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Updated: Aug 21, 2026
Evaluation of Cardiac Contractility Modulation Therapy in 2D Human Stem Cell-Derived Cardiomyocytes
Published on: December 16, 2022
Efficacy of multi-layered human iPS cell-derived cardiovascular cell sheets in a pacing-induced canine dilated
Yu Shimoyama1, Kenji Kakuta2, Kiho Araki1
1iHeart Japan Corporation, Kyoto, Japan.
Insights
Induced pluripotent stem cell (iPSC)-based therapy (IHJ-301) significantly improved cardiac function in a novel large-animal model of dilated cardiomyopathy (DCM). This preclinical study offers hope for new DCM treatments beyond heart transplantation.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Stem Cell Therapy
Background:
- Dilated cardiomyopathy (DCM) is a progressive heart failure condition with limited treatment options, primarily heart transplantation.
- Donor scarcity restricts access to transplantation, highlighting the need for alternative therapies like induced pluripotent stem cell (iPSC)-based treatments.
- Preclinical data and large-animal models for iPSC therapies in DCM have been insufficient.
Purpose of the Study:
- To develop and validate a large-animal model for non-ischemic heart failure suitable for testing iPSC-based therapies.
- To evaluate the therapeutic efficacy of a novel cardiovascular cell sheet construct (IHJ-301) derived from human iPSCs in this model.
Main Methods:
- Generated multi-layered cardiovascular cell sheets (IHJ-301) from human iPSCs, incorporating cardiomyocytes, endothelial, and stromal cells, using gelatin hydrogel microspheres.
- Established a Step-Down Pacing Heart Failure model in canines to maintain depressed cardiac function without mortality for preclinical testing.
- Implanted IHJ-301 epicardially onto the left ventricle and assessed cardiac function using echocardiography and right-heart catheterization.
Main Results:
- The canine model successfully maintained depressed cardiac function (LVEF ~45%) for 4 weeks without mortality.
- IHJ-301 implantation led to significant improvements in left ventricular ejection fraction (ΔLVEF: 9.38% vs. 1.90%), fractional shortening (ΔFS: 4.84% vs. 0.97%), stroke volume, and cardiac output compared to sham controls.
- All functional parameters showed statistically significant improvement (p < 0.05) in the IHJ-301 group at 4 weeks post-implantation.
Conclusions:
- A robust non-ischemic large-animal heart failure model was established, suitable for evaluating therapeutic interventions.
- IHJ-301 demonstrated significant functional recovery in a preclinical setting, indicating its potential as a promising cell-based therapy for DCM.
- These findings provide crucial preclinical evidence supporting the advancement of IHJ-301 for DCM treatment.
Background:
Dilated cardiomyopathy (DCM) is a progressive, intractable disease that leads to heart failure. Heart transplantation is the only curative treatment; however, access is limited by donor scarcity. Induced pluripotent stem cell (iPSC)-based therapies are attracting attention for DCM, but suitable large-animal models and robust preclinical data have been limited.
Methods:
We generated multi-layered cardiovascular cell sheets from human iPSCs by combining cardiomyocytes with endothelial and stromal cells and overcoming stacking limits using interleaved gelatin hydrogel microspheres, yielding a thicker cardiac tissue-like construct (product code: IHJ-301). To enable rigorous testing in non-ischemic heart failure, we established a modified canine rapid-pacing heart failure model that maintains depressed function without mortality by continuing pacing at a slightly reduced rate after induction (Step-Down Pacing Heart Failure model). IHJ-301 was implanted epicardially onto the left ventricular surface via thoracotomy, and cardiac function was assessed by echocardiography and right-heart catheterization.
Results:
After 4 weeks of rapid pacing (230 ± 10 bpm), left ventricular ejection fraction (LVEF) was reduced from 77.8 ± 1.1% (pre-pacing) to 44.9 ± 1.9% (n = 11) (0 W). Continued pacing at 210 ± 10 bpm for additional 4 weeks resulted in no mortality and maintained depressed function (4 W LVEF 47.3 ± 2.6%). IHJ-301 was implanted at 0 W. At 4 weeks post-implantation (4 W), all animals in the IHJ-301 group (n = 5) showed greater functional improvement than sham (n = 6). Absolute changes from 0 W to 4 W were: ΔLVEF (%) 9.38 ± 1.47 vs. 1.90 ± 0.34; Δfractional shortening (%) 4.84 ± 0.75 vs. 0.97 ± 0.18; stroke volume (mL/beat) 1.21 ± 1.26 vs. -2.99 ± 0.60; cardiac output (L/min) 0.19 ± 0.19 vs. -0.58 ± 0.12 (all p < 0.05).
Conclusions:
We established a non-ischemic large-animal heart failure model that sustains depressed function for one month, enabling clear therapeutic readouts. IHJ-301 significantly improved multiple parameters of cardiac function, providing preclinical evidence that IHJ-301 could offer a promising therapeutic option for DCM.
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