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TAZ sends 'mixed signals' to stem cells
According to new research from the Keck School of Medicine, University of Southern California (USC), Los Angeles, and published in Stem Cell Reports, a protein called TAZ can send very different signals — depending upon which variety of stem cell initiates the signal, and also which part of a stem cell receives the signal.
When it comes to stem cells, some are "naïve" blank slates while others are "primed" to differentiate into certain types of specialized cells. Among truly naïve cells are mouse embryonic stem cells (ESCs), while a primed variety includes slightly more differentiated mouse epiblast stem cells (EpiSCs) and so-called human "ESCs" - which may not be true ESCs at all.
"TAZ provides a new tool to stimulate stem cells to either differentiate or self-renew. This could prove important in regenerative medicine, including the development of a better way to generate the desired cell types for cell replacement therapy."
In this new study, PhD student Xingliang Zhou, and colleagues in the laboratory of Qi-Long Ying, demonstrate that naïve mouse ESCs don't require TAZ in order to self-renew and produce more stem cells. However, they do need TAZ in order to differentiate into mouse EpiSCs.
The scientists observed an even more nuanced situation for the primed varieties of stem cells: mouse EpiSCs and human ESCs. When TAZ is located in the nucleus, this prompts primed stem cells to differentiate into more specialized cell types — a response similar to that of the naïve cells. However, if TAZ is in the cytoplasm, or the region between the nucleus and outer membrane, primed stem cells have the opposite reaction: they self-renew.
"TAZ has stirred up a lot of controversy in our field, because it appears to produce diverse and sometimes opposite effects in pluripotent stem cells.
• TAZ is a binding partner of cytoplasmic ß-catenin
• TAZ is essential for the conversion of mESCs to mEpiSCs
• Cytoplasmic retention of TAZ promotes mEpiSC and hESC self-renewal
• Nuclear translocation of TAZ induces mEpiSC and hESC differentiation
Mouse epiblast stem cells (mEpiSCs) and human embryonic stem cells (hESCs) are primed pluripotent stem cells whose self-renewal can be maintained through cytoplasmic stabilization and retention of ß-catenin. The underlying mechanism, however, remains largely unknown. Here, we show that cytoplasmic ß-catenin interacts with and retains TAZ, a Hippo pathway effector, in the cytoplasm. Cytoplasmic retention of TAZ promotes mEpiSC self-renewal in the absence of nuclear ß-catenin, whereas nuclear translocation of TAZ induces mEpiSC differentiation. TAZ is dispensable for naive mouse embryonic stem cell (mESC) self-renewal but required for the proper conversion of mESCs to mEpiSCs. The self-renewal of hESCs, like that of mEpiSCs, can also be maintained through the cytoplasmic retention ofß-catenin and TAZ. Our study indicates that how TAZ regulates cell fate depends on not only the cell type but also its subcellular localization.
ß-catenin, TAZ, Hippo pathway, Wnt signaling pathway, epiblast stem cell, human embryonic stem cell, primed pluripotency, stem cell self-renewal
Authors of the study: Xingliang Zhou, Jean Paul Chadarevian, Bryan Ruiz, Qi-Long Ying
This research project was funded by a California Institute for Regenerative Medicine (CIRM) New Faculty Award II (RN2-00938), a CIRM Scientific Excellence through Exploration and Development (SEED) Grant (RS1-00327), and the Chen Yong Foundation of the Zhongmei Group. Zhou was also supported by a federally funded predoctoral fellowship from the Eunice Kennedy Shriver National Institute of Child Health and Human Development/USC Joint T32 Training Program in Developmental Biology, Stem Cells, and Regeneration.
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The protein TAZ (GREEN) in the cytoplasm (BLUE: the region outside of the nuclei) promotes the self-renewal of human embryonic stem cells. Image Credit: Xingliang Zhou/Ying Lab, USC Stem Cell