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著作: [石田 昌義]/El-Mounayri Omar/Kattman Steven/Zandstra Peter/Sakamoto Hiroshi/Ogawa Minetaro/Keller Gordon/Husain Mansoor/Regulated expression and role of c-Myb in the cardiovascular-directed differentiation of mouse embryonic stem cells./[Circulation Research]

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EID
264969
EOID
770664
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0
LastModified
2015年3月20日(金) 14:45:51
Operator
三木 ちひろ
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TRUE
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Owner
[副研究部長]/[大学院ヘルスバイオサイエンス研究部]
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種別 必須 学術論文(審査論文)
言語 必須 英語
招待 推奨
審査 推奨 Peer Review
カテゴリ 推奨 研究
共著種別 推奨
学究種別 推奨
組織 推奨
著者 必須
  1. 石田 昌義
    役割 任意
    貢献度 任意
    学籍番号 推奨
  2. (英) El-Mounayri Omar
    役割 任意
    貢献度 任意
    学籍番号 推奨
  3. (英) Kattman Steven
    役割 任意
    貢献度 任意
    学籍番号 推奨
  4. (英) Zandstra Peter
    役割 任意
    貢献度 任意
    学籍番号 推奨
  5. (英) Sakamoto Hiroshi
    役割 任意
    貢献度 任意
    学籍番号 推奨
  6. (英) Ogawa Minetaro
    役割 任意
    貢献度 任意
    学籍番号 推奨
  7. (英) Keller Gordon
    役割 任意
    貢献度 任意
    学籍番号 推奨
  8. (英) Husain Mansoor
    役割 任意
    貢献度 任意
    学籍番号 推奨
題名 必須

(英) Regulated expression and role of c-Myb in the cardiovascular-directed differentiation of mouse embryonic stem cells.

副題 任意
要約 任意

(英) RATIONALE:c-myb null (knockout) embryonic stem cells (ESC) can differentiate into cardiomyocytes but not contractile smooth muscle cells (SMC) in embryoid bodies (EB).OBJECTIVE:To define the role of c-Myb in SMC differentiation from ESC.METHODS AND RESULTS:In wild-type (WT) EB, high c-Myb levels on days 0-2 of differentiation undergo ubiquitin-mediated proteosomal degradation on days 2.5-3, resurging on days 4-6, without changing c-myb mRNA levels. Activin-A and bone morphogenetic protein 4-induced cardiovascular progenitors were isolated by FACS for expression of vascular endothelial growth factor receptor (VEGFR)2 and platelet-derived growth factor receptor (PDGFR). By day 3.75, hematopoesis-capable VEGFR2+ cells were fewer, whereas cardiomyocyte-directed VEGFR2+/PDGFR+ cells did not differ in abundance in knockout versus WT EB. Importantly, highest and lowest levels of c-Myb were observed in VEGFR2+ and VEGFR2+/PDGFR+ cells, respectively. Proteosome inhibitor MG132 and lentiviruses enabling inducible expression or knockdown of c-myb were used to regulate c-Myb in WT and knockout EB. These experiments showed that c-Myb promotes expression of VEGFR2 over PDGFR, with chromatin immunopreciptation and promoter-reporter assays defining specific c-Myb-responsive binding sites in the VEGFR2 promoter. Next, FACS-sorted VEGFR2+ cells expressed highest and lowest levels of SMC- and fibroblast-specific markers, respectively, at days 7-14 after retinoic acid (RA) as compared with VEGFR2+/PDGFR+ cells. By contrast, VEGFR2+/PDGFR+ cells cultured without RA beat spontaneously, like cardiomyocytes between days 7 and 14, and expressed cardiac troponin. Notably, RA was required to more fully differentiate SMC from VEGFR2+ cells and completely blocked differentiation of cardiomyocytes from VEGFR2+/PDGFR+ cells.CONCLUSIONS:c-Myb is tightly regulated by proteosomal degradation during cardiovascular-directed differentiation of ESC, expanding early-stage VEGFR2+ progenitors capable of RA-responsive SMC formation.

キーワード 推奨
  1. (英) c-Myb
  2. (英) Smooth muscle cells
  3. (英) Flk-1
  4. (英) PDGFRa
  5. 転写因子(transcription factor)
  6. 細胞増殖·分化(cell proliferation and differentiation)
  7. 細胞分離(cell separation)
  8. (英) Chromatin Immunoprecipitation
  9. プロテアソーム(proteasome)
  10. (英) Embryonic Stem Cells
  11. (英) Flow Cytometry
  12. (英) Gene Expression Regulation, Developmental
  13. (英) Reporter assay
  14. (英) RNA Interference
  15. (英) RNA, Messenger
  16. (英) Ubiquitination
発行所 推奨 American Heart Association
誌名 必須 Circulation Research([American Heart Association])
(pISSN: 0009-7330, eISSN: 1524-4571)
ISSN 任意 1524-4571
ISSN: 0009-7330 (pISSN: 0009-7330, eISSN: 1524-4571)
Title: Circulation research
Title(ISO): Circ. Res.
Publisher: American Heart Association
 (NLM Catalog  (Scopus  (CrossRef (Scopus information is found. [need login])
必須 110
必須 2
必須 253 264
都市 任意
年月日 必須 2011年 11月 23日
URL 任意
DOI 任意 10.1161/CIRCRESAHA.111.259499    (→Scopusで検索)
PMID 任意 22116818    (→Scopusで検索)
NAID 任意
WOS 任意 000299432600009
Scopus 任意 2-s2.0-84856059943
評価値 任意
被引用数 任意
指導教員 推奨
備考 任意
  1. (英) Affiliation: Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada, M5G 1L7.

  2. (英) PublicationType: Journal Article

  3. (英) PublicationType: Research Support, Non-U.S. Gov't