The transitions from egg to embryo to adult require that cells communicate with each other to acquire specialized fates at the right times in the correct places. Cancer is in part the result of aberrant regulation. Most of our information on signaling pathways comes from genetics and biochemistry on populations of cells, with stimuli typically reduced to a binary on/off. This project will adapt contemporary microfluidic technology to accurately control the concentrations of signaling molecules in time in multiple small chambers while continuously imaging the response of single cells via fluorescently tagged proteins that move in response to signals. We will use human embryonic stem cells (hESC) for this purpose because of their relevance to regenerative medicine. We will stimulate the cells with ligands from the TGF? pathway since they can induce the first round of developmental choices these cells naturally make. This pathway has two sub-branches that interfere, making it a natural context in which to study pathway interactions. Our data will be organized and developed into a predictive tool with which to rationally reprogram specialized fates from hESCs.
To use human embryonic stem cells for regenerative medicine requires the ability to direct the differentiation of these cells to the required fates without causing genetic damage. We will follow the first steps of stem cell differentiation using new high-resolution techniques drawn from Physics and integrate the results using topological methods into predictive models.
|Deglincerti, Alessia; Haremaki, Tomomi; Warmflash, Aryeh et al. (2015) Coco is a dual activity modulator of TGFÎ² signaling. Development 142:2678-85|
|Warmflash, Aryeh; Sorre, Benoit; Etoc, Fred et al. (2014) A method to recapitulate early embryonic spatial patterning in human embryonic stem cells. Nat Methods 11:847-54|
|Sorre, Benoit; Warmflash, Aryeh; Brivanlou, Ali H et al. (2014) Encoding of temporal signals by the TGF-Î² pathway and implications for embryonic patterning. Dev Cell 30:334-42|
|Siggia, Eric D; Vergassola, Massimo (2013) Decisions on the fly in cellular sensory systems. Proc Natl Acad Sci U S A 110:E3704-12|
|Ozair, Mohammad Zeeshan; Noggle, Scott; Warmflash, Aryeh et al. (2013) SMAD7 directly converts human embryonic stem cells to telencephalic fate by a default mechanism. Stem Cells 31:35-47|
|Warmflash, Aryeh; Francois, Paul; Siggia, Eric D (2012) Pareto evolution of gene networks: an algorithm to optimize multiple fitness objectives. Phys Biol 9:056001|
|Warmflash, Aryeh; Zhang, Qixiang; Sorre, Benoit et al. (2012) Dynamics of TGF-Î² signaling reveal adaptive and pulsatile behaviors reflected in the nuclear localization of transcription factor Smad4. Proc Natl Acad Sci U S A 109:E1947-56|
|Warmflash, Aryeh; Arduini, Brigitte L; Brivanlou, Ali H (2012) The molecular circuitry underlying pluripotency in embryonic stem cells. Wiley Interdiscip Rev Syst Biol Med 4:443-56|
|Warmflash, Aryeh; Siggia, Eric D; Brivanlou, Ali H (2012) Signaling dynamics and embryonic development. Cell Cycle 11:3529-30|
|FranÃ§ois, Paul; Siggia, Eric D (2012) Phenotypic models of evolution and development: geometry as destiny. Curr Opin Genet Dev 22:627-33|