Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Review Article

A Revolution in Reprogramming: Small Molecules

Author(s): Jin Zhou and Jie Sun*

Volume 19, Issue 2, 2019

Page: [77 - 90] Pages: 14

DOI: 10.2174/1566524019666190325113945

Price: $65

Abstract

Transplantation of reprogrammed cells from accessible sources and in vivo reprogramming are potential therapies for regenerative medicine. During the last decade, genetic approaches, which mostly involved transcription factors and microRNAs, have been shown to affect cell fates. However, their potential carcinogenicity and other unexpected effects limit their translation into clinical applications. Recently, with the power of modern biology-oriented design and synthetic chemistry, as well as high-throughput screening technology, small molecules have been shown to enhance reprogramming efficiency, replace genetic factors, and help elucidate the molecular mechanisms underlying cellular plasticity and degenerative diseases. As a non-viral and non-integrating approach, small molecules not only show revolutionary capacities in generating desired exogenous cell types but also have potential as drugs that can restore tissues through repairing or reprogramming endogenous cells. Here, we focus on the recent progress made to use small molecules in cell reprogramming along with some related mechanisms to elucidate these issues.

Keywords: Small molecules, reprogramming, transdifferentiation, stem cells, regenerative medicine, chemical compounds.

« Previous
[1]
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126(4): 663-76.
[2]
Ieda M, Fu JD, Delgado-Olguin P, et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 2010; 142(3): 375-86.
[3]
Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010; 463(7284): 1035-41.
[4]
Huang P, He Z, Ji S, et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 2011; 475(7356): 386-9.
[5]
Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 2008; 455(7213): 627-32.
[6]
Jayawardena TM, Egemnazarov B, Finch EA, et al. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res 2012; 110(11): 1465-73.
[7]
Zhao Y, Londono P, Cao Y, et al. High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling Nat Commun.2 015; 6:8243.
[8]
Ladewig J, Mertens J, Kesavan J, et al. Small molecules enable highly efficient neuronal conversion of human fibroblasts. Nat Methods 2012; 9(6): 575-8.
[9]
Li X, Zuo X, Jing J, et al. Small-molecule-driven direct reprogramming of mouse fibroblasts into functional neurons. Cell Stem Cell 2015; 17(2): 195-203.
[10]
Park G, Yoon BS, Kim YS, et al. Conversion of mouse fibroblasts into cardiomyocyte-like cells using small molecule treatments. Biomaterials 2015; 54: 201-12.
[11]
Yuan Y, Hartland K, Boskovic Z, et al. A small-molecule inducer of PDX1 expression identified by high-throughput screening. Chem Biol 2013; 20(12): 1513-22.
[12]
Macielag MJ. Chemical Properties of Antimicrobials and Their Uniqueness. In: Dougherty TJ, Pucci MJ, editors.Antibiotic Discovery and Development. Boston, MA: Springer US. 2012; pp. 793-820.
[13]
Hou P, Li Y, Zhang X, et al. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 2013; 341(6146): 651-4.
[14]
Ye J, Ge J, Zhang X, et al. Pluripotent stem cells induced from mouse neural stem cells and small intestinal epithelial cells by small molecule compounds. Cell Res 2016; 26: 34-45.
[15]
Li W, Ding S. Small molecules that modulate embryonic stem cell fate and somatic cell reprogramming. Trends Pharmacol Sci 2010; 31: 36-45.
[16]
Ichida JK, Blanchard J, Lam K, et al. A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell 2009; 5(5): 491-503.
[17]
Maherali N, Hochedlinger K. Tgfbeta signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc. Curr Biol 2009; 19(20): 1718-23.
[18]
Lim KT, Lee SC, Gao Y, et al. Small Molecules Facilitate Single Factor-Mediated Hepatic Reprogramming. Cell Reports 2016; 15(4): 814-29.
[19]
Samavarchi-Tehrani P, Golipour A, David L, et al. Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 2010; 7: 64-77.
[20]
Li R, Liang J, Ni S, et al. A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 2010; 7: 51-63.
[21]
Peinado H, Quintanilla M, Cano A. Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: Mechanisms for epithelial mesenchymal transitions. J Biol Chem 2003; 278(23): 21113-23.
[22]
Lin T, Ambasudhan R, Yuan X, et al. A chemical platform for improved induction of human iPSCs. Nat Methods 2009; 6(11): 805-8.
[23]
Li W, Zhou H, Abujarour R, et al. Generation of human-induced pluripotent stem cells in the absence of exogenous Sox2. Stem Cells 2009; 27(12): 2992-3000.
[24]
Ying QL, Wray J, Nichols J, et al. The ground state of embryonic stem cell self-renewal. Nature 2008; 453(7194): 519-23.
[25]
Qin H, Zhao A, Ma K, Fu X. Chemical conversion of human and mouse fibroblasts into motor neurons. Sci China Life Sci 2018; 61(10): 1151-67.
[26]
Meshorer E, Yellajoshula D, George E, Scambler PJ, Brown DT, Misteli T. Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev Cell 2006; 10: 105-16.
[27]
Meshorer E, Misteli T. Chromatin in pluripotent embryonic stem cells and differentiation. Nat Rev Mol Cell Biol 2006; 7(7): 540-6.
[28]
Li Y, Zhang Q, Yin X, Yang W, Du Y, Hou P, et al. Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Res 2011; 21(1): 196-204.
[29]
Mikkelsen TS, Hanna J, Zhang X, et al. Dissecting direct reprogramming through integrative genomic analysis. Nature 2008; 454(7200): 49-55.
[30]
Xu X, Duan S, Yi F, Ocampo A, Liu GH, Izpisua Belmonte JC. Mitochondrial regulation in pluripotent stem cells. Cell Metab 2013; 18(3): 325-32.
[31]
Zhu S, Li W, Zhou H, et al. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 2010; 7(6): 651-5.
[32]
Hindie V, Stroba A, Zhang H, et al. Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1. Nat Chem Biol 2009; 5(10): 758-64.
[33]
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metab 2008; 7(1): 11-20.
[34]
Kanda Y. Cardiac differentiation of human iPS cells: Nihon yakurigaku zasshi Folia pharmacologica Japonica 2013; 141(1): 32-6.
[35]
Rasekhi M, Soleimani M, Bakhshandeh B, Sadeghizadeh M. A novel protocol to provide a suitable cardiac model from induced pluripotent stem cells. Biologicals 2017; 50: 42-8.
[36]
Marczenke M, Fell J, Piccini I, Ropke A, Seebohm G, Greber B. Generation and cardiac subtype-specific differentiation of PITX2-deficient human iPS cell lines for exploring familial atrial fibrillation. Stem Cell Res 2017; 21: 26-8.
[37]
McComish SF, Caldwell MA. Generation of defined neural populations from pluripotent stem cells. Philos Trans R Soc Lond B Biol Sci 2018: 373(1750).
[38]
Haller C, Chaskar P, Piccand J, et al. Insights into islet differentiation and maturation through proteomic characterization of a human ipsc-derived pancreatic endocrine model. Proteomics Clin Appl 2018; 12(5): e1600173.
[39]
Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131(5): 861-72.
[40]
Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science (New York, NY) 2007; 318(5858): 1917-20.
[41]
Huangfu D, Maehr R, Guo W, et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol 2008; 26(7): 795-7.
[42]
Huangfu D, Osafune K, Maehr R, et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 2008; 26(11): 1269-75.
[43]
Lyssiotis CA, Foreman RK, Staerk J, et al. Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4. Proc Natl Acad Sci USA 2009; 106(22): 8912-7.
[44]
Shi Y, Desponts C, Do JT, Hahm HS, Scholer HR, Ding S. Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 2008; 3(5): 568-74.
[45]
Yuan X, Wan H, Zhao X, Zhu S, Zhou Q, Ding S. Brief report: combined chemical treatment enables Oct4-induced reprogramming from mouse embryonic fibroblasts. Stem Cells (Dayton, Ohio) 2011; 29(3): 549-53.
[46]
Li Y, Zhang Q, Yin X, et al. Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Res 2011; 21: 196-204.
[47]
Li W, Tian E, Chen ZX, et al. Identification of oct4-activating compounds that enhance reprogramming efficiency. Proc Natl Acad Sci USA 2012; 109(51): 20853-8.
[48]
Zhao Y, Zhao T, Guan J, et al. A xen-like state bridges somatic cells to pluripotency during chemical reprogramming. Cell 2015; 163(7): 1678-91.
[49]
Zhou T, Benda C, Duzinger S, et al. Generation of induced pluripotent stem cells from urine. J Am Soc Nephrol 2011; 22(7): 1221-8.
[50]
Zhou T, Benda C, Dunzinger S, et al. Generation of human induced pluripotent stem cells from urine samples. Nat Protoc 2012; 7(12): 2080-9.
[51]
Xue Y, Cai X, Wang L, et al. Generating a non-integrating human induced pluripotent stem cell bank from urine-derived cells. PLoS One 2013; 8(8): e70573.
[52]
Li D, Wang L, Hou J, et al. Optimized approaches for generation of integration-free ipscs from human urine-derived cells with small molecules and autologous feeder. Stem Cell Reports 2016; 6(5): 717-28.
[53]
Mercola M, Ruiz-Lozano P, Schneider MD. Cardiac muscle regeneration: Lessons from development. Genes Dev 2011; 25(4): 299-309.
[54]
Wang H, Naghavi M, Allen C, et al. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet (London, England) 2016; 388(10053): 1459-544.
[55]
Qian L, Huang Y, Spencer CI, et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 2012; 485(7400): 593-8.
[56]
Song K, Nam YJ, Luo X, et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 2012; 485(7400): 599-604.
[57]
Zhou Y, Wang L, Vaseghi HR, et al. Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming. Cell Stem Cell 2016; 18(3): 382-95.
[58]
Fu JD, Stone NR, Liu L, et al. Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state. Stem Cell Reports 2013; 1(3): 235-47.
[59]
Wada R, Muraoka N, Inagawa K, et al. Induction of human cardiomyocyte-like cells from fibroblasts by defined factors. Proc Natl Acad Sci USA 2013; 110(31): 12667-72.
[60]
Nam YJ, Song K, Luo X, et al. Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci USA 2013; 110(14): 5588-93.
[61]
Yamakawa H, Muraoka N, Miyamoto K, et al. Fibroblast growth factors and vascular endothelial growth factor promote cardiac reprogramming under defined conditions. Stem Cell Reports 2015; 5(6): 1128-42.
[62]
Wu X, Ding S, Ding Q, Gray NS, Schultz PG. Small molecules that induce cardiomyogenesis in embryonic stem cells. J Am Chem Soc 2004; 126(6): 1590-1.
[63]
Yau WW, Tang MK, Chen E, et al. Cardiogenol c can induce mouse hair bulge progenitor cells to transdifferentiate into cardiomyocyte-like cells. Proteome Sci 2011; 9(1): 3.
[64]
Wang H, Cao N, Spencer CI, et al. Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4. Cell Reports 2014; 6(5): 951-60.
[65]
Fu Y, Huang C, Xu X, et al. Direct reprogramming of mouse fibroblasts into cardiomyocytes with chemical cocktails. Cell Res 2015; 25(9): 1013-24.
[66]
Cao N, Huang Y, Zheng J, Spencer CI, Zhang Y, Fu JD, et al. Conversion of human fibroblasts into functional cardiomyocytes by small molecules. Science (New York,NY) 2016; 352(6290): 1216-20.
[67]
Porter KE, Turner NA. Cardiac fibroblasts: At the heart of myocardial remodeling. Pharmacol Ther 2009; 123(2): 255-78.
[68]
Wapinski OL, Vierbuchen T, Qu K, et al. Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell 2013; 155(3): 621-35.
[69]
Pang ZP, Yang N, Vierbuchen T, et al. Induction of human neuronal cells by defined transcription factors. Nature 2011; 476(7359): 220-3.
[70]
Ambasudhan R, Talantova M, Coleman R, et al. Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 2011; 9(2): 113-8.
[71]
Yoo AS, Sun AX, Li L, et al. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 2011; 476(7359): 228-31.
[72]
Liu ML, Zang T, Zou Y, et al. Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons. Nat Commun 2013; 4: 2183.
[73]
Hu W, Qiu B, Guan W, et al. Direct conversion of normal and alzheimer’s disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell 2015; 17(2): 204-12.
[74]
Caiazzo M, Dell’Anno MT, Dvoretskova E, et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 2011; 476(7359): 224-7.
[75]
Pfisterer U, Kirkeby A, Torper O, et al. Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci USA 2011; 108(25): 10343-8.
[76]
Son EY, Ichida JK, Wainger BJ, et al. Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 2011; 9(3): 205-18.
[77]
Wang Y, Yang H, Yang Q, et al. Chemical conversion of mouse fibroblasts into functional dopaminergic neurons. Exp Cell Res 2016; 347(2): 283-92.
[78]
Cheng L, Gao L, Guan W, et al. Direct conversion of astrocytes into neuronal cells by drug cocktail. Cell Res 2015; 25(11): 1269-72.
[79]
Molofsky AV, Krencik R, Ullian EM, et al. Astrocytes and disease: A neurodevelopmental perspective. Genes Dev 2012; 26(9): 891-907.
[80]
Heinrich C, Gascon S, Masserdotti G, et al. Generation of subtype-specific neurons from postnatal astroglia of the mouse cerebral cortex. Nat Protoc 2011; 6(2): 214-28.
[81]
Zhang L, Yin JC, Yeh H, et al. Small molecules efficiently reprogram human astroglial cells into functional neurons. Cell Stem Cell 2015; 17(6): 735-47.
[82]
Gao L, Guan W, Wang M, et al. Direct generation of human neuronal cells from adult astrocytes by small molecules. Stem Cell Reports 2017; 8(3): 538-47.
[83]
Rivetti di Val Cervo P, Romanov RA, Spigolon G, Masini D, Martin-Montanez E, Toledo EM. Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a parkinson’s disease model. Nat Biotechnol 2017; 35(5): 444-52.
[84]
Lee J, Sugiyama T, Liu Y, et al. Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells. eLife 2013; 2: e00940.
[85]
Farney AC, Sutherland DE, Opara EC. Evolution of islet transplantation for the last 30 years. Pancreas 2016; 45(1): 8-20.
[86]
Banga A, Akinci E, Greder LV, Dutton JR, Slack JM. In vivo reprogramming of Sox9+ cells in the liver to insulin-secreting ducts. Proc Natl Acad Sci USA 2012; 109(38): 15336-41.
[87]
Gu G, Dubauskaite J, Melton DA. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development (Cambridge,England) 2002; 129(10): 2447-57.
[88]
Li W, Cavelti-Weder C, Zhang Y, et al. Long-term persistence and development of induced pancreatic beta cells generated by lineage conversion of acinar cells. Nat Biotechnol 2014; 32(12): 1223-30.
[89]
Chen YJ, Finkbeiner SR, Weinblatt D, et al. De novo formation of insulin-producing “neo-beta cell islets” from intestinal crypts. Cell Reports 2014; 6(6): 1046-58.
[90]
Ariyachet C, Tovaglieri A, Xiang G, et al. Reprogrammed stomach tissue as a renewable source of functional beta cells for blood glucose regulation. Cell Stem Cell 2016; 18(3): 410-21.
[91]
Li W, Nakanishi M, Zumsteg A, et al. In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes. eLife 2014; 3: e01846.
[92]
Courtney M, Gjernes E, Druelle N, et al. The inactivation of arx in pancreatic alpha-cells triggers their neogenesis and conversion into functional beta-like cells. PLoS Genet 2013; 9(10): e1003934.
[93]
Minami K, Okuno M, Miyawaki K, et al. Lineage tracing and characterization of insulin-secreting cells generated from adult pancreatic acinar cells. Proc Natl Acad Sci USA 2005; 102(42): 15116-21.
[94]
Baeyens L, Lemper M, Leuckx G, et al. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat Biotechnol 2014; 32(1): 76-83.
[95]
Lefebvre B, Belaich S, Longue J, et al. 5′-AZA induces Ngn3 expression and endocrine differentiation in the PANC-1 human ductal cell line. Biochem Biophys Res Commun 2010; 391(1): 305-9.
[96]
Fomina-Yadlin D, Kubicek S, Walpita D, et al. Small-molecule inducers of insulin expression in pancreatic alpha-cells. Proc Natl Acad Sci USA 2010; 107(34): 15099-104.
[97]
Li J, Casteels T, Frogne T, et al. Artemisinins target gabaa receptor signaling and impair alpha cell identity. Cell 2017; 168(1-2): 86-100.e15.
[98]
Chen S, Borowiak M, Fox JL, et al. A small molecule that directs differentiation of human escs into the pancreatic lineage. Nat Chem Biol 2009; 5(4): 258-65.
[99]
Li K, Zhu S, Russ HA, et al. Small molecules facilitate the reprogramming of mouse fibroblasts into pancreatic lineages. Cell Stem Cell 2014; 14(2): 228-36.
[100]
Zhu S, Russ HA, Wang X, et al. Human pancreatic beta-like cells converted from fibroblasts. Nat Commun 2016; 7: 10080.
[101]
Okita K, Matsumura Y, Sato Y, et al. A more efficient method to generate integration-free human iPS cells. Nat Methods 2011; 8(5): 409-12.
[102]
Amatori S, Bagaloni I, Donati B, Fanelli M. DNA demethylating antineoplastic strategies: A comparative point of view. Genes Cancer 2010; 1(3): 197-209.
[103]
Schirrmacher E, Beck C, Brueckner B, et al. Synthesis and in vitro evaluation of biotinylated RG108: A high affinity compound for studying binding interactions with human DNA methyltransferases. Bioconjug Chem 2006; 17(2): 261-6.
[104]
Brayton CF. Dimethyl sulfoxide (DMSO):A review. Cornell Vet 1986; 76(1): 61-90.
[105]
Ferk P, Daris B. The influence of dimethyl sulfoxide (DMSO) on metabolic activity and morphology of melanoma cell line WM-266-4. Cell Mol Biol (Noisy-le-grand) 2018; 64(11): 41-3.
[106]
Hebling J, Bianchi L, Basso FG, et al. Cytotoxicity of dimethyl sulfoxide (DMSO) in direct contact with odontoblast-like cells. Dent Mater 2015; 31(4): 399-405.
[107]
Majdi S, Najafinobar N, Dunevall J, Lovric J, Ewing AG. DMSO chemically alters cell membranes to slow exocytosis and increase the fraction of partial transmitter released. A European journal of Chembiochem. 2017; 18(19): 1898-902.
[108]
Tsai HJ, Chou SY. A novel hydroxyfuroic acid compound as an insulin receptor activator. Structure and activity relationship of a prenylindole moiety to insulin receptor activation. J Biomed Sci 2009; 16: 68.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy