Joint Research Chair

Cardiac of Regeneration and Therapeutics

Regenerative medicine for heart disease
  • Cardiac differentiation study via single-cell expression profiling
  • Discovery of novel biomarkers
  • ES/iPS cell-derived cardiomyocytes and other cardiac-related cells
  • Development of the myocardium layer of the heart ventricle
  • Clinical application of human ES/iPS cells

Heart Development and Regenerative Medicine

Despite the recent advances in medicine, the prognosis of end-stage heart failure remains poor. Heart transplantation, a last resort treatment, suffers from donor-shortage. Thus, it is vital to urgently bring an alternative therapy into the clinical arena. Regeneration/cell replacement therapy with human pluripotent stem (ES and iPS) cells seems promising to compensate the damaged cardiac muscle (cardiomyocytes) in the failed heart. However, currently proposed strategy is insufficient. We must know further cardiac differentiation and stem cells to solve unmet medical needs.

Cardiomyocytes originate from ES/iPS cells through cardiac progenitor cells (CPCs). CPCs are now classified into two major subpopulations; the first heart field (the origin of left ventricle and a part of atria) and the second heart field (the origin of right ventricle, remaining part of atria and outflow tract). We have studied the molecular biological mechanism underlying the differentiation of CPCs, thus far. In our original study, we showed that T-box transcription factor Tbx5 is specific for the first heart field. This Tbx5-positive population is surprisingly unipotent to produce only cardiomyocytes, whereas CPCs have been regarded as multipotent [1]. Furthermore, we have recently found that a GPI-anchor containing neurotrophic factor receptor, GFRA2 is a specific cell surface antigen for CPCs. This molecule is common to both of the heart fields. In combination with other biomarkers, this molecule allows to deliberately and purposely isolate unipotent CPCs to only cardiomyocytes or multipotent CPCs to cardiomyocytes, smooth muscle cells and endothelial cells. More importantly, an anomalous signal pathway via GFRA2 in the faetus led to non-compaction cardiomyopathy whose prognosis is extremely poor [2].

Figure 1

We have recently established a new research laboratory in the Graduate School of Medicine, Osaka University, in collaboration with industry, Terumo Corporation (Tokyo, Japan) and Dai Nippon Printing Co, Ltd (Tokyo, Japan). Our ultimate goal is to develop a sophisticated regeneration/cell replacement therapy in the clinical arena by integration of varied expertise including medicine (cardiovascular surgery, cardiology, and paediatric cardiology), biology (developmental biology, cell biology, molecular biology, stem cell science, and system biology), and engineering (developmental engineering, genome editing technology, tissue engineering, biomaterial engineering, imaging technology and artificial intelligence). Based on our knowledge of heart development, this multidisciplinary research team will challenge innovation in medicine.

Figure 2

References

1. Kokkinopoulos et al. PLoS One 10 (10): e 0140831, 2015. 2. Ishida et al. Cell Rports 16 (4): 1026-38, 2016."