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BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Kruppel-like Factors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan..
Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan..
Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan..
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2016 (English)In: Stem Cell Reports, ISSN 2213-6711, Vol. 6, no 1, 64-73 p.Article in journal (Refereed) Published
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Abstract [en]

Bone morphogenetic protein (BMP) signaling exerts paradoxical roles in pluripotent stem cells (PSCs); it sustains self-renewal of mouse embryonic stem cells (ESCs), while it induces differentiation in other PSCs, including human ESCs. Here, we revisit the roles of BMP-4 using mouse ESCs (mESCs) in naive and primed states. SMAD1 and SMAD5, which transduce BMP signals, recognize enhancer regions together with KLF4 and KLF5 in naive mESCs. KLF4 physically interacts with SMAD1 and suppresses its activity. Consistently, a subpopulation of cells with active BMP-SMAD can be ablated without disturbing the naive state of the culture. Moreover, Smad1/5 double-knockout mESCs stay in the naive state, indicating that the BMP-SMAD pathway is dispensable for it. In contrast, the MEK5-ERK5 pathway mediates BMP-4-induced self-renewal of mESCs by inducing Klf2, a critical factor for the ground state pluripotency. Our study illustrates that BMP exerts its self-renewing effect through distinct functions of different Kruppel-like factors.

Place, publisher, year, edition, pages
2016. Vol. 6, no 1, 64-73 p.
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Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
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URN: urn:nbn:se:uu:diva-276812DOI: 10.1016/j.stemcr.2015.12.004ISI: 000368099500008PubMedID: 26771354OAI: oai:DiVA.org:uu-276812DiVA: diva2:903534
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Swedish Cancer Society, 100452
Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2017-11-30Bibliographically approved

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Holmborn, KatarinaSundqvist, AndersHeldin, Carl-Henrik

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