title: Fas-Activated Mitochondrial Apoptosis Culls Stalled Embryonic Stem Cells to Promote Differentiation.
abstract: The intrinsic (mitochondrial) apoptotic pathway is a conserved cell death program crucial for eliminating superfluous, damaged, or incorrectly specified cells, and the multi-domain pro-death BCL-2 family proteins BAX and BAK are required for its activation. In response to internal damage or developmental signals, BAX and/or BAK permeabilize the mitochondrial outer membrane, resulting in cytochrome c release and activation of effector caspases such as Caspase-3 (Casp3). While the mitochondrial apoptotic pathway plays a critical role during late embryonic development in mammals, its role during early development remains controversial. Here, we show that Bax(-/-)Bak(-/-) murine embryonic stem cells (ESCs) display defects during the exit from pluripotency, both in culture and during teratoma formation. Specifically, we find that when ESCs are stimulated to differentiate, a subpopulation fails to do so and instead upregulates FAS in a p53-dependent manner to trigger Bax/Bak-dependent apoptosis. Blocking this apoptotic pathway prevents the removal of these poorly differentiated cells, resulting in the retention of cells that have not exited pluripotency. Taken together, our results provide further evidence for heterogeneity in the potential of ESCs to successfully differentiate and reveal a novel role for apoptosis in promoting efficient ESC differentiation by culling cells that are slow to exit pluripotency.
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Nichole A
authors.initials: NA
authors.lastname: Reyes
authors.affiliation: Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Collin
authors.initials: C
authors.lastname: Melton
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Noelle E
authors.initials: NE
authors.lastname: Huskey
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Momcilovic
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
authors.affiliation: Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: blellochr@stemcell.ucsf.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Blelloch
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: scott.oakes@ucsf.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Oakes
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D015398:Signal Transduction; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: C491899:Fas protein, mouse; D019014:fas Receptor