Abstract
The use of stem cells in regenerative medicine is a promising approach to the treatment of disease and injury. Natural and synthetic small molecules have been shown to be useful chemical tools for controlling and manipulating the fates of cells. Small molecules can target signaling transduction pathways (for example, tyrosine kinase receptors) and affect DNA replication, cell differentiation, tumor metastasis and apoptosis. Stem cells share many properties with cancer cells and these similarities can provide insights to control and direct cell behavior; small molecules are already standard chemotherapeutics in the treatment of cancer. Libraries of small molecules have been examined for anticancer behavior (especially apoptosis), and, more recently, for stem cell self-renewal and differentiation capabilities in potential approaches to regenerative medicine. Differentiation therapy for cancer is based on the idea that cancer cells are undifferentiated embryonic-like cells and proposes to promote the differentiation and hence block cell proliferation. For example, retinoids have a role in stem cell differentiation to several lineages and have also been used to promote differentiation of acute promyeloic leukemic cells. Small molecules are also important tools for understanding mechanistic and developmental processes. Strategies for generating functional small molecule libraries have been outlined previously. In this review, we will look at several small molecules that have been described in the recent literature as effectors of stem cell self-renewal or differentiation as associated with the Wnt, Hedgehog or NF-κB pathways.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Emre N, Coleman R, Ding S . A chemical approach to stem cell biology. Curr Opin Chem Biol 2007; 11: 252–258.
Longo FM, Yang T, Xie Y, Massa SM . Small molecule approaches for promoting neurogenesis. Curr Alzheimer Res 2006; 3: 5–10.
Tutter AV, Baltus GA, Kadam S . Embryonic stem cells: a great hope for a new era of medicine. Curr Opin Drug Discov Dev 2006; 9: 169–175.
Prockop DJ, Olson SD . Clinical trials with adult stem/progenitor cells for tissue repair: let's not overlook some essential precautions. Blood 2007; 109: 3147–3151.
Dor Y, Melton DA . How important are adult stem cells for tissue maintenance? Cell Cycle 2004; 3: 1104–1106.
Ying Q-L, Nichols J, Chambers I, Smith A . BMP induction of id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 2003; 115: 281–292.
Qi X, Li TG, Hao J, Hu J, Wang J, Simmons H et al. BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways. Proc Natl Acad Sci USA 2004; 101: 6027–6032.
Sell S . Cancer stem cells and differentiation therapy. Tumour Biol 2006; 27: 59–70.
Sell S . Leukemia: stem cells, maturation arrest, and differentiation therapy. Stem Cell Rev 2005; 1: 197–205.
Jones PA . Altering gene expression with 5-azacytidine. Cell 1985; 40: 485–486.
Taylor SM, Jones PA . Multiple new phenotypes induced in 10T1/2 and 3T3 cells treated with 5-azacytidine. Cell 1979; 17: 771–779.
Chiu CP, Blau HM . 5-Azacytidine permits gene activation in a previously noninducible cell type. Cell 1985; 40: 417–424.
Choi SC, Yoon J, Shim WJ, Ro YM, Lim DS . 5-azacytidine induces cardiac differentiation of P19 embryonic stem cells. Exp Mol Med 2004; 36: 515–523.
Konieczny SF, Emerson Jr CP . 5-Azacytidine induction of stable mesodermal stem cell lineages from 10T1/2 cells: evidence for regulatory genes controlling determination. Cell 1984; 38: 791–800.
Enjoji M, Nakashima M, Honda M, Sakai H, Nawata H . Hepatocytic phenotypes induced in sarcomatous cholangiocarcinoma cells treated with 5-azacytidine. Hepatology 1997; 26: 288–294.
Darmon M, Nicolas JF, Lamblin D . 5-Azacytidine is able to induce the conversion of teratocarcinoma-derived mesenchymal cells into epithelia cells. EMBO J 1984; 3: 961–967.
Lassar AB, Paterson BM, Weintraub H . Transfection of a DNA locus that mediates the conversion of 10T1/2 fibroblasts to myoblasts. Cell 1986; 47: 649–656.
McNeish JD . Stem cells as screening tools in drug discovery. Curr Opin Pharmacol 2007; 4: 4.
Chen S, Hilcove S, Ding S . Exploring stem cell biology with small molecules. Mol Biosyst 2006; 2: 18–24.
Ding S, Schultz PG . A role for chemistry in stem cell biology. Nat Biotechnol 2004; 22: 833–840.
Ding S, Schultz PG . Small molecules and future regenerative medicine. Curr Top Med Chem 2005; 5: 383–395.
Ding S, Wu TY, Brinker A, Peters EC, Hur W, Gray NS et al. Synthetic small molecules that control stem cell fate. Proc Natl Acad Sci USA 2003; 100: 7632–7637.
Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH . Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 2004; 10: 55–63.
Naito AT, Shiojima I, Akazawa H, Hidaka K, Morisaki T, Kikuchi A et al. Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis. Proc Natl Acad Sci USA 2006; 103: 19812–19817.
Tseng AS, Engel FB, Keating MT . The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes. Chem Biol 2006; 13: 957–963.
Reinhold MI, Kapadia RM, Liao Z, Naski MC . The Wnt-inducible transcription factor Twist1 inhibits chondrogenesis. J Biol Chem 2006; 281: 1381–1388.
Chen JK, Taipale J, Cooper MK, Beachy PA . Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 2002; 16: 2743–2748.
Wu X, Walker J, Zhang J, Ding S, Schultz PG . Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway. Chem Biol 2004; 11: 1229–1238.
Pevsner-Fischer M, Morad V, Cohen-Sfady M, Rousso-Noori L, Zanin-Zhorov A, Cohen S et al. Toll-like receptors and their ligands control mesenchymal stem cell functions. Blood 2007; 109: 1422–1432.
Habens F, Srinivasan N, Oakley F, Mann DA, Ganesan A, Packham G . Novel sulfasalazine analogues with enhanced NF-kB inhibitory and apoptosis promoting activity. Apoptosis 2005; 10: 481–491.
Daheron L, Opitz SL, Zaehres H, Lensch WM, Andrews PW, Itskovitz-Eldor J et al. LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells 2004; 22: 770–778.
Xu C, Inokuma MS, Denham J, Golds K, Kundu P, Gold JD et al. Feeder-free growth of undifferentiated human embryonic stem cells. Nat Biotech 2001; 19: 971–974.
Miyabayashi T, Teo JL, Yamamoto M, McMillan M, Nguyen C, Kahn M . Wnt/beta-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency. Proc Natl Acad Sci USA 2007; 104: 5668–5673.
Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP et al. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 1988; 336: 684–687.
He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT et al. Identification of c-MYC as a target of the APC pathway. Science 1998; 281: 1509–1512.
Gradl D, Kuhl M, Wedlich D . The Wnt/Wg signal transducer beta-catenin controls fibronectin expression. Mol Cell Biol 1999; 19: 5576–5587.
Tetsu O, McCormick F . [beta]-Catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999; 398: 422–426.
Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003; 423: 409–414.
Meijer L, Skaltsounis AL, Magiatis P, Polychronopoulos P, Knockaert M, Leost M et al. GSK-3-selective inhibitors derived from Tyrian purple indirubins. Chem Biol 2003; 10: 1255–1266.
Gupta S, Zhu H, Zon LI, Evans T . BMP signaling restricts hemato-vascular development from lateral mesoderm during somitogenesis. Development 2006; 133: 2177–2187.
Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang R, Zhang Z et al. Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev 2004; 18: 1072–1087.
Lefebvre V, Huang W, Harley VR, Goodfellow PN, de Crombrugghe B . SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene. Mol Cell Biol 1997; 17: 2336–2346.
Bell DM, Leung KK, Wheatley SC, Ng LJ, Zhou S, Ling KW et al. SOX9 directly regulates the type-II collagen gene. Nat Genet 1997; 16: 174–178.
Aubert J, Dunstan H, Chambers I, Smith A . Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiation. Nat Biotechnol 2002; 20: 1240–1245.
Lee HY, Kleber M, Hari L, Brault V, Suter U, Taketo MM et al. Instructive role of Wnt/beta-catenin in sensory fate specification in neural crest stem cells. Science 2004; 303: 1020–1023.
Baker JC, Beddington RS, Harland RM . Wnt signaling in Xenopus embryos inhibits bmp4 expression and activates neural development. Genes Dev 1999; 13: 3149–3159.
Hirabayashi Y, Itoh Y, Tabata H, Nakajima K, Akiyama T, Masuyama N et al. The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development 2004; 131: 2791–2801.
Moon RT, Kohn AD, Ferrari GVD, Kaykas A . Wnt and [beta]-catenin signalling: diseases and therapies. Nat Rev Gen 2004; 5: 691–701.
McMillan M, Kahn M . Investigating Wnt signaling: a chemogenomic safari. Drug Discov Today 2005; 10: 1467–1474.
Zhang Q, Major MB, Takanashi S, Camp ND, Nishiya N, Peters EC et al. Small-molecule synergist of the Wnt/beta-catenin signaling pathway. Proc Natl Acad Sci USA 2007; 104: 7444–7448.
Katoh Y, Katoh M . Hedgehog signaling pathway and gastrointestinal stem cell signaling network (review). Int J Mol Med 2006; 18: 1019–1023.
Katoh Y, Katoh M . WNT antagonist, SFRP1, is Hedgehog signaling target. Int J Mol Med 2006; 17: 171–175.
Ingham PW, McMahon AP . Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001; 15: 3059–3087.
Frank-Kamenetsky M, Zhang XM, Bottega S, Guicherit O, Wichterle H, Dudek H et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J Biol 2002; 1: 10.
Romer J, Curran T . Targeting medulloblastoma: small-molecule inhibitors of the Sonic Hedgehog pathway as potential cancer therapeutics. Cancer Res 2005; 65: 4975–4978.
Lee KJ, Jessell TM . The specification of dorsal cell fates in the vertebrate central nervous system. Annu Rev Neurosci 1999; 22: 261–294.
Gianakopoulos PJ, Skerjanc IS . Hedgehog signaling induces cardiomyogenesis in P19 cells. J Biol Chem 2005; 280: 21022–21028.
Gering M, Patient R . Hedgehog signaling is required for adult blood stem cell formation in zebrafish embryos. Dev Cell 2005; 8: 389–400.
Wu X, Ding S, Ding Q, Gray NS, Schultz PG . A small molecule with osteogenesis-inducing activity in multipotent mesenchymal progenitor cells. J Am Chem Soc 2002; 124: 14520–14521.
Kinto N, Iwamoto M, Enomoto-Iwamoto M, Noji S, Ohuchi H, Yoshioka H et al. Fibroblasts expressing Sonic hedgehog induce osteoblast differentiation and ectopic bone formation. FEBS Lett 1997; 404: 319–323.
Nakamura T, Aikawa T, Iwamoto-Enomoto M, Iwamoto M, Higuchi Y, Pacifici M et al. Induction of osteogenic differentiation by hedgehog proteins. Biochem Biophys Res Commun 1997; 237: 465–469.
Spinella-Jaegle S, Rawadi G, Kawai S, Gallea S, Faucheu C, Mollat P et al. Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation. J Cell Sci 2001; 114: 2085–2094.
Wichterle H, Lieberam I, Porter JA, Jessell TM . Directed Differentiation of Embryonic Stem Cells into Motor Neurons. Cell 2002; 110: 385–397.
Pepinsky RB, Shapiro RI, Wang S, Chakraborty A, Gill A, Lepage DJ et al. Long-acting forms of Sonic hedgehog with improved pharmacokinetic and pharmacodynamic properties are efficacious in a nerve injury model. J Pharm Sci 2002; 91: 371–387.
Nakashima H, Nakamura M, Yamaguchi H, Yamanaka N, Akiyoshi T, Koga K et al. Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer. Cancer Res 2006; 66: 7041–7049.
Hayden MS, Ghosh S . Signaling to NF-kappaB. Genes Dev 2004; 18: 2195–2224.
Gilmore TD . Introduction to NF-kappaB: players, pathways, perspectives. Oncogene 2006; 25: 6680–6684.
Shakhov AN, Collart MA, Vassalli P, Nedospasov SA, Jongeneel CV . Kappa B-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor alpha gene in primary macrophages. J Exp Med 1990; 171: 35–47.
Collart MA, Baeuerle P, Vassalli P . Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four kappa B-like motifs and of constitutive and inducible forms of NF-kappa B. Mol Cell Biol 1990; 10: 1498–1506.
Zhu NL, Li C, Huang HH, Sebald M, Londhe VA, Heisterkamp N et al. TNF-alpha represses transcription of human bone morphogenetic protein-4 in lung epithelial cells. Gene 2007; 393: 70–80.
Armstrong K, Robson CN, Leung HY . NF-kappaB activation upregulates fibroblast growth factor 8 expression in prostate cancer cells. Prostate 2006; 66: 1223–1234.
Panepucci RA, Calado RT, Rocha V, Proto-Siqueira R, Silva Jr WA, Zago MA . Higher expression of transcription targets and components of the nuclear factor-kappaB pathway is a distinctive feature of umbilical cord blood CD34+ precursors. Stem Cells 2007; 25: 189–196.
Shojaei F, Gallacher L, Bhatia M . Differential gene expression of human stem progenitor cells derived from early stages of in utero human hematopoiesis. Blood 2004; 103: 2530–2540.
Acharyya S, Villalta SA, Bakkar N, Bupha-Intr T, Janssen PM, Carathers M et al. Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy. J Clin Invest 2007; 117: 889–901.
Guttridge DC, Mayo MW, Madrid LV, Wang CY, Baldwin Jr AS . NF-kappaB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 2000; 289: 2363–2366.
Mourkioti F, Kratsios P, Luedde T, Song YH, Delafontaine P, Adami R et al. Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration. J Clin Invest 2006; 116: 2945–2954.
Partridge TA, Morgan JE, Coulton GR, Hoffman EP, Kunkel LM . Conversion of mdx myofibres from dystrophin-negative to -positive by injection of normal myoblasts. Nature 1989; 337: 176–179.
Thaloor D, Miller KJ, Gephart J, Mitchell PO, Pavlath GK . Systemic administration of the NF-kappaB inhibitor curcumin stimulates muscle regeneration after traumatic injury. Am J Physiol 1999; 277: C320–C329.
Kanzler H, Barrat FJ, Hessel EM, Coffman RL . Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med 2007; 13: 552–559.
Peterson RT, Link BA, Dowling JE, Schreiber SL . Small molecule developmental screens reveal the logic and timing of vertebrate development. Proc Natl Acad Sci USA 2000; 97: 12965–12969.
Chen JN, Haffter P, Odenthal J, Vogelsang E, Brand M, van Eeden FJ et al. Mutations affecting the cardiovascular system and other internal organs in zebrafish. Development 1996; 123: 293–302.
Peterson RT, Mably JD, Chen J-N, Fishman MC . Convergence of distinct pathways to heart patterning revealed by the small molecule concentramide and the mutation heart-and-soul. Curr Biol 2001; 11: 1481–1491.
Acknowledgements
The authors thank D Humiston for editorial assistance and artistic contribution for Figure 1. The authors also thank Drs J Huard and B Péault of the Stem Cell Research Center for scientific discussions. This work was supported by the Research Advisory Committee, Children's Hospital of Pittsburgh and the United States Department of Defense.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Schugar, R., Robbins, P. & Deasy, B. Small molecules in stem cell self-renewal and differentiation. Gene Ther 15, 126–135 (2008). https://doi.org/10.1038/sj.gt.3303062
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3303062
Keywords
This article is cited by
-
Nucleic acid drug vectors for diagnosis and treatment of brain diseases
Signal Transduction and Targeted Therapy (2023)
-
Small Molecules that Promote Self-Renewal of Stem Cells and Somatic Cell Reprogramming
Stem Cell Reviews and Reports (2020)
-
Resveratrol improves human umbilical cord-derived mesenchymal stem cells repair for cisplatin-induced acute kidney injury
Cell Death & Disease (2018)
-
The many faces of Pluripotency: in vitro adaptations of a continuum of in vivo states
BMC Developmental Biology (2017)
-
Novel chemical attempts at ex vivo hematopoietic stem cell expansion
International Journal of Hematology (2016)