Abstract
During embryogenesis and further development, mammalian epigenome undergoes global remodeling, which leads to the emergence of multiple fate-restricted cell lines as well as to their further differentiation into different specialized cell types. There are multiple lines of evidence suggesting that all these processes are mainly controlled by epigenetic mechanisms such as DNA methylation, histone covalent modifications, and the regulation of ATP-dependent remolding of chromatin structure. Based on the histone code hypothesis, distinct chromatin covalent modifications can lead to functionally distinct chromatin structures and thus distinctive gene expression that determine the fate of the cells. A large amount of recently accumulated data showed that small molecule biologically active compounds that involved in the regulation of chromatin structure and function in discriminative signaling environments can promote changes in cells fate. These data suggest that agents that involved in the regulation of chromatin modifying enzymes combined with factors that modulate specific cell signaling pathways could be effective tools for cell reprogramming. The goal of this review is to gather the most relevant and most recent literature that supports this proposition.
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References
Gurdon JB (1962) The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol 10:622–640
Briggs R, King TJ (1952) Transplantation of living nuclei from blastula cells into enucleated frogs’ eggs. Proc Natl Acad Sci USA 38:455–463
Tada M, Takahama Y, Abe K, Nakatsuji N, Tada T (2001) Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr Biol 11:1553–1558
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920
Kim JB, Sebastiano V, Wu G, Arauzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D, Meyer J, Hubner K, Bernemann C, Ortmeier C, Zenke M, Fleischmann BK, Zaehres H, Scholer HR (2009) Oct4-induced pluripotency in adult neural stem cells. Cell 136:411–419. https://doi.org/10.1016/j.cell.2009.01.023
Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, Muhlestein W, Melton DA (2008) Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 26:1269–1275. https://doi.org/10.1038/nbt.1502
Wang LL, Serrano C, Zhong X, Ma S, Zou Y, Zhang CL (2021) Revisiting astrocyte to neuron conversion with lineage tracing in vivo. Cell 184(5465–5481):e16. https://doi.org/10.1016/j.cell.2021.09.005
Tai W, Wu W, Wang LL, Ni H, Chen C, Yang J, Zang T, Zou Y, Xu XM, Zhang CL (2021) In vivo reprogramming of NG2 glia enables adult neurogenesis and functional recovery following spinal cord injury. Cell Stem Cell 28(923–937):e4. https://doi.org/10.1016/j.stem.2021.02.009
Liu ML, Zang T, Zhang CL (2016) Direct lineage reprogramming reveals disease-specific phenotypes of motor neurons from human ALS patients. Cell Rep 14:115–128. https://doi.org/10.1016/j.celrep.2015.12.018
Wang LL, Su Z, Tai W, Zou Y, Xu XM, Zhang CL (2016) The p53 pathway controls SOX2-mediated reprogramming in the adult mouse spinal cord. Cell Rep 17:891–903. https://doi.org/10.1016/j.celrep.2016.09.038
Niu W, Zang T, Zou Y, Fang S, Smith DK, Bachoo R, Zhang CL (2013) In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nat Cell Biol 15:1164–1175. https://doi.org/10.1038/ncb2843
Liu ML, Zang T, Zou Y, Chang JC, Gibson JR, Huber KM, Zhang CL (2013) Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons. Nat Commun 4:2183. https://doi.org/10.1038/ncomms3183
Xu Y, Zhang M, Li W, Zhu X, Bao X, Qin B, Hutchins AP, Esteban MA (2016) Transcriptional control of somatic cell reprogramming. Trends Cell Biol 26:272–288. https://doi.org/10.1016/j.tcb.2015.12.003
Ghazizadeh Z, Rassouli H, Fonoudi H, Alikhani M, Talkhabi M, Darbandi-Azar A, Chen S, Baharvand H, Aghdami N, Salekdeh GH (2017) Transient activation of reprogramming transcription factors using protein transduction facilitates conversion of human fibroblasts toward cardiomyocyte-like cells. Mol Biotechnol 59:207–220. https://doi.org/10.1007/s12033-017-0007-x
Colasante G, Rubio A, Massimino L, Broccoli V (2019) Direct neuronal reprogramming reveals unknown functions for known transcription factors. Front Neurosci 13:283. https://doi.org/10.3389/fnins.2019.00283
Xiao D, Liu X, Zhang M, Zou M, Deng Q, Sun D, Bian X, Cai Y, Guo Y, Liu S, Li S, Shiang E, Zhong H, Cheng L, Xu H, Jin K, Xiang M (2018) Direct reprogramming of fibroblasts into neural stem cells by single non-neural progenitor transcription factor Ptf1a. Nat Commun 9:2865. https://doi.org/10.1038/s41467-018-05209-1
Rombaut M, Boeckmans J, Rodrigues RM, van Grunsven LA, Vanhaecke T, De Kock J (2021) Direct reprogramming of somatic cells into induced hepatocytes: cracking the Enigma code. J Hepatol 75:690–705. https://doi.org/10.1016/j.jhep.2021.04.048
Razi Soofiyani S, Baradaran B, Lotfipour F, Kazemi T, Mohammadnejad L (2013) Gene therapy, early promises, subsequent problems, and recent breakthroughs. Adv Pharm Bull 3:249–255. https://doi.org/10.5681/apb.2013.041
Wang H, Yang Y, Liu J, Qian L (2021) Direct cell reprogramming: approaches, mechanisms and progress. Nat Rev Mol Cell Biol 22:410–424. https://doi.org/10.1038/s41580-021-00335-z
Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, Zhao T, Ye J, Yang W, Liu K, Ge J, Xu J, Zhang Q, Zhao Y, Deng H (2013) Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 341:651–654. https://doi.org/10.1126/science.1239278
Huangfu D, Maehr R, Guo W, Eijkelenboom A, Snitow M, Chen AE, Melton DA (2008) Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol 26:795–797. https://doi.org/10.1038/nbt1418
Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T, Trauger S, Bien G, Yao S, Zhu Y, Siuzdak G, Scholer HR, Duan L, Ding S (2009) Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4:381–384. https://doi.org/10.1016/j.stem.2009.04.005
Teng HF, Kuo YL, Loo MR, Li CL, Chu TW, Suo H, Liu HS, Lin KH, Chen SL (2010) Valproic acid enhances Oct4 promoter activity in myogenic cells. J Cell Biochem 110:995–1004. https://doi.org/10.1002/jcb.22613
Mao T, Han C, Deng R, Wei B, Meng P, Luo Y, Zhang Y (2018) Treating donor cells with 2-PCPA corrects aberrant histone H3K4 dimethylation and improves cloned goat embryo development. Syst Biol Reprod Med 64:174–182. https://doi.org/10.1080/19396368.2018.1446229
Sun H, Liang L, Li Y, Feng C, Li L, Zhang Y, He S, Pei D, Guo Y, Zheng H (2016) Lysine-specific histone demethylase 1 inhibition promotes reprogramming by facilitating the expression of exogenous transcriptional factors and metabolic switch. Sci Rep 6:30903. https://doi.org/10.1038/srep30903
Azghadi S, Clark AT (2011) Epigenetically reprogramming of human embryonic stem cells by 3-deazaneplanocin a and sodium butyrate. Int J Prev Med 2:73–78
Mali P, Chou BK, Yen J, Ye Z, Zou J, Dowey S, Brodsky RA, Ohm JE, Yu W, Baylin SB, Yusa K, Bradley A, Meyers DJ, Mukherjee C, Cole PA, Cheng L (2010) Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells 28:713–720. https://doi.org/10.1002/stem.402
Liang G, Taranova O, Xia K, Zhang Y (2010) Butyrate promotes induced pluripotent stem cell generation. J Biol Chem 285:25516–25521. https://doi.org/10.1074/jbc.M110.142059
Kishigami S, Bui HT, Wakayama S, Tokunaga K, Van Thuan N, Hikichi T, Mizutani E, Ohta H, Suetsugu R, Sata T, Wakayama T (2007) Successful mouse cloning of an outbred strain by trichostatin A treatment after somatic nuclear transfer. J Reprod Dev 53:165–170
Zhao J, Hao Y, Ross JW, Spate LD, Walters EM, Samuel MS, Rieke A, Murphy CN, Prather RS (2010) Histone deacetylase inhibitors improve in vitro and in vivo developmental competence of somatic cell nuclear transfer porcine embryos. Cell Reprogram 12:75–83. https://doi.org/10.1089/cell.2009.0038
Li X, Zuo X, Jing J, Ma Y, Wang J, Liu D, Zhu J, Du X, Xiong L, Du Y, Xu J, Xiao X, Wang J, Chai Z, Zhao Y, Deng H (2015) Small-molecule-driven direct reprogramming of mouse fibroblasts into functional neurons. Cell Stem Cell 17:195–203. https://doi.org/10.1016/j.stem.2015.06.003
Long Y, Wang M, Gu H, Xie X (2015) Bromodeoxyuridine promotes full-chemical induction of mouse pluripotent stem cells. Cell Res 25:1171–1174. https://doi.org/10.1038/cr.2015.96
Ye J, Ge J, Zhang X, Cheng L, Zhang Z, He S, Wang Y, Lin H, Yang W, Liu J, Zhao Y, Deng H (2016) Pluripotent stem cells induced from mouse neural stem cells and small intestinal epithelial cells by small molecule compounds. Cell Res 26:34–45. https://doi.org/10.1038/cr.2015.142
Cheng L, Hu W, Qiu B, Zhao J, Yu Y, Guan W, Wang M, Yang W, Pei G (2014) Generation of neural progenitor cells by chemical cocktails and hypoxia. Cell Res 24:665–679. https://doi.org/10.1038/cr.2014.32
Zhang M, Lin YH, Sun YJ, Zhu S, Zheng J, Liu K, Cao N, Li K, Huang Y, Ding S (2016) Pharmacological reprogramming of fibroblasts into neural stem cells by signaling-directed transcriptional activation. Cell Stem Cell 18:653–667. https://doi.org/10.1016/j.stem.2016.03.020
Hu W, Qiu B, Guan W, Wang Q, Wang M, Li W, Gao L, Shen L, Huang Y, Xie G, Zhao H, Jin Y, Tang B, Yu Y, Zhao J, Pei G (2015) Direct conversion of normal and Alzheimer’s disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell 17:204–212. https://doi.org/10.1016/j.stem.2015.07.006
Zhang L, Yin JC, Yeh H, Ma NX, Lee G, Chen XA, Wang Y, Lin L, Chen L, Jin P, Wu GY, Chen G (2015) Small molecules efficiently reprogram human astroglial cells into functional neurons. Cell Stem Cell 17:735–747. https://doi.org/10.1016/j.stem.2015.09.012
Fu Y, Huang C, Xu X, Gu H, Ye Y, Jiang C, Qiu Z, Xie X (2015) Direct reprogramming of mouse fibroblasts into cardiomyocytes with chemical cocktails. Cell Res 25:1013–1024. https://doi.org/10.1038/cr.2015.99
Cao N, Huang Y, Zheng J, Spencer CI, Zhang Y, Fu JD, Nie B, Xie M, Zhang M, Wang H, Ma T, Xu T, Shi G, Srivastava D, Ding S (2016) Conversion of human fibroblasts into functional cardiomyocytes by small molecules. Science 352:1216–1220. https://doi.org/10.1126/science.aaf1502
Katsuda T, Kawamata M, Hagiwara K, Takahashi RU, Yamamoto Y, Camargo FD, Ochiya T (2017) Conversion of terminally committed hepatocytes to culturable bipotent progenitor cells with regenerative capacity. Cell Stem Cell 20:41–55. https://doi.org/10.1016/j.stem.2016.10.007
Ichida JK, Blanchard J, Lam K, Son EY, Chung JE, Egli D, Loh KM, Carter AC, Di Giorgio FP, Koszka K, Huangfu D, Akutsu H, Liu DR, Rubin LL, Eggan K (2009) A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell 5:491–503. https://doi.org/10.1016/j.stem.2009.09.012
Ma X, Kong L, Zhu S (2017) Reprogramming cell fates by small molecules. Protein Cell 8:328–348. https://doi.org/10.1007/s13238-016-0362-6
Xie X, Fu Y, Liu J (2017) Chemical reprogramming and transdifferentiation. Curr Opin Genet Dev 46:104–113. https://doi.org/10.1016/j.gde.2017.07.003
Alexanian AR (2010) An efficient method for generation of neural-like cells from adult human bone marrow-derived mesenchymal stem cells. Regen Med 5:891–900
Zhang Z, Maiman DJ, Kurpad SN, Crowe MJ, Alexanian AR (2011) Feline bone marrow-derived mesenchymal stem cells express several pluripotent and neural markers and easily turn into neural-like cells by manipulation with chromatin modifying agents and neural inducing factors. Cell Reprogram 13:385–390. https://doi.org/10.1089/cell.2011.0007
Zhang Z, Alexanian AR (2012) Dopaminergic-like cells from epigenetically reprogrammed mesenchymal stem cells. J Cell Mol Med 16:2708–2714. https://doi.org/10.1111/j.1582-4934.2012.01591.x
Alexanian AR, Liu QS, Zhang Z (2013) Enhancing the efficiency of direct reprogramming of human mesenchymal stem cells into mature neuronal-like cells with the combination of small molecule modulators of chromatin modifying enzymes, SMAD signaling and cyclic adenosine monophosphate levels. Int J Biochem Cell Biol 45:1633–1638. https://doi.org/10.1016/j.biocel.2013.04.022
Funk RT, Alexanian AR (2013) Enhanced dopamine release by mesenchymal stem cells reprogrammed neuronally by the modulators of SMAD signaling, chromatin modifying enzymes, and cyclic adenosine monophosphate levels. Transl Res 162:317–323. https://doi.org/10.1016/j.trsl.2013.08.002
Wan XY, Xu LY, Li B, Sun QH, Ji QL, Huang DD, Zhao L, Xiao YT (2018) Chemical conversion of human lung fibroblasts into neuronal cells. Int J Mol Med 41:1463–1468. https://doi.org/10.3892/ijmm.2018.3375
Thoma EC, Merkl C, Heckel T, Haab R, Knoflach F, Nowaczyk C, Flint N, Jagasia R, Jensen Zoffmann S, Truong HH, Petitjean P, Jessberger S, Graf M, Iacone R (2014) Chemical conversion of human fibroblasts into functional Schwann cells. Stem cell reports 3:539–547. https://doi.org/10.1016/j.stemcr.2014.07.014
Pennarossa G, Maffei S, Campagnol M, Tarantini L, Gandolfi F, Brevini TA (2013) Brief demethylation step allows the conversion of adult human skin fibroblasts into insulin-secreting cells. Proc Natl Acad Sci USA 110:8948–8953. https://doi.org/10.1073/pnas.1220637110
Tian E, Sun G, Chao J, Ye P, Warden C, Riggs AD, Shi Y (2016) Small-molecule-based lineage reprogramming creates functional astrocytes. Cell Rep 16:781–792. https://doi.org/10.1016/j.celrep.2016.06.042
Bansal V, De D, An J, Kang TM, Jeong HJ, Kang JS, Kim KK (2019) Chemical induced conversion of mouse fibroblasts and human adipose-derived stem cells into skeletal muscle-like cells. Biomaterials 193:30–46. https://doi.org/10.1016/j.biomaterials.2018.11.037
Ye D, Li T, Heraud P, Parnpai R (2016) Effect of chromatin-remodeling agents in hepatic differentiation of rat bone marrow-derived mesenchymal stem cells in vitro and in vivo. Stem Cells Int 2016:3038764. https://doi.org/10.1155/2016/3038764
Liu J, Liu Y, Wang H, Hao H, Han Q, Shen J, Shi J, Li C, Mu Y, Han W (2013) Direct differentiation of hepatic stem-like WB cells into insulin-producing cells using small molecules. Sci Rep 3:1185. https://doi.org/10.1038/srep01185
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Alexanian, A.R. Combination of the modulators of epigenetic machinery and specific cell signaling pathways as a promising approach for cell reprogramming. Mol Cell Biochem 477, 2309–2317 (2022). https://doi.org/10.1007/s11010-022-04442-z
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DOI: https://doi.org/10.1007/s11010-022-04442-z