Creation of innovative myocardial regeneration strategy with soft and highly dividing cardiomyocytes

2023 Fiscal Year Final Research Report

• Project/Area Number: 20H04521
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 90110:Biomedical engineering-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: Hashimoto Ken 川崎医科大学, 医学部, 准教授 (80341080)
• Co-Investigator(Kenkyū-buntansha): 毛利 聡 川崎医科大学, 医学部, 教授 (00294413) ; 花島 章 川崎医科大学, 医学部, 講師 (70572981) ; 氏原 嘉洋 名古屋工業大学, 工学(系)研究科(研究院), 准教授 (80610021)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 心筋 / 分裂 / 再生 / 酸素環境 / Fam64a / Novex-3

Outline of Final Research Achievements

Fetal cardiomyocytes (CMs) actively proliferate to form the primitive heart,
but they stop dividing shortly after birth. Therefore, CM regenerative potential upon injury is very limited in adult hearts. Here we tested the heart regenerative potential of Fam64a and Novex-3, which we have recently identified as a candidate gene. We have established regenerative potential of Fam64a using CM-specific transgenic/knock out mice models and transient and local administration of Fam64a upon heart injury in adult mice. As for Novex-3, using Novex-3 KO mice models, we demonstrated that Novex-3 in fetal CMs maintained the integrity of the centrosome, which was essential for cell division, and inhibited microtubule relocation from the centrosome to nuclear envelope, thereby keeping CM nuclei compliant and thus promoting CM proliferation. Combined introduction of Fam64a and Novex-3 will be a promising strategy for heart regeneration.

Free Research Field

心臓生理学

Academic Significance and Societal Importance of the Research Achievements

心筋細胞は出生直後に分裂能を失う為、成体期において心不全等の心疾患で失われた心筋を再生することは出来ない。iPS細胞由来の心筋は現段階では未熟な胎児様心筋であり、成体心筋の代替としては不十分である。本研究では、我々が同定した心筋分裂促進因子Fam64a, Novex-3の分子作用機序を検討し、将来的な心再生への適用可能性を探った。マウスを用いた過剰発現、ノックアウト、傷害心筋に対する一過性・局所性の導入発現等の手法により、Fam64aの心再生効果を確認できた。Novex-3についても心再生のベースとなる心筋分裂促進機序を明らかにすることが出来た。今後は、両者を組み合わせた心再生の実現を目指す。