Mixl1 and Flk1 Are Key Players of Wnt/TGF-β Signaling During DMSO-Induced Mesodermal Specification in P19 cells
Dimethyl sulfoxide (DMSO) is widely used to induce multilineage differentiation of embryonic and adult progenitor cells. To date, little is known about the mechanisms underlying DMSO‐induced mesodermal specification. In this study, we investigated the signaling pathways and lineage‐determining genes...
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| Published in: | Journal of cellular physiology Vol. 230; no. 8; pp. 1807 - 1821 |
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| Main Authors: | , , , , , , , , , , |
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01-08-2015
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| Abstract | Dimethyl sulfoxide (DMSO) is widely used to induce multilineage differentiation of embryonic and adult progenitor cells. To date, little is known about the mechanisms underlying DMSO‐induced mesodermal specification. In this study, we investigated the signaling pathways and lineage‐determining genes involved in DMSO‐induced mesodermal specification in P19 cells. Wnt/β‐catenin and TGF‐β superfamily signaling pathways such as BMP, TGF‐β and GDF1 signaling were significantly activated during DMSO‐induced mesodermal specification. In contrast, Nodal/Cripto signaling pathway molecules, required for endoderm specification, were severely downregulated. DMSO significantly upregulated the expression of cardiac mesoderm markers but inhibited the expression of endodermal and hematopoietic lineage markers. Among the DMSO‐activated cell lineage markers, the expression of Mixl1 and Flk1 was dramatically upregulated at both the transcript and protein levels, and the populations of Mixl1+, Flk1+ and Mixl1+/Flk1+ cells also increased significantly. DMSO modulated cell cycle molecules and induced cell apoptosis, resulting in significant cell death during EB formation of P19 cells. An inhibitor of Flk1, SU5416 significantly blocked expressions of TGF‐β superfamily members, mesodermal cell lineage markers and cell cycle molecules but it did not affect Wnt molecules. These results demonstrate that Mixl1 and Flk1 play roles as key downstream or interacting effectors of Wnt/TGF‐β signaling pathway during DMSO‐induced mesodermal specification in P19 cells. J. Cell. Physiol. 230: 1807–1821, 2015. © 2014 Wiley Periodicals, Inc. |
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| AbstractList | Dimethyl sulfoxide (DMSO) is widely used to induce multilineage differentiation of embryonic and adult progenitor cells. To date, little is known about the mechanisms underlying DMSO-induced mesodermal specification. In this study, we investigated the signaling pathways and lineage-determining genes involved in DMSO-induced mesodermal specification in P19 cells. Wnt/β-catenin and TGF-β superfamily signaling pathways such as BMP, TGF-β and GDF1 signaling were significantly activated during DMSO-induced mesodermal specification. In contrast, Nodal/Cripto signaling pathway molecules, required for endoderm specification, were severely downregulated. DMSO significantly upregulated the expression of cardiac mesoderm markers but inhibited the expression of endodermal and hematopoietic lineage markers. Among the DMSO-activated cell lineage markers, the expression of Mixl1 and Flk1 was dramatically upregulated at both the transcript and protein levels, and the populations of Mixl1+, Flk1+ and Mixl1+/Flk1+ cells also increased significantly. DMSO modulated cell cycle molecules and induced cell apoptosis, resulting in significant cell death during EB formation of P19 cells. An inhibitor of Flk1, SU5416 significantly blocked expressions of TGF-β superfamily members, mesodermal cell lineage markers and cell cycle molecules but it did not affect Wnt molecules. These results demonstrate that Mixl1 and Flk1 play roles as key downstream or interacting effectors of Wnt/TGF-β signaling pathway during DMSO-induced mesodermal specification in P19 cells. Dimethyl sulfoxide (DMSO) is widely used to induce multilineage differentiation of embryonic and adult progenitor cells. To date, little is known about the mechanisms underlying DMSO‐induced mesodermal specification. In this study, we investigated the signaling pathways and lineage‐determining genes involved in DMSO‐induced mesodermal specification in P19 cells. Wnt/β‐catenin and TGF‐β superfamily signaling pathways such as BMP, TGF‐β and GDF1 signaling were significantly activated during DMSO‐induced mesodermal specification. In contrast, Nodal/Cripto signaling pathway molecules, required for endoderm specification, were severely downregulated. DMSO significantly upregulated the expression of cardiac mesoderm markers but inhibited the expression of endodermal and hematopoietic lineage markers. Among the DMSO‐activated cell lineage markers, the expression of Mixl1 and Flk1 was dramatically upregulated at both the transcript and protein levels, and the populations of Mixl1+, Flk1+ and Mixl1+/Flk1+ cells also increased significantly. DMSO modulated cell cycle molecules and induced cell apoptosis, resulting in significant cell death during EB formation of P19 cells. An inhibitor of Flk1, SU5416 significantly blocked expressions of TGF‐β superfamily members, mesodermal cell lineage markers and cell cycle molecules but it did not affect Wnt molecules. These results demonstrate that Mixl1 and Flk1 play roles as key downstream or interacting effectors of Wnt/TGF‐β signaling pathway during DMSO‐induced mesodermal specification in P19 cells. J. Cell. Physiol. 230: 1807–1821, 2015. © 2014 Wiley Periodicals, Inc. |
| Author | Lim, Do-Sun Seo, Ha-Rim Kim, Jong-Ho Choi, Seung-Cheol Park, Chi-Yeon Choi, Ji-Hyun Yu, Cheol-Woong Park, Jae-Hyoung Hong, Soon-Jun Cui, Long-Hui Joo, Hyung-Joon |
| Author_xml | – sequence: 1 givenname: Seung-Cheol surname: Choi fullname: Choi, Seung-Cheol organization: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea – sequence: 2 givenname: Ji-Hyun surname: Choi fullname: Choi, Ji-Hyun organization: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea – sequence: 3 givenname: Long-Hui surname: Cui fullname: Cui, Long-Hui organization: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea – sequence: 4 givenname: Ha-Rim surname: Seo fullname: Seo, Ha-Rim organization: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea – sequence: 5 givenname: Jong-Ho surname: Kim fullname: Kim, Jong-Ho organization: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea – sequence: 6 givenname: Chi-Yeon surname: Park fullname: Park, Chi-Yeon organization: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea – sequence: 7 givenname: Hyung-Joon surname: Joo fullname: Joo, Hyung-Joon organization: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea – sequence: 8 givenname: Jae-Hyoung surname: Park fullname: Park, Jae-Hyoung organization: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea – sequence: 9 givenname: Soon-Jun surname: Hong fullname: Hong, Soon-Jun organization: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea – sequence: 10 givenname: Cheol-Woong surname: Yu fullname: Yu, Cheol-Woong organization: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea – sequence: 11 givenname: Do-Sun surname: Lim fullname: Lim, Do-Sun email: Correspondence to: Do-Sun Lim, Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, 126-1, 5ka, Anam-dong, Sungbuk-Ku, Seoul 136-705, Republic of Korea, dslmd@kumc.or.kr organization: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea |
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| SubjectTerms | Apoptosis - drug effects Blotting, Western Cell Differentiation - drug effects Cell Differentiation - physiology Cell Line, Tumor Dimethyl Sulfoxide - pharmacology Embryoid Bodies - drug effects Embryoid Bodies - metabolism Embryonic Stem Cells - cytology Flow Cytometry Homeodomain Proteins - metabolism Humans Immunohistochemistry Mesoderm - cytology Mesoderm - drug effects Real-Time Polymerase Chain Reaction Transforming Growth Factor beta - metabolism Vascular Endothelial Growth Factor Receptor-2 - metabolism Wnt Proteins - metabolism |
| Title | Mixl1 and Flk1 Are Key Players of Wnt/TGF-β Signaling During DMSO-Induced Mesodermal Specification in P19 cells |
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