Chemical modulation of cell fates: in situ regeneration

  • Hua Qin
  • Andong Zhao
  • Xiaobing Fu
Review SPECIAL TOPIC: Regenerative medicine in China: new advances and hopes


Chemical modulation of cell fates has been widely used to promote tissue and organ regeneration. Small molecules can target the self-renewal, expansion, differentiation, and survival of endogenous stem cells for enhancing their regenerative power or induce dedifferentiation or transdifferentiation of mature cells into proliferative progenitors or specialized cell types needed for regeneration. Here, we discuss current progress and potential using small molecules to promote in vivo regenerative processes by regulating the cell fate. Current studies of small molecules in regeneration will provide insights into developing safe and efficient chemical approaches for in situ tissue repair and regeneration.


small molecule in situ regeneration adult stem cells somatic cells dedifferentiation transdifferentiation reprogramming 


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This work was supported by the National Natural Science Foundation of China (81721092) and the National Key R&D Program of China (2017YFC1103304).


  1. Andersson, O., Adams, B.A., Yoo, D., Ellis, G.C., Gut, P., Anderson, R.M., German, M.S., and Stainier, D.Y.R. (2012). Adenosine signaling promotes regeneration of pancreatic β cells in vivo. Cell Metab 15, 885–894.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Androutsellis-Theotokis, A., Leker, R.R., Soldner, F., Hoeppner, D.J., Ravin, R., Poser, S.W., Rueger, M.A., Bae, S.K., Kittappa, R., and Mc-Kay, R.D.G. (2006). Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442, 823–826.PubMedCrossRefGoogle Scholar
  3. Annes, J.P., Hyoje Ryu, J., Lam, K., Carolan, P.J., Utz, K., Hollister-Lock, J., Arvanites, A.C., Rubin, L.L., Weir, G., and Melton, D.A. (2012). Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication. Proc Natl Acad Sci USA 109, 3915–3920.PubMedCrossRefGoogle Scholar
  4. Ashcroft, F.M., and Rorsman, P. (2012). Diabetes mellitus and the β cell: the last ten years. Cell 148, 1160–1171.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Azim, K., Angonin, D., Marcy, G., Pieropan, F., Rivera, A., Donega, V., Cantù, C., Williams, G., Berninger, B., Butt, A.M., et al. (2017). Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity. PLoS Biol 15, e2000698.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Ben-Othman, N., Vieira, A., Courtney, M., Record, F., Gjernes, E., Avolio, F., Hadzic, B., Druelle, N., Napolitano, T., Navarro-Sanz, S., et al. (2017). Long-term GABA administration induces alpha cell-mediated beta-like cell neogenesis. Cell 168, 73–85.e11.PubMedCrossRefGoogle Scholar
  7. Benthuysen, J.R., Carrano, A.C., and Sander, M. (2016). Advances in β cell replacement and regeneration strategies for treating diabetes. J Clin Investig 126, 3651–3660.PubMedCrossRefGoogle Scholar
  8. Bergmann, O., Bhardwaj, R.D., Bernard, S., Zdunek, S., Barnabé-Heider, F., Walsh, S., Zupicich, J., Alkass, K., Buchholz, B.A., Druid, H., et al. (2009). Evidence for cardiomyocyte renewal in humans. Science 324, 98–102.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Boitano, A.E., Wang, J., Romeo, R., Bouchez, L.C., Parker, A.E., Sutton, S. E., Walker, J.R., Flaveny, C.A., Perdew, G.H., Denison, M.S., et al. (2010). Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329, 1345–1348.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bussel, J.B., Cheng, G., Saleh, M.N., Psaila, B., Kovaleva, L., Meddeb, B., Kloczko, J., Hassani, H., Mayer, B., Stone, N.L., et al. (2007). Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 357, 2237–2247.PubMedCrossRefGoogle Scholar
  11. Cahill, T.J., Choudhury, R.P., and Riley, P.R. (2017). Heart regeneration and repair after myocardial infarction: translational opportunities for novel therapeutics. Nat Rev Drug Discov 16, 699–717.PubMedCrossRefGoogle Scholar
  12. Cao, N., Huang, Y., Zheng, J., Spencer, C.I., Zhang, Y., Fu, J.D., Nie, B., Xie, M., Zhang, M., Wang, H., et al. (2016). Conversion of human fibroblasts into functional cardiomyocytes by small molecules. Science 352, 1216–1220.PubMedCrossRefGoogle Scholar
  13. Chechneva, O.V., Mayrhofer, F., Daugherty, D.J., Krishnamurty, R.G., Bannerman, P., Pleasure, D.E., and Deng, W. (2014). A Smoothened receptor agonist is neuroprotective and promotes regeneration after ischemic brain injury. Cell Death Dis 5, e1481.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Chen, W.P., Liu, Y.H., Ho, Y.J., and Wu, S.M. (2015). Pharmacological inhibition of TGFβ receptor improves Nkx2.5 cardiomyoblast-mediated regeneration. Cardiovasc Res 105, 44–54.PubMedCrossRefGoogle Scholar
  15. Christopherson, K.W., Hangoc, G., Mantel, C.R., and Broxmeyer, H.E. (2004). Modulation of hematopoietic stem cell homing and engraftment by CD26. Science 305, 1000–1003.PubMedCrossRefGoogle Scholar
  16. Cottage, C.T., Bailey, B., Fischer, K.M., Avitabile, D., Avitable, D., Collins, B., Tuck, S., Quijada, P., Gude, N., Alvarez, R., et al. (2010). Cardiac progenitor cell cycling stimulated by pim-1 kinase. Circul Res 106, 891–901.CrossRefGoogle Scholar
  17. Crane, G.M., Jeffery, E., and Morrison, S.J. (2017). Adult haematopoietic stem cell niches. Nat Rev Immunol 17, 573–590.PubMedCrossRefGoogle Scholar
  18. Degousee, N., Fazel, S., Angoulvant, D., Stefanski, E., Pawelzik, S.C., Korotkova, M., Arab, S., Liu, P., Lindsay, T.F., Zhuo, S., et al. (2008). Microsomal prostaglandin E2 synthase-1 deletion leads to adverse left ventricular remodeling after myocardial infarction. Circulation 117, 1701–1710.PubMedCrossRefGoogle Scholar
  19. Del Re, D.P., and Sadoshima, J. (2012). Enhancing the potential of cardiac progenitor cells: pushing forward with Pim-1. Circul Res 110, 1154–1156.CrossRefGoogle Scholar
  20. Demcollari, T.I., Cujba, A.M., and Sancho, R. (2017). Phenotypic plasticity in the pancreas: new triggers, new players. Curr Opin Cell Biol 49, 38–46.PubMedCrossRefGoogle Scholar
  21. Ebrahimi, B. (2017). In vivo reprogramming for heart regeneration: a glance at efficiency, environmental impacts, challenges and future directions. J Mol Cell Cardiol 108, 61–72.PubMedCrossRefGoogle Scholar
  22. Engel, F.B., Hsieh, P.C.H., Lee, R.T., and Keating, M.T. (2006). FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction. Proc Natl Acad Sci USA 103, 15546–15551.PubMedCrossRefGoogle Scholar
  23. English, A.W., Liu, K., Nicolini, J.M., Mulligan, A.M., and Ye, K. (2013). Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves. Proc Natl Acad Sci USA 110, 16217–16222.PubMedCrossRefGoogle Scholar
  24. Fancy, S.P.J., Harrington, E.P., Yuen, T.J., Silbereis, J.C., Zhao, C., Baranzini, S.E., Bruce, C.C., Otero, J.J., Huang, E.J., Nusse, R., et al. (2011). Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nat Neurosci 14, 1009–1016.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Flomenberg, N., Devine, S.M., Dipersio, J.F., Liesveld, J.L., McCarty, J.M., Rowley, S.D., Vesole, D.H., Badel, K., and Calandra, G. (2005). The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone. Blood 106, 1867–1874.PubMedCrossRefGoogle Scholar
  26. Florian, M.C., Dörr, K., Niebel, A., Daria, D., Schrezenmeier, H., Rojewski, M., Filippi, M.D., Hasenberg, A., Gunzer, M., Scharffetter-Kochanek, K., et al. (2012). Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 10, 520–530.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Fomina-Yadlin, D., Kubicek, S., Walpita, D., Dancik, V., Hecksher-Sørensen, J., Bittker, J.A., Sharifnia, T., Shamji, A., Clemons, P.A., Wagner, B.K., et al. (2010). Small-molecule inducers of insulin expression in pancreatic β-cells. Proc Natl Acad Sci USA 107, 15099–15104.PubMedCrossRefGoogle Scholar
  28. Frank-Kamenetsky, M., Zhang, X.M., Bottega, S., Guicherit, O., Wichterle, H., Dudek, H., Bumcrot, D., Wang, F.Y., Jones, S., Shulok, J., et al. (2002). Small-molecule modulators of Hedgehog signaling. J Biol 1, 10.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Frasch, M. (2016). Dedifferentiation, redifferentiation, and transdifferentiation of striated muscles during regeneration and development. Curr Top Dev Biol 116, 331–355.PubMedCrossRefGoogle Scholar
  30. Fu, Y., Huang, C., Xu, X., Gu, H., Ye, Y., Jiang, C., Qiu, Z., and Xie, X. (2015). Direct reprogramming of mouse fibroblasts into cardiomyocytes with chemical cocktails. Cell Res 25, 1013–1024.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Gemberling, M., Bailey, T.J., Hyde, D.R., and Poss, K.D. (2013). The zebrafish as a model for complex tissue regeneration. Trends Genets 29, 611–620.CrossRefGoogle Scholar
  32. Green, E.M., and Lee, R.T. (2013). Proteins and small molecules for cellular regenerative medicine. Physiol Rev 93, 311–325.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Gu, D., Wang, S., Zhang, S., Zhang, P., and Zhou, G. (2017). Directed transdifferentiation of Müller glial cells to photoreceptors using the sonic hedgehog signaling pathway agonist purmorphamine. Mol Med Rep 16, 7993–8002.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Gude, N., Muraski, J., Rubio, M., Kajstura, J., Schaefer, E., Anversa, P., and Sussman, M.A. (2006). Akt promotes increased cardiomyocyte cycling and expansion of the cardiac progenitor cell population. Circul Res 99, 381–388.CrossRefGoogle Scholar
  35. Hankenson, K.D., Gagne, K., and Shaughnessy, M. (2015). Extracellular signaling molecules to promote fracture healing and bone regeneration. Adv Drug Deliver Rev 94, 3–12.CrossRefGoogle Scholar
  36. Hariharan, N., Quijada, P., Mohsin, S., Joyo, A., Samse, K., Monsanto, M., De La Torre, A., Avitabile, D., Ormachea, L., McGregor, M.J., et al. (2015). Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging. J Am College Cardiol 65, 133–147.CrossRefGoogle Scholar
  37. He, X., Zhang, L., Queme, L.F., Liu, X., Lu, A., Waclaw, R.R., Dong, X., Zhou, W., Kidd, G., Yoon, S.O., et al. (2018). A histone deacetylase 3- dependent pathway delimits peripheral myelin growth and functional regeneration. Nat Med 24, 338–351.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Hsueh, Y.C., Wu, J.M.F., Yu, C.K., Wu, K.K., and Hsieh, P.C.H. (2014). Prostaglandin E promotes post-infarction cardiomyocyte replenishment by endogenous stem cells. EMBO Mol Med 6, 496–503.PubMedPubMedCentralGoogle Scholar
  39. Ieda, M., Fu, J.D., Delgado-Olguin, P., Vedantham, V., Hayashi, Y., Bruneau, B.G., and Srivastava, D. (2010). Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375–386.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Ieronimakis, N., Pantoja, M., Hays, A.L., Dosey, T.L., Qi, J., Fischer, K.A., Hoofnagle, A.N., Sadilek, M., Chamberlain, J.S., Ruohola-Baker, H., et al. (2013). Increased sphingosine-1-phosphate improves muscle regeneration in acutely injured mdx mice. Skeletal Muscle 3, 20.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Jeon, O.H., and Elisseeff, J. (2016). Orthopedic tissue regeneration: cells, scaffolds, and small molecules. Drug Deliv Transl Res 6, 105–120.PubMedCrossRefGoogle Scholar
  42. Johnson, K., Zhu, S., Tremblay, M.S., Payette, J.N., Wang, J., Bouchez, L. C., Meeusen, S., Althage, A., Cho, C.Y., Wu, X., et al. (2012). A stem cell-based approach to cartilage repair. Science 336, 717–721.PubMedCrossRefGoogle Scholar
  43. Jopling, C., Boue, S., and Izpisua Belmonte, J.C. (2011). Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nat Rev Mol Cell Biol 12, 79–89.PubMedCrossRefGoogle Scholar
  44. Jung, D.W., and Williams, D.R. (2011). Novel chemically defined approach to produce multipotent cells from terminally differentiated tissue syncytia. ACS Chem Biol 6, 553–562.PubMedCrossRefGoogle Scholar
  45. Kaplan, A., Morquette, B., Kroner, A., Leong, S.Y., Madwar, C., Sanz, R., Banerjee, S.L., Antel, J., Bisson, N., David, S., et al. (2017). Smallmolecule stabilization of 14-3-3 protein-protein interactions stimulates axon regeneration. Neuron 93, 1082–1093.e5.PubMedCrossRefGoogle Scholar
  46. Khan, M., Mohsin, S., Avitabile, D., Siddiqi, S., Nguyen, J., Wallach, K., Quijada, P., McGregor, M., Gude, N., Alvarez, R., et al. (2013). β- Adrenergic regulation of cardiac progenitor cell death versus survival and proliferation. Circ Res 112, 476–486.PubMedCrossRefGoogle Scholar
  47. Kim, W.H., Jung, D.W., Kim, J., Im, S.H., Hwang, S.Y., and Williams, D.R. (2012). Small molecules that recapitulate the early steps of urodele amphibian limb regeneration and confer multipotency. ACS Chem Biol 7, 732–743.PubMedCrossRefGoogle Scholar
  48. Kusano, K., Ebara, S., Tachibana, K., Nishimura, T., Sato, S., Kuwaki, T., and Taniyama, T. (2004). A potential therapeutic role for small nonpeptidyl compounds that mimic human granulocyte colony-stimulating factor. Blood 103, 836–842.PubMedCrossRefGoogle Scholar
  49. Kuter, D.J., and Begley, C.G. (2002). Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood 100, 3457–3469.PubMedCrossRefGoogle Scholar
  50. Kwon, C., Arnold, J., Hsiao, E.C., Taketo, M.M., Conklin, B.R., and Srivastava, D. (2007). Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitors. Proc Natl Acad Sci USA 104, 10894–10899.PubMedCrossRefGoogle Scholar
  51. Lane, S.W., Williams, D.A., and Watt, F.M. (2014). Modulating the stem cell niche for tissue regeneration. Nat Biotechnol 32, 795–803.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Laurencin, C.T., Ashe, K.M., Henry, N., Kan, H.M., and Lo, K.W.H. (2014). Delivery of small molecules for bone regenerative engineering: preclinical studies and potential clinical applications. Drug Discov Today 19, 794–800.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Li, J., Casteels, T., Frogne, T., Ingvorsen, C., Honoré, C., Courtney, M., Huber, K.V.M., Schmitner, N., Kimmel, R.A., Romanov, R.A., et al. (2017). Artemisinins target GABAA receptor signaling and impair α cell identity. Cell 168, 86–100.e15.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Li, J., Yang, C., Xia, Y., Bertino, A., Glaspy, J., Roberts, M., and Kuter, D.J. (2001). Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 98, 3241–3248.PubMedCrossRefGoogle Scholar
  55. Li, K., Zhu, S., Russ, H.A., Xu, S., Xu, T., Zhang, Y., Ma, T., Hebrok, M., and Ding, S. (2014). Small molecules facilitate the reprogramming of mouse fibroblasts into pancreatic lineages. Cell Stem Cell 14, 228–236.PubMedPubMedCentralCrossRefGoogle Scholar
  56. de Lichtervelde, L., Boitano, A.E., Wang, Y., Krastel, P., Petersen, F., Cooke, M.P., and Schultz, P.G. (2013). Eupalinilide E inhibits erythropoiesis and promotes the expansion of hematopoietic progenitor cells. ACS Chem Biol 8, 866–870.PubMedCrossRefGoogle Scholar
  57. Liles, W.C., Broxmeyer, H.E., Rodger, E., Wood, B., Hübel, K., Cooper, S., Hangoc, G., Bridger, G.J., Henson, G.W., Calandra, G., et al. (2003). Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood 102, 2728–2730.PubMedCrossRefGoogle Scholar
  58. Lin, S.C., Dollé, P., Ryckebüsch, L., Noseda, M., Zaffran, S., Schneider, M. D., and Niederreither, K. (2010). Endogenous retinoic acid regulates cardiac progenitor differentiation. Proc Natl Acad Sci USA 107, 9234–9239.PubMedCrossRefGoogle Scholar
  59. Lyssiotis, C.A., Lairson, L.L., Boitano, A.E., Wurdak, H., Zhu, S., and Schultz, P.G. (2011). Chemical control of stem cell fate and developmental potential. Angew Chem Int Ed 50, 200–242.CrossRefGoogle Scholar
  60. Ma, T.C., Campana, A., Lange, P.S., Lee, H.H., Banerjee, K., Bryson, J.B., Mahishi, L., Alam, S., Giger, R.J., Barnes, S., et al. (2010). A largescale chemical screen for regulators of the arginase 1 promoter identifies the soy isoflavone daidzeinas a clinically approved small molecule that can promote neuronal protection or regeneration via a cAMP-independent pathway. J Neurosci 30, 739–748.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Matrone, G., Tucker, C.S., and Denvir, M.A. (2017). Cardiomyocyte proliferation in zebrafish and mammals: lessons for human disease. Cell Mol Life Sci 74, 1367–1378.PubMedCrossRefGoogle Scholar
  62. Mei, F., Mayoral, S.R., Nobuta, H., Wang, F., Desponts, C., Lorrain, D.S., Xiao, L., Green, A.J., Rowitch, D., Whistler, J., et al. (2016). Identification of the kappa-opioid receptor as a therapeutic target for oligodendrocyte remyelination. J Neurosci 36, 7925–7935.PubMedPubMedCentralCrossRefGoogle Scholar
  63. Mendelson, A., and Frenette, P.S. (2014). Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med 20, 833–846.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Merrell, A.J., and Stanger, B.Z. (2016). Adult cell plasticity in vivo: dedifferentiation and transdifferentiation are back in style. Nat Rev Mol Cell Biol 17, 413–425.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Mohamed, T.M.A., Stone, N.R., Berry, E.C., Radzinsky, E., Huang, Y., Pratt, K., Ang, Y.S., Yu, P., Wang, H., Tang, S., et al. (2017). Chemical enhancement of in vitro and in vivo direct cardiac reprogramming clinical perspective. Circulation 135, 978–995.PubMedCrossRefGoogle Scholar
  66. Mohsin, S., Khan, M., Nguyen, J., Alkatib, M., Siddiqi, S., Hariharan, N., Wallach, K., Monsanto, M., Gude, N., Dembitsky, W., et al. (2013). Rejuvenation of human cardiac progenitor cells with Pim-1 kinase. Circul Res 113, 1169–1179.CrossRefGoogle Scholar
  67. Mosqueira, D., Pagliari, S., Uto, K., Ebara, M., Romanazzo, S., Escobedo-Lucea, C., Nakanishi, J., Taniguchi, A., Franzese, O., Di Nardo, P., et al. (2014). Hippo pathway effectors control cardiac progenitor cell fate by acting as dynamic sensors of substrate mechanics and nanostructure. ACS Nano 8, 2033–2047.PubMedCrossRefGoogle Scholar
  68. Murry, C.E., and Pu, W.T. (2011). Reprogramming fibroblasts into cardiomyocytes. N Engl J Med 364, 177–178.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Neidhart, J., Mangalik, A., Kohler, W., Stidley, C., Saiki, J., Duncan, P., Souza, L., and Downing, M. (1989). Granulocyte colony-stimulating factor stimulates recovery of granulocytes in patients receiving doseintensive chemotherapy without bone marrow transplantation. J Clin Oncol 7, 1685–1692.PubMedCrossRefGoogle Scholar
  70. Németh, Z.H., Bleich, D., Csóka, B., Pacher, P., Mabley, J.G., Himer, L., Vizi, E.S., Deitch, E.A., Szabó, C., Cronstein, B.N., and Haskó, G. (2007). Adenosine receptor activation ameliorates type 1 diabetes. FASEB J 21, 2379–2388.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Orth, P., Cucchiarini, M., Wagenpfeil, S., Menger, M.D., and Madry, H. (2014). PTH [1-34]-induced alterations of the subchondral bone provoke early osteoarthritis. Osteoarthritis Cartilage 22, 813–821.PubMedCrossRefGoogle Scholar
  72. Otte, A.P., van Run, P., Heideveld, M., van Driel, R., and Durston, A.J. (1989). Neural induction is mediated by cross-talk between the protein kinase C and cyclic AMP pathways. Cell 58, 641–648.PubMedCrossRefGoogle Scholar
  73. Pacelli, S., Basu, S., Whitlow, J., Chakravarti, A., Acosta, F., Varshney, A., Modaresi, S., Berkland, C., and Paul, A. (2017). Strategies to develop endogenous stem cell-recruiting bioactive materials for tissue repair and regeneration. Adv Drug Deliver Rev 120, 50–70.CrossRefGoogle Scholar
  74. Pajcini, K.V., Corbel, S.Y., Sage, J., Pomerantz, J.H., and Blau, H.M. (2010). Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle. Cell Stem Cell 7, 198–213.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Paliwal, P., and Conboy, I.M. (2011). Inhibitors of tyrosine phosphatases and apoptosis reprogram lineage-marked differentiated muscle to myogenic progenitor cells. Chem Biol 18, 1153–1166.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Papapetrou, E.P. (2016). Induced pluripotent stem cells, past and future. Science 353, 991–992.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Park, G., Yoon, B.S., Kim, Y.S., Choi, S.C., Moon, J.H., Kwon, S., Hwang, J., Yun, W., Kim, J.H., Park, C.Y., et al. (2015). Conversion of mouse fibroblasts into cardiomyocyte-like cells using small molecule treatments. Biomaterials 54, 201–212.PubMedCrossRefGoogle Scholar
  78. de Pater, E., Ciampricotti, M., Priller, F., Veerkamp, J., Strate, I., Smith, K., Lagendijk, A.K., Schilling, T.F., Herzog, W., Abdelilah-Seyfried, S., et al. (2012). Bmp signaling exerts opposite effects on cardiac differentiation. Circul Res 110, 578–587.CrossRefGoogle Scholar
  79. Porrello, E.R., Mahmoud, A.I., Simpson, E., Hill, J.A., Richardson, J.A., Olson, E.N., and Sadek, H.A. (2011). Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Qian, L., Huang, Y., Spencer, C.I., Foley, A., Vedantham, V., Liu, L., Conway, S.J., Fu, J.D., and Srivastava, D. (2012). In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485, 593–598.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Qyang, Y., Martin-Puig, S., Chiravuri, M., Chen, S., Xu, H., Bu, L., Jiang, X., Lin, L., Granger, A., Moretti, A., et al. (2007). The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a wnt/β-catenin pathway. Cell Stem Cell 1, 165–179.PubMedCrossRefGoogle Scholar
  82. Racioppi, L., Lento, W., Huang, W., Arvai, S., Doan, P.L., Harris, J.R., Marcon, F., Nakaya, H.I., Liu, Y., and Chao, N. (2017). Calcium/calmodulin- dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration. Cell Death Dis 8, e3076.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Ramirez, P., Rettig, M.P., Uy, G.L., Deych, E., Holt, M.S., Ritchey, J.K., and DiPersio, J.F. (2009). BIO5192, a small molecule inhibitor of VLA- 4, mobilizes hematopoietic stem and progenitor cells. Blood 114, 1340–1343.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Rennekamp, A.J., and Peterson, R.T. (2015). 15 years of zebrafish chemical screening. Curr Opin Chem Biol 24, 58–70.PubMedCrossRefGoogle Scholar
  85. Rosania, G.R., Chang, Y.T., Perez, O., Sutherlin, D., Dong, H., Lockhart, D.J., and Schultz, P.G. (2000). Myoseverin, a microtubule-binding molecule with novel cellular effects. Nat Biotechnol 18, 304–308.PubMedCrossRefGoogle Scholar
  86. Russell, J.L., Goetsch, S.C., Aguilar, H.R., Frantz, D.E., and Schneider, J. W. (2012). Targeting native adult heart progenitors with cardiogenic small molecules. ACS Chem Biol 7, 1067–1076.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Sakami, S., Etter, P., and Reh, T.A. (2008). Activin signaling limits the competence for retinal regeneration from the pigmented epithelium. Mech Dev 125, 106–116.PubMedCrossRefGoogle Scholar
  88. Samara, C., Rohde, C.B., Gilleland, C.L., Norton, S., Haggarty, S.J., and Yanik, M.F. (2010). Large-scale in vivo femtosecond laser neurosurgery screen reveals small-molecule enhancer of regeneration. Proc Natl Acad Sci USA 107, 18342–18347.PubMedCrossRefGoogle Scholar
  89. Sampson, E.R., Hilton, M.J., Tian, Y., Chen, D., Schwarz, E.M., Mooney, R.A., Bukata, S.V., O'Keefe, R.J., Awad, H., Puzas, J.E., et al. (2011). Teriparatide as a chondroregenerative therapy for injury-induced osteoarthritis. Sci Transl Med 3, 101ra93.CrossRefGoogle Scholar
  90. Sánchez Alvarado, A., and Yamanaka, S. (2014). Rethinking differentiation. Cell 157, 110–119.PubMedCrossRefGoogle Scholar
  91. Saraswati, S., Alfaro, M.P., Thorne, C.A., Atkinson, J., Lee, E., and Young, P.P. (2010). Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post-MI cardiac remodeling. PLoS ONE 5, e15521.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Sasaki, T., Hwang, H., Nguyen, C., Kloner, R.A., and Kahn, M. (2013). The small molecule Wnt signaling modulator ICG-001 improves contractile function in chronically infarcted rat myocardium. PLoS ONE 8, e75010.PubMedPubMedCentralCrossRefGoogle Scholar
  93. Senyo, S.E., Steinhauser, M.L., Pizzimenti, C.L., Yang, V.K., Cai, L., Wang, M., Wu, T.D., Guerquin-Kern, J.L., Lechene, C.P., and Lee, R.T. (2013). Mammalian heart renewal by pre-existing cardiomyocytes. Nature 493, 433–436.PubMedCrossRefGoogle Scholar
  94. Shen, W., Tremblay, M.S., Deshmukh, V.A., Wang, W., Filippi, C.M., Harb, G., Zhang, Y., Kamireddy, A., Baaten, J.E., Jin, Q., et al. (2013). Smallmolecule inducer of β cell proliferation identified by high-throughput screening. J Am Chem Soc 135, 1669–1672.PubMedCrossRefGoogle Scholar
  95. Sheridan, W.P., Wolf, M., Lusk, J., Layton, J.E., Souza, L., Morstyn, G., Dodds, A., Maher, D., Green, M.D., and Fox, R.M. (1989). Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lancet 334, 891–895.CrossRefGoogle Scholar
  96. Smith, A.M., Maguire-Nguyen, K.K., Rando, T.A., Zasloff, M.A., Strange, K.B., and Yin, V.P. (2017). The protein tyrosine phosphatase 1B inhibitor MSI-1436 stimulates regeneration of heart and multiple other tissues. NPJ Regen Med 2, 4.PubMedPubMedCentralCrossRefGoogle Scholar
  97. Song, K., Nam, Y.J., Luo, X., Qi, X., Tan, W., Huang, G.N., Acharya, A., Smith, C.L., Tallquist, M.D., Neilson, E.G., et al. (2012). Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 485, 599–604.PubMedPubMedCentralCrossRefGoogle Scholar
  98. Sundararaman, B., Avitabile, D., Konstandin, M.H., Cottage, C.T., Gude, N., and Sussman, M.A. (2012). Asymmetric chromatid segregation in cardiac progenitor cells is enhanced by Pim-1 kinase. Circul Res 110, 1169–1173.CrossRefGoogle Scholar
  99. Taguchi, J., and Yamada, Y. (2017). In vivo reprogramming for tissue regeneration and organismal rejuvenation. Curr Opin Genet Dev 46, 132–140.PubMedCrossRefGoogle Scholar
  100. Tanaka, E.M. (2016). The molecular and cellular choreography of appendage regeneration. Cell 165, 1598–1608.PubMedCrossRefGoogle Scholar
  101. Tappeiner, C., Maurer, E., Sallin, P., Bise, T., Enzmann, V., and Tschopp, M. (2016). Inhibition of the TGFβ pathway enhances retinal regeneration in adult zebrafish. PLoS ONE 11, e0167073.PubMedPubMedCentralCrossRefGoogle Scholar
  102. Theiss, H.D., Gross, L., Vallaster, M., David, R., Brunner, S., Brenner, C., Nathan, P., Assmann, G., Mueller-Hoecker, J., Vogeser, M., et al. (2013). Antidiabetic gliptins in combination with G-CSF enhances myocardial function and survival after acute myocardial infarction. Int J Cardiol 168, 3359–3369.PubMedCrossRefGoogle Scholar
  103. Ti, D., Hao, H., Fu, X., and Han, W. (2016). Mesenchymal stem cellsderived exosomal microRNAs contribute to wound inflammation. Sci China Life Sci 59, 1305–1312.PubMedCrossRefGoogle Scholar
  104. Tian, S.S., Lamb, P., King, A.G., Miller, S.G., Kessler, L., Luengo, J.I., Averill, L., Johnson, R.K., Gleason, J.G., Pelus, L.M., et al. (1998). A small, nonpeptidyl mimic of granulocyte-colony-stimulating factor. Science 281, 257–259.PubMedCrossRefGoogle Scholar
  105. Tönges, L., Frank, T., Tatenhorst, L., Saal, K.A., Koch, J.C., Szego, É.M., Bähr, M., Weishaupt, J.H., and Lingor, P. (2012). Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson’s disease. Brain 135, 3355–3370.PubMedPubMedCentralCrossRefGoogle Scholar
  106. Tornini, V.A., and Poss, K.D. (2014). Keeping at arm’s length during regeneration. Dev Cell 29, 139–145.PubMedPubMedCentralCrossRefGoogle Scholar
  107. Trounson, A., and McDonald, C. (2015). Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17, 11–22.PubMedCrossRefGoogle Scholar
  108. Tseng, A.S., Beane, W.S., Lemire, J.M., Masi, A., and Levin, M. (2010). Induction of vertebrate regeneration by a transient sodium current. J Neurosci 30, 13192–13200.PubMedPubMedCentralCrossRefGoogle Scholar
  109. Tseng, A.S., Engel, F.B., and Keating, M.T. (2006). The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes. Chem Biol 13, 957–963.PubMedCrossRefGoogle Scholar
  110. Uccelli, A., Moretta, L., and Pistoia, V. (2008). Mesenchymal stem cells in health and disease. Nat Rev Immunol 8, 726–736.PubMedCrossRefGoogle Scholar
  111. Uosaki, H., Magadum, A., Seo, K., Fukushima, H., Takeuchi, A., Nakagawa, Y., Moyes, K.W., Narazaki, G., Kuwahara, K., Laflamme, M., et al. (2013). Identification of chemicals inducing cardiomyocyte proliferation in developmental stage-specific manner with pluripotent stem cells. Circul Cardiovasc Genet 6, 624–633.CrossRefGoogle Scholar
  112. Wang, H., and Simon, A. (2016). Skeletal muscle dedifferentiation during salamander limb regeneration. Curr Opin Genet Dev 40, 108–112.PubMedCrossRefGoogle Scholar
  113. Wang, P., Alvarez-Perez, J.C., Felsenfeld, D.P., Liu, H., Sivendran, S., Bender, A., Kumar, A., Sanchez, R., Scott, D.K., Garcia-Ocaña, A., et al. (2015a). A high-throughput chemical screen reveals that harminemediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med 21, 383–388.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Wang, W., Walker, J.R., Wang, X., Tremblay, M.S., Lee, J.W., Wu, X., and Schultz, P.G. (2009). Identification of small-molecule inducers of pancreatic β-cell expansion. Proc Natl Acad Sci USA 106, 1427–1432.PubMedCrossRefGoogle Scholar
  115. Wang, W.E., Li, L., Xia, X., Fu, W., Liao, Q., Lan, C., Yang, D., Chen, H., Yue, R., Zeng, C., et al. (2017). Dedifferentiation, proliferation, and redifferentiation of adult mammalian cardiomyocytes after ischemic injury. Circulation 136, 834–848.PubMedCrossRefPubMedCentralGoogle Scholar
  116. Wang, X., Zhu, S., Jiang, X., Li, Y., Song, D., and Hu, J. (2015b). Systemic administration of lithium improves distracted bone regeneration in rats. Calcif Tissue Int 96, 534–540.PubMedCrossRefGoogle Scholar
  117. Wu, X., Ding, S., Ding, Q., Gray, N.S., and Schultz, P.G. (2002). A small molecule with osteogenesis-inducing activity in multipotent mesenchymal progenitor cells. J Am Chem Soc 124, 14520–14521.PubMedCrossRefGoogle Scholar
  118. Xie, Y., Song, W., Zhao, W., Gao, Y., Shang, J., Hao, P., Yang, Z., Duan, H., and Li, X. (2018). Application of the sodium hyaluronate-CNTF scaffolds in repairing adult rat spinal cord injury and facilitating neural network formation. Sci China Life Sci 61, 559–568.PubMedCrossRefGoogle Scholar
  119. Xu, J., Du, Y., and Deng, H. (2015). Direct lineage reprogramming: strategies, mechanisms, and applications. Cell Stem Cell 16, 119–134.PubMedCrossRefGoogle Scholar
  120. Xu, J., Lacoske, M.H., and Theodorakis, E.A. (2014). Neurotrophic natural products: chemistry and biology. Angew Chem Int Ed 53, 956–987.CrossRefGoogle Scholar
  121. Yuen, T.J., Johnson, K.R., Miron, V.E., Zhao, C., Quandt, J., Harrisingh, M. C., Swire, M., Williams, A., McFarland, H.F., Franklin, R.J.M., et al. (2013). Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination. Brain 136, 1035–1047.PubMedPubMedCentralCrossRefGoogle Scholar
  122. Zaruba, M.M., Theiss, H.D., Vallaster, M., Mehl, U., Brunner, S., David, R., Fischer, R., Krieg, L., Hirsch, E., Huber, B., et al. (2009). Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell 4, 313–323.PubMedCrossRefGoogle Scholar
  123. Zhang, J., Liu, J., Huang, Y., Chang, J.Y.F., Liu, L., McKeehan, W.L., Martin, J.F., and Wang, F. (2012a). FRS2α-mediated FGF signals suppress premature differentiation of cardiac stem cells through regulating autophagy activity. Circul Res 110, e29–e39.CrossRefGoogle Scholar
  124. Zhang, Y., Li, W., Laurent, T., and Ding, S. (2012b). Small molecules, big roles—the chemical manipulation of stem cell fate and somatic cell reprogramming. J Cell Sci 125, 5609–5620.PubMedPubMedCentralCrossRefGoogle Scholar
  125. Zhao, A., Qin, H., and Fu, X. (2016). What determines the regenerative capacity in animals? Bioscience 66, 735–746.CrossRefGoogle Scholar
  126. Zhao, Y., Londono, P., Cao, Y., Sharpe, E.J., Proenza, C., O'Rourke, R., Jones, K.L., Jeong, M.Y., Walker, L.A., Buttrick, P.M., et al. (2015). High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling. Nat Commun 6, 8243.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Graduate School of Tianjin Medical UniversityTianjinChina
  2. 2.Cell Biology and Tissue Repair LaboratoryKey Laboratory of Wound Repair and Regeneration of PLA, the First Hospital Affiliated to the PLA General HospitalBeijingChina
  3. 3.College of Life SciencesPLA General Hospital, PLA Medical CollegeBeijingChina

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