Grant Award Details
- The goal of this award is to interrogate the mechanisms underlying STAT3 function in mESC, which are known to require the activity of the LIF/STAT3 pathway, and to determine the role this pathway plays in hESC, if any.
Grant Application Details
- Mechanisms Underlying the Diverse Functions of STAT3 in Embryonic Stem Cell Fate Regulation
Embryonic stem cells (ESCs) are derived from very early stage embryos. ESCs can be maintained in culture indefinitely while retain the ability to make any type of cell in the body. These properties make ESCs a very powerful tool to address basic biology questions. ESCs also offer an important renewable resource for future cell replacement therapies for many diseases such as Parkinson’s disease, spinal cord injury, etc. However, before the full potential of ESCs can be exploited in the clinic, we need to understand more about their biological properties so that we can control their fate towards either self-renewal or differentiation into a specific cell type required for cell replacement therapy. STAT3 is a major player in controlling the fates of a variety of cell types including ESCs. Recently we demonstrated that STAT3 has diverse and distinct roles in regulating cell fate in both mouse and human ESCs. In mouse ESCs, STAT3 is involved in cell adhesion, cell growth/survival and maintenance of self-renewal. Interestingly, STAT3 seems to have opposite roles in human ESCs. It induces growth arrest and differentiation of human ESCs. Why does the same factor play such diverse and contradictory roles between these very similar cells? The answer may lie on how STAT3 is in action. STAT3 is present in every type of cell. It contains six distinct functional regions. STAT3 can directly induce the expression of many genes. STAT3 can also cooperate with other proteins to regulate gene expression. We recently derived STAT3-/- ES cells in which the STAT3 gene was removed. These cells will provide us a powerful tool to dissect STAT3 function. We will first determine the role of each of its six functional regions. Then we will try to understand why they function differently. Is it because they induce different sets of genes, or because they cooperate with different partners? Understanding how STAT3 works is important for us to control the fate of ESCs, and for their eventual clinical application.
Human embryonic stem cells (hESCs) can reproduce themselves in a culture dish. They can also give rise to every cell type in the body. In the future, hESCs may hold the key to replacing cells lost in many devastating diseases such as Parkinson’s disease, spinal cord injury, etc. Before hESCs can be used clinically, however, we must learn more about how to control their fate. STAT3 is a key player in regulating ES cell fate. STAT3 is also involved in the pathogenesis of diverse human cancers. In this proposed research, we will use a unique tool developed by us to understand STAT3's function. Our work will lead to a better understanding how hESC fate is regulated, which will be an important step towards achieving the therapeutic potential of hESCs. We also expect that our research will have a great implication in developing effective cancer therapies against novel STAT3 targets identified in this study.
- Biol Open (2017) Depletion of Tcf3 and Lef1 maintains mouse embryonic stem cell self-renewal. (PubMed: 28288968)
- J Cell Sci (2016) Wnt/beta-catenin and LIF-Stat3 signaling pathways converge on Sp5 to promote mouse embryonic stem cell self-renewal. (PubMed: 26598557)
- Cell Mol Life Sci (2015) Molecular basis of embryonic stem cell self-renewal: from signaling pathways to pluripotency network. (PubMed: 25595304)
- Stem Cells Int (2015) Dual Function of Wnt Signaling during Neuronal Differentiation of Mouse Embryonic Stem Cells. (PubMed: 25945099)
- Curr Opin Genet Dev (2015) New insights into the conserved mechanism of pluripotency maintenance. (PubMed: 26183186)
- Stem Cell Reports (2015) Klf2 and Tfcp2l1, Two Wnt/beta-Catenin Targets, Act Synergistically to Induce and Maintain Naive Pluripotency. (PubMed: 26321140)
- BMB Rep (2015) Stem cell maintenance by manipulating signaling pathways: past, current and future. (PubMed: 26497581)
- Stem Cells (2014) STAT3 Phosphorylation at Tyrosine 705 and Serine 727 Differentially Regulates Mouse ESC Fates. (PubMed: 24302476)
- Curr Opin Genet Dev (2014) Signaling pathways in induced naive pluripotency. (PubMed: 25173148)
- Biol Open (2014) Stat3 signaling regulates embryonic stem cell fate in a dose-dependent manner. (PubMed: 25238758)
- J Cell Sci (2013) Gbx2, a LIF/Stat3 target, promotes reprogramming to and retention of the pluripotent ground state. (PubMed: 23345404)
- Nat Commun (2013) Modulation of beta-catenin function maintains mouse epiblast stem cell and human embryonic stem cell self-renewal. (PubMed: 23985566)
- EMBO J (2013) Embryonic stem cell self-renewal pathways converge on the transcription factor Tfcp2l1. (PubMed: 23942238)