Office: (217) 333-5972
Lab: (217) 333-6007
Mail to: Dept. of Cell and Developmental Biology
University of Illinois
601 S. Goodwin Avenue
Urbana, IL 61801
Associate Professor of Cell and Developmental Biology
Development, Drug Discovery, Neurobiology, Reproductive Biology, Signal Transduction
B.S., Beijing University (Biochemistry)
M.S., University of Illinois at Urbana-Champaign (Biochemistry)
Ph.D., University of California at Berkeley (Biochemistry and Molecular Biology)
Postdoc., University of California at San Francisco (Cell and Developmental Biology)
Human pluripotent stem cells; early embryonic development; neutrophil polarity and chemotaxis
1. The molecular programs that control fate decisions of human pluripotent stem cells
Nearly 20 years after murine embryonic stem cells (mESC) were isolated, the first report of the derivation of human embryonic stem cells (hESCs) in 1998 spawned the field of hESC research. Although this field is only in its infancy, hESCs have already been shown to be capable of long-term self-renewal in culture and have remarkable potential to develop into many different cell types in the body (known as pluripotency). They therefore represent a theoretically inexhaustible source of precursor cells to treat degenerative, malignant, or genetic diseases, or injury due to inflammation, infection, and trauma. Meanwhile, hESCs are an invaluable research tool to study human development, both normal and abnormal, and can serve as a platform to develop and test new drugs. In addition to hESCs, the recent derivation of human induced pluripotent stem cells (hiPSCs) from somatic cells has made it possible to use pluripotent stem cells for patient-specific therapy.
Our long-term goal is to define new conditions and molecular programs that govern fate decisions of hESCs/hiPSCs. The knowledge is essential if we are ultimately to use these cells for therapy. To dissect the mechanism underlying hESC/hiPSC fate determination, we screened a collection of pharmacological inhibitors (~50) against kinases and other signaling molecules, enabling us to identify mTOR as a critical pluripotency-maintaining molecule in hESCs and uncover an mTOR-dependent signaling mechanism that suppresses mesoderm and endoderm differentiation (Zhou et al, PNAS, 2009). The screening efforts led us to also identify an E-cadherin-based highly integrated biochemical and mechanical signaling network essential for intercellular adhesion, stability of the transcriptional circuitry for pluripotency and long-term survival of hESCs/hiPSCs (Li et al, JCB, 2010). In addition, we discovered compound C, a kinase inhibitor, as a potent regulator of hESC/hiPSC fate. Compound C suppresses mesoderm, endoderm and trophoectoderm differentiation and induces rapid and high-efficiency neural conversion in both hESCs and hiPSCs (up to 90%) (Zhou et al, Stem Cells, 2010). Compound C targets at least seven TGF-beta superfamily receptors and thereby blocks both the Activin and BMP signaling pathways, which accounts for compound C's ability to induce high-efficiency neural conversion.This small-scale screening provided proof-of-concept for applying large-scale library screening to the study of hESCs/hiPSCs. Through large-scale screening of small molecules and shRNAs, we have identified a number of novel regulatory components of hESC/hiPSC pluripotency and directed differentiation. In the next few years we will extend these findings to gain new and more comprehensive mechanistic insights into pluripotency and early lineage specifications in hESCs/hiPSCs. The results of these studies will markedly improve our knowledge of the molecular mechanisms underlying hESC fate determination and may contribute to effective strategies for tissue repair and regeneration. They may also facilitate the derivation, characterization, and/or utilization of hiPSCs.
Figure 1. H9 human embryonic stem cells (hESCs) expressing GFP (left) or GFP tagged PDCD4 (middle), which shows a nuclear localization. The phase-contrast image for GFP-PDCD4 cells is also shown (right). hESCs grow in large compact colonies.
2. The mechanisms of neutrophil polarity and chemotaxis
Cell migration is a highly integrated multi-step process that mediates embryonic development, contributes to tissue repair and regeneration, and drives disease progression in cancer, mental retardation, atherosclerosis, and arthritis. Although the understanding of cell-extracellular matrix (ECM) substrate adhesion in slow-migrating mesenchymal cells has been significantly improved in the past two decades, this key step of cell migration remains poorly defined in highly polarized and rapidly moving amoeboid cells, such as leukocytes, hematopoietic stem cells, and tumor cells. Because of the rapid membrane turnover rates during amoeboid movement, cell adhesion to ECM substrate is viewed as very limited.
Our recent studies contradict this notion and suggest a complex and highly dynamic pattern of adhesion during neutrophil polarization and chemotaxis. We found that cell adhesion is required for neutrophils to establish and maintain polarity. In addition, we have begun to uncover the potential key regulatory components of adhesion. We show that myosin light chain kinase (MLCK) is necessary for leading edge attachment and mediates integrin activity by inducing myosin II-dependent contractility and tension stresses (Shin et al., Blood, 2010). We are also characteriring other regulatory components of neutrophil adhesion such as the non-receptor tyrosine kinase Lyn (He et al, J Cell Science, 2011). These experiments will yield a new level of understanding of the mechanisms that control cell adhesion in neutrophils and in other amoeboid cells. The results from this study will also have direct relevance to the treatment of multiple human diseases, including autoimmune disorders and cancer.
Figure 2. Human neutrophils stimulated with chemoattractant exhibit polarized morphology and asymmetric cytoskeletal assemblies.
1988 Outstanding Undergraduate Award, Beijing University
1992 Named to the Chancellor’s List of Teachers Ranked as Excellent by Their Students, UIUC
1993-1994 Vivian Bryan Nelson Scholarship for Graduate Study, University of California at Berkeley
1995 American Society of Cell Biology (ASCB) Predoctoral Student Travel Award
1996-1997 Regents Fellowship for Graduate Study, Univ. of California at Berkeley
2000-2003 NIH Ruth L Kirschstein - NRSA Postdoctoral Fellowship
2006 Research Award, Illinois Regenerative Medicine Institute (IRMI).
2007 Outstanding Overseas Young Chinese Scholars Award, Chinese National Science Foundation
2009 National Science Foundation CAREER Award
2009-2010 Arnold O. Beckman Research Award (four times)
2010-2012 Teacher Ranked as Excellent, UIUC Center for Teaching Excellence
2012-2013 Center for Nutrition, Learning and Memory (CNLM) Research Award, Abbott Nutrition (project highlighted as showing special promise)
2006 - present
He, Y., Li, D., Cook, S., Yoon, M., Kapoor, A., Rao, C. V., Kenis, P., Chen, J. and Wang, F. (2013) Mammalian Target of Rapamycin and Rictor control neutrophil chemotaxis by regulating Rac/Cdc42 activity and actin polymerization, Mol Biol Cell, in press (Selected for Highlights from MBoC in the ASCB Newsletter).
Zhou, Y., Hunkapiller, N. M., Gormley, M. J., Kapidzic, M., Stolyarov, Y., Feng, V., Nishida, M., Drake, P. M., Bianco, K., Wang, F.*, McMaster, M. T., and Fisher, S. J. (2013) Culturing Cytotrophoblasts Reverses Gene Dysregulation in Preeclampsia Revealing Possible Causes. J Clin Invest, 123, 2862–2872.
Ouyang, M., Lu, S., Chen, C., Kim, T., Seong, J., Reynolds, A. B., Leckband, D. E., Wang, F.*, Schwartz, M. A., Wang, Y. (2013) N-cadherin regulates spatially polarized signals through distinct p120ctn and β-catenin-dependent signaling pathways, Nat Communications, 4, 1589.
Li, D., Yang, H., Nan , H., Liu, P., Pang, S., Zhao, Q., Karni, R., Kamps, M. P., Xu, Y., Zhou, J., Wiedmer, T., Sims, P. J., and Wang, F.* (2012) Identification of key regulatory pathways of myeloid differentiation using an mESC-based karyotypically normal cell model. Blood, 120, 4712-9 (Highlighted by ESC and iPSC News; ScienceDaily; MedicalXpress; News Release).
Gabrielson, N. P., Lu, H., Yin, L., Li, D., Wang, F.*, and Cheng, J.* (2012) A Reactive and Bioactive Cationic Alpha-Helical Polypeptide Template for Non-Viral Gene Delivery. Angew Chem, 51, 1143-7. *Corresponding author
Zhou, J., Li, D., and Wang, F.* (2012) Assessing the function of mTOR in human embryonic stem cells. Methods in Molecular Biology, 821, 361-72.
Liang, Y., Jeong, J., DeVolder, R. J., Cha, C., Wang, F.*, Tong, Y, and Kong, H. (2011) A Cell-Instructive Hydrogel to Regulate Malignancy of 3D Tumor Spheroids with Matrix Rigidity. Biomaterials, 32, 9308-15.
Lu, H., Bai, Y., Wang, J., Gabrielson, N., Wang, F.*, Lin, Y., and Cheng, J. (2011) Ring-Opening polymerization of γ-(4-Vinylbenzyl)-L-Glutamate N-carboxyanhydride for the synthesis of functional polypeptides. Macromolecules, 44, 6237-6240.
Yang, R., Jiang, M., Kumar, T., Xu, T, Wang, F.*, Xiang, L., and Xu, X. (2011) Generation of melanocytes from Induced pluripotent stem cells. Journal of Investigative Dermatology, 131, 2458-66.
He, Y., Kapoor, A., Cook, S., Liu, S., Xiang, Y., Rao, C. V., Kenis, P., and Wang, F.* (2011) The non-receptor tyrosine kinase Lyn controls neutrophil adhesion by recruiting the CrkL/C3G complex to and activating Rap1 at the leading edge. J Cell Science, 124, 2153-2164
Liu, S., Liu, S., Wang, X., Zhou, J., Cao, Y., Wang, F.*, and Duan, E. (2011) The PI3K-Akt Pathway Inhibits Senescence and Promotes Self-Renewal of Human Skin-Derived Precursors in Vitro. Aging Cell, 10, 661-74.
Li, D., Zhou, J., Chowdhury, F., Cheng, J., Wang, N., and Wang, F.* (2011) Role of mechanical factors in fate decisions of stem cells. Regenerative Medicine, 6, 229-240 (invited review). *Corresponding author
Li, D., Zhou, J., Wang, L., Shin, M. E., Su, P., Lei, X., Kuang, H., Guo, W., Yang, H., Cheng, L., Tanaka, T. S., Reynolds, A. B., Duan, E., and Wang, F.* (2010) Integrated biochemical and mechanical signals regulate multifaceted human embryonic stem cell functions. J Cell Biol, 191,631-44. (highlighted in News - In Focus, J Cell Biol, 191, 2010; Featured in Faculty of 1000)
Shen, Z., Sathyan, K. M., Geng, Y., Zheng, R., Freeman, B., Wang, F.*, Prasanth, K. V., Prasanth, S. G. (2010) A novel WD-repeat protein stabilizes ORC binding to chromatin. Mol Cell, 40, 99-111.
Tang, X., Kuhlenschmidt, T. B., Zhou, J., Bell, P., Wang, F.*, Kuhlenschmidt, M. S., and Saif, T. A. (2010) Mechanical Force affects expression of an In vitro metastasis-like phenotype in HCT-8 cells. Biophys J, 99, 2460-69.
Zhou, J., Su, P., Li, D., Tsang, S., Duan, E., Wang, F.* (2010) High-Efficiency Induction of Neural Conversion in hESCs and hiPSCs with a Single Chemical Inhibitor of TGF-beta Superfamily Receptors. Stem Cells, 28, 1741-50.
Shin, M.E., He, Y., Li, D., Chowdhury, F., Collin, O., Na, S., Pei, S., de Lanerolle, P., Schwartz, M.A., Wang, N., and Wang, F.* (2010) Spatiotemporal organization, regulation and functions of tractions during neutrophil chemotaxis. Blood, 116, 3297-310.
Chowdhury, F., Na, S., Li, D., Poh, Y.C., Tanaka, T., Wang, F.*, and Wang, N. (2010) Material properties of the cell dictate stress-induced spreading and differentiation in embryonic stem cells. Nature Materials, 9:82–8.
Wang, F.* (2009) The signaling mechanisms underlying cell polarity and chemotaxis. Cold Spring Harb Perspect Biol, 1,4.
Zhou, J., Su, P., Wang, L., Chen, J., Zimmermann, M., Genbacev, O., Afonja, O., Horne, M., Tanaka, T., Duan, E., Fisher, S.J., Liao, J., Chen, J., and Wang, F.* (2009) mTOR Supports Long-Term Self-Renewal and Suppresses Mesoderm and Endoderm Activities in human embryonic stem cells. Proc Natl Acad Sci U S A., 106:7840–5. (Direct submission)
Collin, O., Na, S, Chowdhury, F., Hong, M., Shin, M., Wang, F.*, and Wang, N. (2008) Self-organized podosomes are dynamic mechanosensors. Curr Biol, 18:1288-94.
Chen, S., Lin, F., Shin, M., Wang, F.*, Shen, L., and Hamm, H.E. (2008) RACK1 regulates directional cell migration by acting on G betagamma at the interface with its effectors PLC beta and PI3K gamma. Mol Biol Cell, 19:3909-22.
Herzmark, P., Campbell, K., Wang, F.*, El-Samad, H., Groisman, A., and Bourne, H.R. (2007) Bound attractant at the leading vs. the trailing edge determines chemotactic prowess. Proc Natl Acad Sci U S A., 104,13349-54.
Zhao, M., Song, B., Pu, J., Wada, T., Reid, B., Tai, G., Wang, F.*, Guo, A., Walczysko, P., Gu, Y., Sasaki, T., Suzuki, A., Forrester, J. V., Bourne, H. R, Devreotes, P. N., McCaig, C. D., and Penninger, J.M. (2006) Electric signals control wound healing via phosphatidylinositol-3 kinase-gamma and PTEN. Nature, 442:457–60. [Abstract]
1998 - 2005
Xu, J., Wang, F.#, Van Keymeulen, A., Rentel, M., and Bourne, H. R. (2005) Neutrophil microtubules suppress polarity and enhance directional migration. Proc Natl Acad Sci USA, 102:6884–9.[Abstract]
# Co-first author
Xu, J., Wang, F.#, Van Keymeulen, A., Herzmark, P., Straight, A., Kelly, K., Takuwa, Y., Mitchison, T., and Bourne, H. R. (2003) Divergent signals and cytoskeletal assemblies regulates self-organizing polarity in neutrophils. Cell, 114:201–14. [Abstract]
# Co-first author
Srinivasan, S., Wang, F.#, Glavas, S., Ott, A., Hofmann, F., Aktories, K., Kalman, D., Hahn, K., and Bourne, H. R. (2003) Rac and Cdc42 play distinct roles in regulating PI(3,4,5)P3 and polarity during neutrophil chemotaxis. J Cell Biol, 160:375–85.[Abstract]
# Co-first author
Wang, F., Herzmark, P., Weiner, O. W., Srinivasan, S., Servant G., and Bourne, H. R. 2002. The lipid products of PI3K maintain persistent cell polarity and directed motility in neutrophils. Nat Cell Biol, 4:513–8. [Abstract]
Wang, F ., Hansen, R. K., Radisky, D., Petersen, O. W., Yoneda, T., Barcellos-Hoff, M. H., Turley, E. H., and Bissell, M. J. (2002) Phenotypic reversion or death of cancer cells by altering signaling pathways in three-dimensional contexts. J Natl Cancer Inst, 94, 1494-503.
Wang, F ., Weaver, V. M., Petersen, O. W., Larabell, C. A., Dedhar, S., Briand, P., Lupu, R., and Bissell, M. J. (1998) Reciprocal interactions between beta-1 integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in normal and malignant epithelial biology. Proc Natl Acad Sci U S A, 95, 14821-26.