Our long-term goal is to define new conditions and molecular programs that govern fate decisions of human pluripotent stem cells such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (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. 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. 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%). 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. Accordingly, we conducted large-scale screening of small molecules and shRNAs and identified a number of novel regulator components of hESC/hiPSC pluripotency and directed differentiation. In the next few years we will extend these findings to provide new 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 fate determination and may contribute to effective strategies for tissue repair and regeneration.
Dr. Wang received his B.S. degree in Beijing University in 1988, majoring in Biochemistry. He came to the University of Illinois at Urbana-Champaign in 1990 and was awarded a M.S. degree in Biochemistry in 1993. Dr. Wang received his Ph.D training in Dr. Mina Bissell's laboratory at UC Berkeley. As a graduate student in Dr. Bissell's lab, he made significant contributions toward the understanding of signaling mechanisms that regulate normal breast tissue structures and cancer progression. His study was part of Dr. Bissell's pioneering work in understanding the role of the microenvironment and 3-dimensional architecture in cell and cancer biology.
After getting his Ph.D, Dr. Wang went to UCSF and first worked with Dr. Henry Bourne to dissect the signaling network mediating neutrophil polarity and chemotaxis. His studies in the Bourne lab (1998-2004) provided insights into the molecular mechanisms underlying the neutrophil's highly polarized and motile response. Dr. Wang did a short-term postdoctoral study with Dr. Susan Fisher (2004-2005) to work with human adult and embryonic stem cells. Dr. Wang joined the Department of Cell and Developmental Biology at UIUC as an assistant professor in November 2005. He is also a core faculty in the Regenerative Biology and Tissue engineering Theme at IGB and an affiliate member in the Department of Bioengineering and Neuroscience program.
Researchers should cite this work as follows:
1000 MNTL, University of Illinois at Urbana-Champaign, Urbana, IL