Tbx6 Induces Cardiomyocyte Proliferation in Postnatal and Adult Mouse Hearts

• Project/Area Number: 18K15861
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Keio University
• Principal Investigator: HAGINIWA SHO 慶應義塾大学, 医学部(信濃町), 助教 (00772584)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 再生医療 / 遺伝子治療 / 細胞周期 / ダイレクトリプログラミング

Outline of Final Research Achievements

Cardiovascular disease is a leading cause of death worldwide. Mammalian cardiomyocytes (CMs) proliferate during embryonic development, whereas they largely lose their regenerative capacity after birth. Defined factors expressed in cardiac progenitors or embryonic CMs may activate the cell cycle and induce CM proliferation in postnatal and adult hearts. Here, we report that the overexpression of Tbx6, enriched in the cardiac mesoderm (progenitor cells), induces CM proliferation in postnatal and adult mouse hearts.
We next generated a recombinant adeno-associated virus serotype 9 vector encoding Tbx6 (AAV9-Tbx6) for transduction into mouse CMs in vivo. The subcutaneous injection of AAV9-Tbx6 into neonatal mice induced CM proliferation in postnatal and adult mouse hearts.
Mechanistically, Tbx6 overexpression upregulated multiple cell cycle activators. Thus, Tbx6 promotes CM proliferation in postnatal and adult mouse hearts by modifying the expression of cell cycle regulators.

Academic Significance and Societal Importance of the Research Achievements

心筋細胞は胎児期では盛んに増殖するが、生後は再生能力をほとんど失うため、一度心筋障害を受けると回復は困難である。我々は、心臓内の自己の細胞から心筋を作製する、新しい心臓再生研究に取り組んでいる。本研究は、胎児期の心筋細胞に特異的に発現する転写因子の中から、成熟心筋細胞の分裂を促進させる新規因子を同定し、心筋自体を分裂させる新しい心臓再生法を開発することが主眼である。

Research Products

• [Journal Article] 2.Tbx6 induces cardiomyocyte proliferation in postnatal and adult mouse hearts. (2019)
  • Author(s): Haginiwa S, Sadahiro T, Kojima H, Isomi M, Tamura F, Kurotsu S, Tani H, Muraoka N, Miyake N, Miyake K, Fukuda K, Ieda M.
  • Journal Title: Biochem Biophys Res Commun Volume: 513 Issue: 4 Pages: 1041-1047
  • DOI: 10.1016/j.bbrc.2019.04.087
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Identification of new myocardial growth factor and its application to cardiac regeneration (2018)
  • Author(s): Sho Haginiwa
  • Organizer: 国際心臓研究学会（ISHR）日本部会
  • Int'l Joint Research
• [Presentation] Identification of new myocardial growth factor and its application to cardiac regeneration (2018)
  • Author(s): Sho Haginiwa
  • Organizer: The 2nd JCS Council Forum on Basic CardioVascular Research
  • Int'l Joint Research