

表1 利用非转基因方法将primed hPSCs转变为na?ve hPSCs的培养条件

参考文献以及配方名称^*	使用的小分子^**	使用的生长因子
Chan^[5]（3i/L）	MEKi（PD0325901），GSK3i（CHIR99021），AMPKi（dorsomorphin）	hLIF
Gafni^[6]（NHSM）	MEKi（PD0325901），GSK3i（CHIR99021），JNKi （SP600125），p38i（SB203580）	hLIF，FGF2，TGFβ1
Takashima^[9]（t2i/L/Gö）	MEKi（PD0325901），GSK3i（CHIR99021），PKCi（Gö 6983）	hLIF
Ware ^[11]	MEKi（PD0325901），GSK3i（CHIR99021），HDACi （sodium butyrate/SAHA）	FGF2
Theunissen^[7]（5i/L/A）	MEKi（PD0325901），GSK3βi（IM-12），BRAFi （SB590885），SRCi（WH4-023），ROCKi（Y-27632）	hLIF，Activin A
Theunissen^[8]（4i/L/A）	MEKi （PD0325901），BRAFi（SB590885），SRCi （WH4-023），ROCKi（Y-27632）	hLIF，Activin A
Duggal^[12]	MEKi（PD0325901），GSK3i（CHIR99021），Ascorbic acid	hLIF，FGF2，Forskolin
Park^[13]	MEKi（PD0325901），GSK3i（CHIR99021），tankyrasei（XAV939）	hLIF，Forsolin，sHH
Szczerbinska^[14]（FINE）	MEKi（PD0325901），GSK3i（CHIR99021），BRAFi （SB590885），SRCi（Dasatinib），ROCKi（Y-27632）	hLIF，FGF2，Activin A
N. Bredenkamp^[15]（PXGL）	MEKi（PD0325901），tankyrasei（XAV939），PKCi（Gö 6983）	hLIF
Alejandro^[16]（PGCX）	MEKi（PD0325901），GSK3i（CHIR99021），tankyrasei（XAV939），PKCi（Gö 6983）	hLIF

图1 体内外不同多能性细胞的发育或分化潜能（修改自^[29]）注：在体外培养的na?ve hPSCs对应体内着床前上胚层细胞，具有分化为滋养层细胞、原始内胚层以及formative hPSCs的潜能；在体外培养的formative hPSCs对应体内着床后早期上胚层细胞，具有分化为原始内胚层祖细胞、原始生殖细胞、三胚层细胞以及羊膜细胞的潜能；在体外培养的primed hPSCs对应体内着床后晚期上胚层细胞，具有分化为三胚层细胞的潜能。在体外诱导分化时，primed hPSCs也可以分化成生殖细胞和羊膜细胞。这一现象可能是由于primed hPSCs的群体异质性，或者由于primed多能性状态的发育可塑性。hPSCs为人多能干细胞；na?ve为原始态；formative为形成态；primed为始发态

图2 ERK信号通路的组成以及激活和失活途径注：胞外生长因子信号通过以RAF-MEK-ERK为核心的一系列激酶级联，调控下游基因的表达以及底物蛋白的磷酸化；除了细胞中的负性调控因子SEP，SPRY和DUSP对该通路的抑制，下游激酶对上游因子的负反馈调节也防止该通路的过度激活；图中展示哺乳动物细胞中ERK信号通路关键激酶的同源蛋白和其基因名；红色箭头表示激活，蓝色平末端表示抑制。FGF2为成纤维细胞生长因子2；RTK为受体酪氨酸激酶；FRS2为成纤维细胞生长因子受体底物2；GRB2为生长因子受体结合蛋白2；SOS为Ras/Rac鸟嘌呤核苷酸交换因子1；RAS为大鼠肉瘤蛋白；RAF为原癌基因丝氨酸/苏氨酸激酶；MEK为丝裂原活化蛋白激酶的激酶；ERK为丝裂原活化蛋白激酶；RSK为核糖体蛋白S6激酶；MSK为丝裂原和压力激活蛋白激酶；MNK为MAPK信号整合激酶；TCF为T细胞因子；SRF为血清反应因子；ETS为E26转录因子；FOS和JUN均属于立即早期基因；DUSP5/6为双特异性磷酸酶5/6；SPRY为Sprouty受体酪氨酸激酶信号拮抗子；SEF为白细胞介素17受体D；图片使用网站BioRender.com制作

图3 ERK信号通路在primed hPSCs中的作用注：ERK的适度激活维持了primed hPSCs的多能性和细胞增殖，抑制了滋养层分化；而ERK的过度激活促进了中内胚层分化。BMP4为骨形态发生蛋白4；FGF2为成纤维细胞生长因子2；Activin A为激动素A；RAS为大鼠肉瘤蛋白；RAF为原癌基因丝氨酸/苏氨酸激酶；MEK为丝裂原活化蛋白激酶的激酶；ERK为丝裂原活化蛋白激酶；PI3K为磷脂酰肌醇3-激酶；AKT为蛋白激酶B；图片使用网站BioRender.com制作

表2 不同多能性状态hPSCs的特性

hPSCs的特性	naïve	intermediate	primed
naïve转录因子表达（如KLF4）	高	中	低
谱系分化转录因子表达（如TBXT）	无	无	有
体外分化成原始生殖细胞的能力	无	有	无^*
细胞均质性	高	高	低
形成囊胚嵌合体的能力	有	低	无
ERK信号依赖性	低	中	高
培养基中的ERK抑制剂	必要	部分配方需要	不需要
培养基中的FGF2	部分配方需要	部分配方需要	必要

表2 不同多能性状态hPSCs的特性

hPSCs的特性	naïve	intermediate	primed
naïve转录因子表达（如KLF4）	高	中	低
谱系分化转录因子表达（如TBXT）	无	无	有
体外分化成原始生殖细胞的能力	无	有	无^*
细胞均质性	高	高	低
形成囊胚嵌合体的能力	有	低	无
ERK信号依赖性	低	中	高
培养基中的ERK抑制剂	必要	部分配方需要	不需要
培养基中的FGF2	部分配方需要	部分配方需要	必要

图4 ERK信号通路活性与hPSCs多能性状态间关系的示意图注：在hPSCs多能性状态从na?ve向primed转变时，hPSCs中ERK信号通路活性从低到高转变。ERK为丝裂原活化蛋白激酶；hPSCs为人多能干细胞；na?ve为原始态；intermediate为中间态；formative为形成态；primed为始发态

1	De Los Angeles A, Ferrari F, Xi R, et al. Hallmarks of pluripotency[J]. Nature, 2015, 525(7570):469-478.
2	Ying QL, Wray J, Nichols J, et al. The ground state of embryonic stem cell self-renewal[J]. Nature, 2008, 453(7194):519-523.
3	Tesar PJ, Chenoweth JG, Brook FA, et al. New cell lines from mouse epiblast share defining features with human embryonic stem cells[J]. Nature, 2007, 448(7150):196-199.
4	Yu L, Wei Y, Duan J, et al. Blastocyst-like structures generated from human pluripotent stem cells[J]. Nature, 2021, 591(7851):620-626.
5	Chan YS, Göke J, Ng JH, et al. Induction of a human pluripotent state with distinct regulatory circuitry that resembles preimplantation epiblast[J]. Cell Stem Cell, 2013, 13(6):663-675.
6	Gafni O, Weinberger L, Mansour AA, et al. Derivation of novel human ground state naive pluripotent stem cells[J]. Nature, 2013, 504(7479):282-286.
7	Theunissen TW, Powell BE, Wang H, et al. Systematic identification of culture conditions for induction and maintenance of naive human pluripotency[J]. Cell Stem Cell, 2014, 15(4):471-487.
8	Theunissen TW, Friedli M, He Y, et al. Molecular Criteria for Defining the Naive Human Pluripotent State[J]. Cell Stem Cell, 2016, 19(4):502-515.
9	Takashima Y, Guo G, Loos R, et al. Resetting transcription factor control circuitry toward ground-state pluripotency in human[J]. Cell, 2014, 158(6):1254-1269.
10	Taei A, Rasooli P, Braun T, et al. Signal regulators of human naive pluripotency[J]. Exp Cell Res, 2020, 389(2):111924.doi: 10.1016/j.yexcr.2020.111924.
11	Ware CB, Nelson AM, Mecham B, et al. Derivation of naive human embryonic stem cells[J]. Proc Natl Acad Sci U S A, 2014, 111(12):4484-4489.
12	Duggal G, Warrier S, Ghimire S, et al. Alternative routes to induce naive pluripotency in human embryonic stem cells[J]. Stem Cells, 2015, 33(9):2686-2698.
13	Park TS, Zimmerlin L, Evans-Moses R, et al. Chemical reversion of conventional human pluripotent stem cells to a naive-like state with improved multilineage differentiation potency[J]. J Vis Exp, 2018, (136):57921. doi: 10.3791/57921.
14	Szczerbinska I, Gonzales KAU, Cukuroglu E, et al. A chemically defined feeder-free system for the establishment and maintenance of the human naive pluripotent state[J]. Stem Cell Reports, 2019, 13(4):612-626.
15	Bredenkamp N, Stirparo GG, Nichols J, et al. The cell-surface marker sushi containing domain 2 facilitates establishment of human naive pluripotent stem cells[J]. Stem Cell Reports, 2019, 12(6):1212-1222.
16	De Los Angeles A. Generation of ERK-independent human and non-human primate pluripotent stem cells[J]. Curr Protoc Stem Cell Biol, 2019, 49(1):e85.doi: 10.1002/cpsc.85.
17	Smith A. Formative pluripotency: the executive phase in a developmental continuum[J]. Development, 2017, 144(3):365-373.
18	Kalkan T, Olova N, Roode M, et al. Tracking the embryonic stem cell transition from ground state pluripotency[J]. Development, 2017, 144(7):1221-1234.
19	Kinoshita M, Barber M, Mansfield W et al. Capture of mouse and human stem cells with features of formative pluripotency[J]. Cell Stem Cell, 2021, 28(12):2180.doi: 10.1016/j.stem.2021.11.002.
20	Boroviak T, Nichols J. Primate embryogenesis predicts the hallmarks of human naive pluripotency[J]. Development, 2017, 144(2):175-186.
21	Cornacchia D, Zhang C, Zimmer B, et al. Lipid deprivation induces a stable, naive-to-primed intermediate state of pluripotency in human PSCs[J]. Cell Stem Cell, 2019, 25(1):120-136.e10.
22	Khan SA, Park KM, Fischer LA, et al. Probing the signaling requirements for naive human pluripotency by high-throughput chemical screening[J]. Cell Rep, 2021, 35(11):109233.doi: 10.1016/j.celrep.2021.109233.
23	Yamauchi K, Ikeda T, Hosokawa M, et al. Overexpression of nuclear receptor 5A1 induces and maintains an intermediate state of conversion between primed and naive pluripotency[J]. Stem Cell Reports, 2020, 14(3):506-519.
24	Rostovskaya M, Stirparo GG, Smith A. Capacitation of human naive pluripotent stem cells for multi-lineage differentiation[J]. Development, 2019, 146(7):dev172916. doi: 10.1242/dev.172916.
25	Dong C, Fischer LA, Theunissen TW. Recent insights into the naive state of human pluripotency and its applications[J]. Exp Cell Res, 2019, 385(1):111645. doi: 10.1016/j.yexcr.2019.111645.
26	Kinoshita M, Barber M, Mansfield W, et al. Capture of mouse and human stem cells with features of formative pluripotency[J]. Cell Stem Cell, 2021, 28(3):453-471.e8.
27	Yu L, Wei Y, Sun HX, et al. Derivation of intermediate pluripotent stem cells amenable to primordial germ cell specification[J]. Cell Stem Cell, 2021, 28(3):550-567.e12.
28	De Los Angeles A. Parsing the pluripotency continuum in humans and non-human primates for interspecies chimera generation[J]. Exp Cell Res, 2020, 387(1):111747.doi: 10.1016/j.yexcr.2019.111747.
29	Pera MF, Rossant J. The exploration of pluripotency space: Charting cell state transitions in peri-implantation development[J]. Cell Stem Cell, 2021, 28(11):1896-1906.
30	Zassadowski F, Rochette-Egly C, Chomienne C, et al. Regulation of the transcriptional activity of nuclear receptors by the MEK/ERK1/2 pathway[J]. Cell Signal, 2012, 24(12):2369-2377.
31	Soszyńska A, Klimczewska K, Suwińska A. FGF/ERK signaling pathway: how it operates in mammalian preimplantation embryos and embryo-derived stem cells[J]. Int J Dev Biol, 2019, 63(3-4-5):171-186.
32	Roskoski R Jr. MEK1/2 dual-specificity protein kinases: structure and regulation[J]. Biochem Biophys Res Commun, 2012, 417(1):5-10.
33	Cruzalegui FH, Cano E, Treisman R. ERK activation induces phosphorylation of Elk-1 at multiple S/T-P motifs to high stoichiometry[J]. Oncogene, 2000, 18(56):7948-7957.
34	Murphy LO, Smith S, Chen RH, et al. Molecular interpretation of ERK signal duration by immediate early gene products[J]. Nat Cell Biol, 2002, 4(8):556-564.
35	Mavrothalassitis G, Ghysdael J. Proteins of the ETS family with transcriptional repressor activity[J]. Oncogene, 2000, 19(55):6524-6532.
36	Wang B, Krall EB, Aguirre AJ, et al. ATXN1L, CIC, and ETS transcription factors modulate sensitivity to MAPK pathway inhibition[J]. Cell Rep, 2017, 18(6):1543-1557.
37	Paronetto MP, Zalfa F, Botti F, et al. The nuclear RNA-binding protein Sam68 translocates to the cytoplasm and associates with the polysomes in mouse spermatocytes[J]. Mol Biol Cell, 2006, 17(1):14-24.
38	Zhao J, Yuan X, Frödin M, et al. ERK-dependent phosphorylation of the transcription initiation factor TIF-IA is required for RNA polymerase I transcription and cell growth[J]. Mol Cell, 2003, 11(2):405-413.
39	Formstecher E, Ramos JW, Fauquet M, et al. PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase[J]. Dev Cell, 2001, 1(2):239-250.
40	Lavoie H, Gagnon J, Therrien M. ERK signalling: a master regulator of cell behaviour, life and fate[J]. Nat Rev Mol Cell Biol, 2020, 21(10):607-632.
41	Cai X, Li M, Vrana J, et al. Glycogen synthase kinase 3- and extracellular signal-regulated kinase-dependent phosphorylation of paxillin regulates cytoskeletal rearrangement[J]. Mol Cell Biol, 2006, 26(7):2857-2868.
42	Wortzel I, Seger R. The ERK Cascade: distinct functions within various subcellular organelles[J]. Genes Cancer, 2011, 2(3):195-209.
43	Eblen ST. Extracellular-Regulated Kinases: signaling from ras to erk substrates to control biological outcomes[J]. Adv Cancer Res, 2018, 138:99-142.
44	Aoidi R, Maltais A, Charron J. Functional redundancy of the kinases MEK1 and MEK2: Rescue of the Mek1 mutant phenotype by Mek2 knock-in reveals a protein threshold effect[J]. Sci Signal, 2016, 9(412):ra9.
45	Plotnikov A, Zehorai E, Procaccia S, et al. The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation[J]. Biochim Biophys Acta, 2011, 1813(9):1619-1633.
46	Dvorak P, Hampl A. Basic fibroblast growth factor and its receptors in human embryonic stem cells[J]. Folia Histochem Cytobiol, 2005, 43(4):203-208.
47	Amit M, Carpenter MK, Inokuma MS, et al. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture[J]. Dev Biol, 2000, 227(2):271-278.
48	Wang G, Zhang H, Zhao Y, et al. Noggin and bFGF cooperate to maintain the pluripotency of human embryonic stem cells in the absence of feeder layers[J]. Biochem Biophys Res Commun, 2005, 330(3):934-942.
49	Wang G, Zhang H, Zhao Y, et al. Noggin and bFGF cooperate to maintain the pluripotency of human embryonic stem cells in the absence of feeder layers[J]. Biochem Biophys Res Commun, 2005, 330(3):934-942.
50	Greber B, Lehrach H, Adjaye J. Fibroblast growth factor 2 modulates transforming growth factor beta signaling in mouse embryonic fibroblasts and human ESCs (hESCs) to support hESC self-renewal[J]. Stem Cells, 2007, 25(2):455-464.
51	Bendall SC, Stewart MH, Menendez P, et al. IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro[J]. Nature, 2007, 448(7157):1015-1021.
52	Haghighi F, Dahlmann J, Nakhaei-Rad S, et al. bFGF-mediated pluripotency maintenance in human induced pluripotent stem cells is associated with NRAS-MAPK signaling[J]. Cell Commun Signal, 2018, 16(1):96. doi: 10.1186/s12964-018-0307-1.
53	Ding VM, Boersema PJ, Foong LY, et al. Tyrosine phosphorylation profiling in FGF-2 stimulated human embryonic stem cells[J]. PLoS One, 2011, 6(3):e17538.doi: 10.1371/journal.pone.0017538.
54	Sudheer S, Bhushan R, Fauler B, et al. FGF inhibition directs BMP4-mediated differentiation of human embryonic stem cells to syncytiotrophoblast[J]. Stem Cells Dev, 2012, 21(16):2987-3000.
55	Levenstein ME, Ludwig TE, Xu RH, et al. Basic fibroblast growth factor support of human embryonic stem cell self-renewal[J]. Stem Cells, 2006, 24(3):568-574.
56	Brill LM, Xiong W, Lee KB, et al. Phosphoproteomic analysis of human embryonic stem cells[J]. Cell Stem Cell, 2009, 5(2):204-213.
57	Hawksworth OA, Coulthard LG, Taylor SM, et al. Brief report: complement C5a promotes human embryonic stem cell pluripotency in the absence of FGF2[J]. Stem Cells, 2015, 32(12):3278-3284. doi: 10.1002/stem.1801.
58	Dzobo K, Vogelsang M, Parker MI. Wnt/beta-catenin and MEK-ERK signaling are required for fibroblast-derived extracellular matrix-mediated endoderm differentiation of embryonic stem cells[J]. Stem Cell Rev, 2015, 11(5):761-773.
59	Bernardo AS, Faial T, Gardner L, et al. BRACHYURY and CDX2 mediate BMP-induced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineages[J]. Cell Stem Cell, 2011, 9(2):144-155.
60	Harding A, Cortez-Toledo E, Magner NL, et al. Highly Efficient Differentiation of Endothelial Cells from Pluripotent Stem Cells Requires the MAPK and the PI3K Pathways[J]. Stem Cells, 2017, 35(4):909-919.
61	Xin C,Zhu C, Jin Y, et al. Discovering the role of VEGF signaling pathway in mesendodermal induction of human embryonic stem cells[J]. Biochem Biophys Res Commun, 2021, 553:58-64.
62	Göke J, Chan YS, Yan J, et al. Genome-wide kinase-chromatin interactions reveal the regulatory network of ERK signaling in human embryonic stem cells[J]. Mol Cell, 2013, 50(6):844-855.
63	Greber B, Wu G, Bernemann C, et al. Conserved and divergent roles of FGF signaling in mouse epiblast stem cells and human embryonic stem cells[J]. Cell Stem Cell, 2010, 6(3):215-226.
64	Na J, Furue MK, Andrews PW. Inhibition of ERK1/2 prevents neural and mesendodermal differentiation and promotes human embryonic stem cell self-renewal[J]. Stem Cell Res, 2010, 5(2):157-169.
65	Das P, Ezashi T, Schulz LC, et al. Effects of fgf2 and oxygen in the bmp4-driven differentiation of trophoblast from human embryonic stem cells[J]. Stem Cell Res, 2007, 1(1):61-74.
66	Yu P, Pan G, Yu J, et al. FGF2 sustains NANOG and switches the outcome of BMP4-induced human embryonic stem cell differentiation[J]. Cell Stem Cell, 2011, 8(3):326-334.
67	Kretzschmar M, Doody J, Massagué J. Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1[J]. Nature, 1997, 389(6651):618-622.
68	Luo K. Signaling Cross Talk between TGF-beta/Smad and other signaling pathways[J]. Cold Spring Harb Perspect Biol, 2017, 9(1):a022137. doi: 10.1101/cshperspect.a022137.
69	Ozair MZ, Noggle S, Warmflash A, et al. SMAD7 directly converts human embryonic stem cells to telencephalic fate by a default mechanism[J]. Stem Cells, 2013, 31(1):35-47.
70	Mossahebi-Mohammadi M, Quan M, Zhang JS, et al. FGF signaling pathway: A key regulator of stem cell pluripotency[J]. Front Cell Dev Biol, 2020, 8:79.doi: 10.3389/fcell.2020.00079.
71	Chen C, Zhang X, Wang Y, et al. Translational and post-translational control of human naïve versus primed pluripotency[J]. iScience, 2021, 25(1):103645.doi: 10.1016/j.isci.2021.103645.
72	Wang SH, Hao J, Zhang C, et al. KLF17 promotes human naive pluripotency through repressing MAPK3 and ZIC2[J]. Sci China Life Sci, 2022, 65(10):1985-1997.
73	Wang Y, Guo B, Xiao Z, et al. Long noncoding RNA CCDC144 NL-AS1 knockdown induces naive-like state conversion of human pluripotent stem cells[J]. Stem Cell Res Ther, 2019, 10(1):220.doi: 10.1186/s13287-019-1323-9.
74	Jiapaer Z, Li G, Ye D, et al. LincU preserves naive pluripotency by restricting ERK activity in embryonic stem cells[J]. Stem Cell Reports, 2018, 11(2):395-409.
75	An C, Feng G, Zhang J, et al. Overcoming autocrine FGF signaling-induced heterogeneity in naive human ESCs enables modeling of random X chromosome inactivation[J]. Cell Stem Cell, 2020, 27(3):482-97.e4.
76	Ficz G, Hore TA, Santos F, et al. FGF signaling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency[J]. Cell Stem Cell, 2013, 13(3):351-359.
77	Nakagawa M, Koyanagi M, Tanabe K, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts[J]. Nat Biotechnol, 2008,26(1):101-106.
78	Kim MO, Kim SH, Cho YY, et al. ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4[J]. Nat Struct Mol Biol, 2012, 19(3):283-290.
79	Li M, Izpisua Belmonte JC. Deconstructing the pluripotency gene regulatory network[J]. Nat Cell Biol, 2018, 20(4):382-392.
80	Choi J, Huebner AJ, Clement K, et al. Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells[J]. Nature, 2017, 548(7666):219-223.
81	Di Stefano B, Ueda M, Sabri S, et al. Reduced MEK inhibition preserves genomic stability in naive human embryonic stem cells[J]. Nat Methods, 2018, 15(9):732-740.
82	Keshet G, Benvenisty N. Large-scale analysis of imprinting in naive human pluripotent stem cells reveals recurrent aberrations and a potential link to FGF signaling[J]. Stem Cell Reports, 2021, 16(10):2520-2533.
83	Bayerl J, Ayyash M, Shani T, et al. Principles of signaling pathway modulation for enhancing human naive pluripotency induction[J]. Cell Stem Cell, 2021, 28(9):1549-1565.e12.
84	Lynch CJ, Bernad R, Martínez-Val A, et al. Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases[J]. Nat Cell Biol, 2020, 22(10):1223-1238.
85	Kalkan T, Bornelöv S, Mulas C, et al. Complementary activity of ETV5, RBPJ, and TCF3 drives formative transition from naive pluripotency[J]. Cell Stem Cell, 2019, 24(5):785-801.e7.

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Functions of the ERK signaling pathway in the regulation of pluripotency states of human pluripotent stem cells

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Functions of the ERK signaling pathway in the regulation of pluripotency states of human pluripotent stem cells