Scientists study the underlying causes of a disease or test new potential drugs in animal models or cells obtained from human biopsy specimens before clinical trials. However, disease models in animals do not mimic the actual human disease, and biopsy specimens are hard to access for research purposes. Lab-grown tissues, engineered from stem cells reprogrammed from human cells, called human induced pluripotent stem cells (hiPSCs), are fast emerging as a more reliable and accessible model in medical research.
A study led by Professor Shugo Tohyama and Senior Assistant Professor Hidenori Tani from the Department of Clinical Regenerative Medicine, Fujita Health University, Japan, has focused on developing robust lab models of cardiomyocytes (CMs), the heart muscle cells. Years of pioneering research have led to the development of high-quality CMs from hiPSCs in a petri dish.
“ During efforts to adjust the concentrations of glucose and fatty acids in the culture medium to promote heart tissue maturation, we discovered that excessive fatty acids adversely affected the dilation capacity of the heart tissues, ” explains Dr. Tani, the first author of the study, regarding this breakthrough. “ Around the same time, a study reported that the administration of high levels of fatty acids and nitric oxide synthase (NOS) inhibitors in mice-induced heart failure (HF) with preserved ejection fraction (HFpEF), which led to the conception of this study.”
The study, which resulted in the development of human engineered heart tissue (hEHT) model of HFpEF, was made available online on July 16, 2026, and was published in Volume 33, Issue 8 of the journal Cell Stem Cell on August 6, 2026. Following its publication, the study was immediately selected as a featured paper in the Preview section of Cell Stem Cell , further highlighting the significance of these findings.
HFpEF is a defect in the relaxation (diastole) of the heart with normal contraction (systole). It affects more than 30 million people globally but has few effective treatment options and, therefore, poor outcomes. Prof. Tohyama and his team induced hiPSC-CMs from readily available hiPSCs, created mature 3D heart tissue using collagen derived from porcine hearts—which the lab had previously developed—and cultured the tissues in vitro using a medium containing high fatty acid levels and L-N G -nitroarginine methyl ester (L-NAME), an NOS inhibitor. Supporting cells like epicardial cells, endothelial cells (ECs), and macrophages were also added to successfully create an HFpEF-hEHT that structurally and functionally mimicked diastolic HF with normal systole. Molecular and genetic markers of HFpEF, like increased NT-proBNP and NPPB mRNA levels, reduced expression of key genes related to Ca 2+ transport ( RYR2 , SERCA2A , and PLN ), increased fibrosis-related genes, and a shift to the stiffer, less pliable type collagen and TITIN, were demonstrated. Increased inflammation was also seen.
Using the newly developed HFpEF model, the researchers then went on to test the effectiveness of six drugs, which are currently being used or explored in research for treatment of HFpEF. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), an anti-diabetic medication, was the only drug that could partially prevent the development of diastolic HF. The combined angiotensin receptor/neprilysin inhibitor, soluble guanylate cyclase activator, phosphodiesterase 5 inhibitor, and nicotinamide phosphoribosyltransferase protein activator had no effect on hEHT relaxation time. On the other hand, a hyperpolarization-activated cyclic nucleotide-gated channel inhibitor worsened the disease.
Transcriptomic analysis revealed that SGLT2i had anti-inflammatory effects and partially prevented the increase in inflammatory molecules like IL-1β and IL-6 in HFpEF-hEHT. Also, the presence of ECs was required for SGLT2i to exert its effects. Further studies on the role of supporting cells revealed that the preventive effect of SGLT2i was exerted through ECs. Inhibition of the eNOS-NO-cGMP-PKG signaling pathway in ECs was found to be the main pathological mechanism of HFpEF. SGLT2i was found to exert its anti-inflammatory effects by partially removing this inhibition, and by improving the removal of Na + and Ca 2+ ions from the cells through their exchanger channels, thereby preventing their accumulation in the tissues.
“ The human HFpEF model established in this study can be applied to uncovering the pathophysiology of HFpEF and to research on aging, ” says Prof. Tohyama. “ Furthermore, it is expected to serve as a research foundation that will contribute to the development of new therapeutic agents, the evaluation of drug efficacy, and personalized medicine for individual patients, paving the way for further research in the future, ” Prof. Tohyama adds.
Reference
Title of original paper: Human iPSC-derived engineered heart tissue model of diastolic dysfunction in heart failure with preserved ejection fraction
Journal: Cell Stem Cell
DOI: https://doi.org/10.1016/j.stem.2026.06.007
About Fujita Health University
Fujita Health University (FHU) is a private medical university located in Aichi, Japan. Established in 1964, it houses one of the largest university hospitals in Japan. Its 900-member faculty provides diverse learning and research opportunities to medical students worldwide. Guided by its founding philosophy of "Our creativity for the people," Fujita Health University believes that its students can shape the future through creativity and innovation. FHU has earned global recognition, ranking eighth among all universities and second among private universities in Japan in the 2020 Times Higher Education (THE) World University Rankings. The university ranked fourth worldwide in the 2024 THE University Impact Rankings for contributions to the "Good Health and Well-being" SDG (Sustainable Development Goals) of the United Nations (UN). In June 2021, the university made history as the first Japanese institution to host the THE Asia Universities Summit. In 2024, Fujita Health University was awarded the Forming Japan’s Peak Research Universities (J-PEAKS) Program by the Japanese government to establish an innovative academic drug discovery ecosystem and hub of a multi-university consortium for research and education.
Website: https://www.fujita-hu.ac.jp/
About Senior Assistant Professor Hidenori Tani from Fujita Health University, Japan
Dr. Hidenori Tani, MD, PhD, is a Senior Assistant Professor at Fujita Health University, Japan. He received his M.D. from Keio University School of Medicine in 2012 and his Ph.D. in 2023. His research focuses on cardiovascular medicine, regenerative medicine, human induced pluripotent stem cell-derived cardiac tissues, disease modeling, and drug discovery.
About Professor Shugo Tohyama from Fujita Health University, Japan
Dr. Shugo Tohyama is a Professor of Clinical Regenerative Medicine at Fujita Health University and a Project Leader at Kanagawa Institute of Industrial Science and Technology. He received his M.D. from Keio University School of Medicine in 2006 and his Ph.D. in 2013. His team focuses on cardiac regenerative medicine using hiPSCs. He developed a simple, low-cost metabolic purification method for hiPSC-derived cardiomyocytes that is now widely used worldwide. His work has contributed to clinical translation of hiPSC-CM transplantation for severe heart failure and to advanced engineered heart tissue models for disease modeling and drug discovery.
Funding information
This work was supported by an AMED grant (24bm1123010 to Shugo Tohyama); JSPS KAKENHI (grant 23K27683 to Shugo Tohyama and 23K15140 to Hidenori Tani); KISTEC (to Shugo Tohyama); a Japan Heart Foundation Research Grant (to Hidenori Tani); the SENSHIN Medical Research Foundation (to Hidenori Tani); the Novartis Pharma Grants for Basic Research (to Hidenori Tani); the Japan Foundation for Applied Enzymology (to Hidenori Tani); and a research grant from Heartseed Inc.
Cell Stem Cell
Experimental study
Cells
Human iPSC-derived engineered heart tissue model of diastolic dysfunction in heart failure with preserved ejection fraction
6-Aug-2026
Shugo Tohyama is an advisor to Heartseed Inc. Keiichi Fukuda is the CEO of Heartseed Inc. Shugo Tohyama and Keiichi Fukuda own equity in Heartseed Inc.