Research Interests
My lab has been developing and applying innovative chemical approaches to stem cell biology and regeneration, with a focus on discovering and characterizing novel small molecules that can control cell fate and function of various cell types, including stem cell maintenance, activation, differentiation and reprogramming in various developmental stages and tissues. Specific projects include
(1) Self-renewal regulation of embryonic and adult stem cells;
(2) Directed and step-wised differentiation of embryonic stem cells toward neuronal, cardiac and pancreatic lineages;
(3) Subtype specification of human tissue-specific stem/progenitor cells;
(4) Cellular plasticity and reprogramming of lineage-restricted somatic cells to alternative cell fate (e.g., toward iPSCs or transdifferentiation);
(5) Functional proliferation of adult cardiomyocytes and pancreatic beta cells;
(6) Developmental signaling pathways (i.e. Wnt, Hh, BMP and FGF) and epigenetic mechanisms (histone and DNA de/methylation);
(7) Development of new technologies for drug discovery. Moreover, major efforts are devoted to characterize the molecular mechanism of these identified small molecules using various approaches, including detailed structure-activity-relationship (SAR) studies, affinity chromatography for target identification, transcriptome profiling, proteomics analysis, chemical/genetic epistasis, and biochemical and functional assays in vitro and in vivo. So far, functional small molecules and fundamental mechanisms have been identified and are being characterized in each of the above twenty plus distinct biological processes involving regulation of stem/progenitor cells. Those studies may ultimately facilitate the therapeutic application of stem cells and the development of small molecule drugs to stimulate tissue and organ regeneration in vivo, or treating cancers.
Scientific Contributions
My lab has pioneered the field of developing and applying innovative chemical approaches to address major challenges in stem cell biology and regeneration. We continue to develop new ways (e.g., screening technology or models) to discover and characterize novel small molecules that can control cell fate of various cell types
in vitro and
in vivo, including stem cell maintenance, differentiation and reprogramming. Many of our small molecule discoveries are enabling, which allow exquisite modulations of specific cell behavior/phenotype
in vitro and
in vivo that otherwise would be very challenging or impossible. In addition, our enabling work has led to new conceptual and mechanistic insights into stem cell regulation. Our ongoing research program on precisely controlling cellular reprogramming from one cell type into another within the tissue or across germ-layer boundaries entirely by pharmacological modulation in vitro and
in vivo represents a radical breakthrough in controlling cell fate, and will ultimately facilitate the development of drug pills as regenerative medicine that can awaken and guide our body's own cells to repair and regenerate
in situ in a tissue/organ specific manner after disease or injury. Furthermore, our works have led to founding of several biotech companies as well as many other initiations in academia and biopharmaceutical industry on developing small molecule-based regenerative therapeutics for treating human diseases.
Selected Achievements
1.Discovered a series of small molecules that can functionally replace the iPSC reprogramming transcription factors and significantly enhance reprogramming efficiency/speed. These small molecules were further used to reveal novel mechanisms underlying the reprogramming process.
2. Developed a novel trans-differentiation (i.e., lineage-specific reprogramming) paradigm for generating expandable cardiac, neural, endothelial, pancreatic and hepatic cells directly from fibroblasts under defined conditions enabled by small molecules.
3.Discovered and mechanistically characterized several novel small molecules that can either replace growth factors to sustain ESC self-renewal, promote ESC survival, or direct their differentiation toward neural, cardiac, and definitive endoderm lineages.
Honors and Awards
2012 “40 Under 40 Emerging Leaders”, San Francisco Business Times
2011 William K. Bowes Jr. Distinguished Investigator, The Gladstone Institutes
2010 NIH Transformative Research Award
2010 Named as one of the 100 most inspiring people in the life sciences industry by
PharmaVoice
2009 #1 of Top 10 Innovations, and Top 5 People in 2009 by The Scientist Magazine
2008 Prostate Cancer Foundation Challenge Award
2008 New Faculty Award from California Institute for Regenerative Medicine
2000 Fellowship in Biological Science, Howard Hughes Medical Institute.
1999 Richard P. Schuster Memorial Prize, Caltech
1998 Carnation Merit Award, Caltech
1997 Rosalind W. Alott Merit Award, Caltech
1997 National Merit Scholar, Phi Tau Phi Honor Association.
1997 Member of Tau Beta Pai, the National Engineering Honor Society.
Selected Publications
1. Zhang M, Lin YH, Sun YJ, Zhu S, Zheng J, Liu K, Cao N, Li K, Huang Y, Ding S. Pharmacological Reprogramming of Fibroblasts into Neural Stem Cells by Signaling-Directed Transcriptional Activation.
Cell Stem Cell. 2016 May 5;18(5):653-67.
2. 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. Conversion of human fibroblasts into functional cardiomyocytes by small molecules.
Science. 2016 Apr 28.[Epub ahead of print]
3. Zhang Y, Cao N, Huang Y, Spencer CI, Fu JD, Yu C, Liu K, Nie B, Xu T, Li K, Xu S, Bruneau BG, Srivastava D, Ding S. Expandable Cardiovascular Progenitor Cells Reprogrammed from Fibroblasts.
Cell Stem Cell. 2016 Mar 3;18(3):368-81.
4. Zhu S, Russ HA, Wang X, Zhang M, Ma T, Xu T, Tang S, Hebrok M, Ding S. Human pancreatic beta-like cells converted from fibroblasts.
Nat Commun. 2016 Jan 6;7:10080.
5. Ma T, Li J, Xu Y, Yu C, Xu T, Wang H, Liu K, Cao N, Nie BM, Zhu SY, Xu S, Li K, Wei WG, Wu Y, Guan KL, Ding S. Atg5-independent autophagy regulates mitochondrial clearance and is essential for iPSC reprogramming.
Nat Cell Biol. 2015 Nov;17(11):1379-87.
6. Tang S, Xie M, Cao N, Ding S. Patient-Specific Induced Pluripotent Stem Cells for Disease Modeling and Phenotypic Drug Discovery.
J Med Chem. 2016 Jan 14;59(1):2-15..
7. Zhu S, Wang H, Ding S.Reprogramming fibroblasts toward cardiomyocytes, neural stem cells and hepatocytes by cell activation and signaling-directed lineage conversion.
Nature Protocol 10(7):959-73, 2015.
8. Nie T, Hui X, Gao X, Nie B, Mao L, Tang X, Yuan R, Li K, Li P, Xu A, Liu P, Ding S, Han W, Cooper GJ, Wu D. Conversion of non-adipogenic fibroblasts into adipocytes by a defined hormone mixture.
Biochem J. 467(3):487-94, 2015.
9. Yu C, Liu Y, Ma T, Liu K, Xu S, Zhang Y, Liu H, La Russa M, Xie M, Ding S, Qi LS. Small molecules enhance CRISPR genome editing in pluripotent stem cells.
Cell Stem Cell 16, 142-7, (2015).
10. Yu C, Liu K, Tang S, Ding S. Chemical approaches to cell reprogramming.
Curr Opin Genet Dev. 28:50-6, (2014).
11. Ding S. Deciphering therapeutic reprogramming.
Nature Medicine 20, 816-817, (2014).
12. Jin C, Yang L, Xie M, Lin C, Merkurjev D, Yang JC, Tanasa B, Oh S, Zhang J, Ohgi K, Zhou H, Li W, Evans CP, Ding S & Rosenfeld MG. Chem-seq permits identification of genomic targets of drugs against androgen receptor regulation selected by functional phenotypic screens.
Proc Natl Acad Sci USA 111, 9235-9240, (2014).
13. Zhu S, Rezvani M, Harbell J, Mattis AN, Wolfe AR, Benet LZ, Willenbring H & Ding S. Mouse liver repopulation with hepatocytes generated from human fibroblasts.
Nature 508, 93-97, (2014).
14. Li K, Zhu S, Russ HA, Xu S, Tao X, Zhang Y, Ma T, Hebrok M and Ding S. Small Molecules Facilitate the Reprogramming of Mouse Fibroblasts into Pancreatic Lineages.
Cell Stem Cell 14, 228-36, (2014).
15. Wang H, Cao N, Spencer CI, Nie B, Ma T, Xu T, Zhang Y, Wang X, Srivastava D, Ding S. Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4.
Cell Report 6(5):951-60, (2014).
16. Xie M, Cao N, Ding S. Small molecules for cell reprogramming and heart repair: progress and perspective.
ACS Chem Biol. 9(1):34-44, (2014).
17. Zhu S, Ambasudhan R, Sun W, Kim HJ, Talantova M, Wang X, Zhang M, Zhang Y, Laurent T, Parker J, Kim HS, Zaremba JD, Saleem S, Sanz-Blasco S, Masliah E, McKercher SR, Cho YS, Lipton SA, Kim J, Ding S. Small molecules enable OCT4-mediated direct reprogramming into expandable human neural stem cells.
Cell Res. 24(1):126-9, (2014).
18. Zhao JJ, Ouyang H, Luo J, Patel S, Xue Y, Quach J, Sfeir N, Zhang M, Fu X, Ding S, Chen S, Zhang K. Induction of Retinal Progenitors and Neurons from Mammalian Muller Glia under Defined Conditions
. J Biol Chem. 289(17):11945-51, (2014).
19. Fu JD, Stone NR, Liu L, Spencer CI, Qian L, Hayashi Y, Delgado-Olguin P, Ding S, Bruneau BG, Srivastava D. Direct Reprogramming of Human Fibroblasts toward a Cardiomyocyte-like State.
Stem Cell Reports 1(3):235-47, (2013).
20. Calvanese V, Chavez L, Laurent T, Ding S, Verdin E. Dual-color HIV reporters trace a population of latently infected cells and enable their purification.
Virology 446(1-2):283-92, (2013).
21. Lu B, Morgans CW, Girman S, Luo J, Zhao J, Du H, Lim S, Ding S, Svendsen C, Zhang K, Wang S. Neural Stem Cells Derived by Small Molecules Preserve Vision.
Transl Vis Sci Technol. 2(1):1, (2013).
22. Li W, Ding S. Converting mouse epiblast stem cells into mouse embryonic stem cells by using small molecules.
Methods Mol Biol. 1074:31-7, (2013).
23. Li W, Li K, Wei W, Ding S. Chemical Approaches to Stem Cell Biology and Therapeutics.
Cell Stem Cell 13, 270-283, (2013).
24. Li W, Ding S. Converting mouse epiblast stem cells into mouse embryonic stem cells by using small molecules.
Methods Mol Biol. 1074:31-7, (2013).
25. Lin C, Yu C, Ding S. Toward directed reprogramming through exogenous factors.
Curr Opin Genet Dev. 23(5):519-25, (2013).
26. Xu T, Zhang M, Laurent T, Xie M, Ding S. chemical approaches for modulating lineage-specific stem cells and progenitors.
Stem Cells Transl Med. 2(5):355-61, (2013).
27. Wang F, Scoville D, He XC, Mahe M, Box A, Perry J, Smith NR, Lei Nanye N, Davies PS, Fuller MK, Haug JS, McClain M, Gracz AD, Ding S, Stelzner M, Dunn JC, Magness ST, Wong MH, Martin M, Helmrath M, Li L. Isolation and Characterization of Intestinal Stem Cells Based on Surface Marker Combinations and Colony-Formation Assay.
Gastroenterology 145(2):383-95.e1-21, (2013).
28. Li J, Huang NF, Zou J, Laurent TJ, Lee JC, Okogbaa J, Cooke JP, Ding S. Conversion of Human Fibroblasts to Functional Endothelial Cells by Defined Factors.
Arterioscler Thromb Vasc Biol. 33(6):1366-75, (2013).
29. Li W, Jiang K, Wei W, Shi Y, Ding S. Chemical approaches to studying stem cell biology.
Cell Res. 23 (1):81-91, (2013).
30. Zhao J, Sun W, Cho HM, Ouyang H, Li W, Lin Y, Do J, Zhang L, Ding S, Liu Y, Lu P, Zhang K. Integration and long distance axonal regeneration in the central nervous system from transplanted primitive neural stem cells.
J Biol Chem. 288(1):164-8, (2013).
31. Ma T, Xie M, Laurent T, Ding S. Progress in the reprogramming of somatic cells.
Circulation Research 112(3):562-74, (2013).
32. Zhang Y, Li W, Laurent T, Ding S. Small molecules, big roles -- the chemical manipulation of stem cell fate and somatic cell reprogramming.
J Cell Sci. 125, 5609-20, (2012).
33. Kim J, Ambasudhan R, Ding S. Direct lineage reprogramming to neural cells.
Current Opinion in Neurobiology 22(5):778-84, (2012).
34. Nie B, Wang H, Laurent T, Ding S. Cellular reprogramming: a small molecule perspective.
Curr Opin Cell Biol. 24(6):784-92, (2012).
35. Westenskow PD, Moreno SK, Krohne TU, Kurihara T, Zhu S, Zhang ZN, Zhao T, Xu Y, Ding S, Friedlander M. Using flow cytometry to compare the dynamics of photoreceptor outer segment phagocytosis in iPS-derived RPE cells.
Invest Ophthalmol Vis Sci. 14;53(10):6282-90, (2012).
36. Liu K, Ding S. Target practice: modeling tumors with stem cells.
Cell 149, 1185-1187, (2012).
37. Li H, Zhou H, Wang D, Qiu J, Zhou Y, Li X, Rosenfeld MG, Ding S, Fu XD. Versatile pathway-centric approach based on high-throughput sequencing to anticancer drug discovery.
Proc Natl Acad Sci U S A 109(12):4609-14, (2012).
38. Li W, Jiang K, Ding S. A chemical approach to control cell fate and function.
Stem Cells 30(1):61-8, (2012).
39. Ukrohne TU, Westenskow PD, Kurihara T, Friedlander DF, Lehmann M, Dorsey AL, Li W, Zhu S, Schultz A, Wang J, Siuzdak G, Ding S, Friedlander M. Generation of retinal pigment epithelial cells from small molecules and OCT4 reprogrammed human induced pluripotent stem cells.
Stem Cells Transl Med. 1(2):96-109, (2012).
40. Krohne TU, Westenskow PD, Kurihara T, Friedlander DF, Lehmann M, Dorsey AL, Li W, Zhu S, Schultz A, Wang J, Siuzdak G, Ding S. Friedlander M. Generation of retinal pigment epithelial cells from small molecules and OCT4-reprogrammed human induced pluripotent stem cells.
Paediatr Int Child Health 1(2):96-109, (2012).
41. Efe JA, Hilcove S, Kim J, Zhou H, Ouyang K, Wang G, Chen J, Ding S. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy.
Nature Cell Biology 13, 215–222, (2011).
42. Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton SA, Ding S. Direct Reprogramming of Adult Human Fibroblasts to Functional Neurons under Defined Conditions.
Cell Stem Cell 9, 113-118, (2011).
43. Zhang K. and Ding S. Stem Cells and Eye Development,
N Engl J Med 365:370 – 372, (2011).
44. Li W, Ding S. Human pluripotent stem cells: decoding the naïve state.
Sci Transl Med. 3(76):76ps10. (2011).
45. Zhu S, Wei W, Ding S. Chemical Strategies for Stem Cell Biology and Regenerative Medicine.
Annu Rev Biomed Eng. 13:73–90, (2011).
46. Li W, Sun W, Zhang Y, Wei W, Ambasudhan R, Xia P, Talantova M, Lin T, Kim J, Wang X, Kim WR, Lipton SA, Zhang K, Ding S. Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors.
Proc. Natl. Acad. Sci. USA 108 (20) 8299-8304, (2011).
47. Yuan X, Wan H, Zhao X, Zhu S, Zhou Q, Ding S, Combined Chemical Treatment Enables Oct4-Induced Reprogramming from Mouse Embryonic Fibroblasts.
Stem Cells 29(3), 549-53, (2011).
48. Kim J, Efe JA, Zhu S, Talantova M, Yuan X, Wang S, Lipton SA, Zhang K, Ding S. Direct reprogramming of mouse fibroblasts to neural progenitors.
Proc. Natl. Acad. Sci. USA 108 (19) 7838-7843, (2011).
49. Li Y, Prasad A, Jia Y, Roy SG, Loison F, Mondal S, Kocjan P, Silberstein LE, Ding S, Luo HR. Pretreatment with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670 augments the efficacy of granulocyte transfusion in a clinically relevant mouse model.
Blood 117(24):6702-13, (2011).
50. P Perry JM, He XC, Sugimura R, Grindley JC, Haug JS, Ding S, Li L. Cooperation between both Wnt/β-catenin and PTEN/PI3K/Akt signaling promotes primitive hematopoietic stem cell self-renewal and expansion.
Genes Dev. 25, 1928-42, (2011).
51. Zhu S, Ma T, Li J, Ding S. Recent advances in chemically induced reprogramming.
Cell Cycle 10(6):871-2 (2011).
52. Xu T, Wang X, Zhong B, Nurieva RI, Ding S, Dong C. Ursolic Acid Suppresses Interleukin-17 (IL-17) Production by Selectively Antagonizing the Function of ROR{gamma}t Protein.
J Biol Chem. 286(26):22707-10, (2011).
53. Efe JA, Ding S. Reprogramming, transdifferentiation and the shifting landscape of cellular identity.
Cell Cycle 10(12):1886-7, (2011).
54. Shen Y, Shi C, Wei W, Yu W, Li W, Yang Y, Xu J, Ying W, Sui X, Fang L, Lin W, Yang H, Ding S, Shen H, Shi Y, Deng H. The heterogeneity and dynamic equilibrium of rat embryonic stem cells.
Cell Res. 21(7):1143-7, (2011).
55. Efe JA, Ding S. The evolving biology of small molecules: controlling cell fate and identity.
Philos Trans R Soc Lond B Biol Sci. 366(1575):2208-21, (2011).
56. Wang Q, Xu X, Li J, Liu J, Gu H, Zhang R, Chen J, Kuang Y, Fei J, Jiang C, Wang P, Pei D, Ding S, Xie X. Lithium, an anti-psychotic drug, greatly enhances the generation of induced pluripotent stem cells.
Cell Res. 21(10):1424-35, (2011).
57. Liu J, Johnson K, Li J, Piamonte V, Steffy BM, Hsieh MH, Ng N, Zhang J, Walker JR, Ding S, Muneoka K, Wu X, Glynne R, Schultz PG. Regenerative phenotype in mice with a point mutation in transforming growth factor beta type I receptor (TGFBR1).
Proc. Natl. Acad. Sci. USA 108(35):14560-5, (2011).
58. Efe JA, Yuan X, Jiang K, Ding S. Development unchained: how cellular reprogramming is redefining our view of cell fate and identity.
Sci Prog. 94, 298-322, (2011).
59. Ko SH, Nauta A, Morrison SD, Zhou H, Zimmermann A, Gurtner GC, Ding S, Longaker MT. Antimycotic ciclopirox olamine in the diabetic environment promotes angiogenesis and enhances wound healing.
PLoS One 6(11):e27844, (2011).
