Trichostatin A, an HDAC inhibitor, induces differentiation of induced pluripotent stem cells into cardiomyocytes in mice

Trichostatin A, an HDAC inhibitor, induces differentiation of induced pluripotent stem cells into cardiomyocytes in mice

Shinji Kaichi1, Koji Hasegawa2, Tomohide Takaya2, Noritaka Yokoo1, Tatsuya Morimoto2, Teruhisa Kawamura2, Koh Ono3, Shiro Baba1, Shinya Yamanaka4, Tatsutoshi Nakahata1, Toshio Heike1.

  1. Department of Pediatrics, Graduate School of Medicine, Kyoto University, Japan.
  2. Division of Translational Research, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
  3. Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan.
  4. Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Japan.

The 17th Asian Pacific Congress of Cardiology (Kyoto, Japan), 2009/05/21 (Poster).

Abstract

Backgrounds: Mouse and human fibroblasts can be reprogrammed to pluripotency by ectopic expression of transcription factors (Oct3/4, Sox2, Klf4, and c-Myc) to yield induced pluripotent stem (iPS) cells. Recently iPS cells can be generated without c-Myc. However, detailed characteristics regarding abilities of iPS cells to differentiate into cardiomyocytes has yet to be determined. The present study examined patterns on myocardial differentiation of 3 cell lines of mouse iPS cells reprogrammed by 3 or 4 factors.

Methods and Results: The level of SSEA-1, a stem cell marker, was almost similar among three cell lines in undifferentiated iPS cells. During induction of differentiation, expression of genes involved in cardiogenesis and spontaneous myogenic contractions occurred similarly as in ES cells. Hoever, in one iPS cell line (20D17) generated by 4 factors, expressions of cardiac-specific genes were extremely low, and no myogenic contractions occurred. In contrast, patterns on VEGF and Flk-1 expressions were similar among three cell lines. Treatment of iPS cells with trichostatin A (TSA), an HDAC inhibitor, increased Nkx2.5 expression in all cell lines. While the basal Nkx2.5 expression was very low in 20D17, TSA-induced increase was greatest. After all, Nkx2.5 mRNA levels in TSA-stimulated cells were similar among three lines.

Conclusions: These findings demonstrate that mouse iPS cells can differentiate into cardiomyocytes while cell line-dependent variation exists. The results also suggested that TSA can overcome such variation.