Ischemic heart disease (IHD), also known as "coronary atherosclerotic heart disease" (CHD), is the leading cause of death from disease worldwide. According to the World Health Statistics 2020, published by the World Health Organization (WHO), ischemic heart disease accounts for 16% of all deaths worldwide and is the disease with the largest increase in the number of deaths in the last 20 years [1].

Ischemic heart disease is a heart disease caused by myocardial ischemia and hypoxia due to alterations in the coronary circulation. Myocardial infarction (infarction) caused by acute and persistent ischemia and hypoxia in the coronary arteries leads to massive death of myocardial cells. Since the regenerative capacity of myocardial cells is very limited, the lost myocardial cells are replaced by fibrous scars that do not have contractile capacity, leading to a decrease in the contractile capacity of the heart, which in turn leads to heart failure. Although existing treatments can reduce the degree of infarction and symptoms, it is difficult to reverse the process of post-infarction heart failure. Therefore, how to reduce post-infarction cardiomyocyte decompensation and promote cardiac function reconstruction is a major scientific and clinical problem that needs to be solved in the field of life medicine to limit the development of heart failure and reduce the mortality of ischemic heart disease.

I. Introduction

With the rapid development of the field of regenerative medicine in recent years, preclinical transplantation studies of human pluripotent stem cells (hPSCs), which include human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) derived cardiac myocytes, have shown their potential to replenish damaged hearts with new cardiomyocytes, providing a new strategy of myocardial regenerative medicine for the treatment of heart failure [2-3], and clinical trials are currently underway in China and abroad to assess the feasibility of their clinical application [4-8]. However, little is known about the exact mechanisms by which implanted cardiomyocytes exert their beneficial effects, and it is unclear whether implanted cardiomyocytes are directly involved in the enhancement of contractility of injured myocardium. The elucidation of the mechanism of action is not only of academic interest, but also of great value for the clinical translation of cell therapy.

Recently, researchers from the University Medical Center Hamburg-Eppendorf (Hamburg, Germany) published a paper in Circulation entitled "Contractile Force of Transplanted Cardiomyocytes Actively Supports Heart Function After Injury" [9]. This work successfully demonstrated that transplanted hiPSC-derived cardiomyocytes can actively participate in cardiac function and enhance the active contractility of the injured heart using an optogenetic approach (photochemical complex protein suppressor gene iLMO4), adding to the evidence for hPSCs-based cardiac regenerative cell therapy [9].

In response to the study, Professor Yang Huangtian, Distinguished Research Fellow of the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, said that the findings enriched the understanding of the mechanism of hiPSCs-derived cardiomyocyte transplantation to improve injured heart function, demonstrated that the reconstruction of damaged myocardial tissue is a strategy to improve heart function, and supported the hypothesis that transplantation of cardiomyocytes/tissue with contractile function can promote myocardial regeneration, which is encouraging and has important reference value for ongoing clinical trials based on hPSCs-derived cardiomyocytes for the treatment of heart failure.

II. Interpretation of the paper

Research Basis: Validation of Light Stimulation to Reversibly Block iLMO4 Gene Editing in Cardiomyocyte Contraction

In this study, researchers used hiPSC-derived engineered myocardial tissue (EHT) as a wild-type control (WT) compared with a cell treatment group of iLMO4-cardiomyocyte-EHT (α-Actinin staining showing more intact tissue structure and normal GFP expression).

The experimental results showed that iLMO4-cardiomyocyte-EHT could stop contracting under light stimulation and resume contraction after stopping light stimulation and re-pacing; while the wild type did not have any feedback to light stimulation. This demonstrates that light stimulation with ILMO4 gene editing can be used as an effective tool to characterize the contractile ability of cardiomyocytes.

In vivo validation: iLMO4-cardiomyocyte transplantation regenerates damaged myocardium and protects left ventricular function

Using a guinea pig model, researchers transplanted iLMO4-cardiomyocytes into damaged guinea pig hearts, and after 4 weeks could observe that the transplanted cardiomyocytes expressed cardiomyocyte markers such as cTnI, formed connections with native myocardial tissue, and protected against further deterioration of left ventricular function.

In vitro validation: using optogenetic methods to demonstrate that transplanted cardiomyocytes can actively participate in cardiac left ventricular systolic function

To better observe contractility, the researchers removed the transplanted hearts for in vitro studies. Irradiation of the anterior epicardium with blue light (470 nm) for 30-60 seconds resulted in an instantaneous drop in left ventricular pressure in the 7/13 iLMO4-edited heart. The contractility of the heart was gradually restored after cessation of light stimulation. It was confirmed that transplanted cardiomyocytes could actively participate in left ventricular contractile function.

III. Outlook

The clinical trial mentioned by the research team in the paper (HEAL-CHF [Treating Heart Failure With hPSC-CMs], NCT03763136) is one of the major clinical milestones in the global treatment of chronic heart failure by hiPSC-differentiated cardiomyocytes, conducted by Nanjing Gulou Hospital (investigator: Prof. Dongjin Wang) in collaboration with Help Therapeutics.

A search through ClinicalTrials.gov showed that there are 6 clinical registrations in the field of hiPSC differentiated cardiomyocytes for heart failure worldwide: 4 in China; 1 each in Japan and Germany.

The number of patients with heart failure in China is roughly 25 million, with an annual incidence of about 1.3%. There is a lack of truly effective treatments in the field of heart failure. For end-stage heart failure, heart transplantation is one of the ultimate effective treatment modalities, but donor resources are scarce, and donor matching conditions and surgical difficulties are high. Only a few hundred operations can be performed in China. At the same time, complications of heart transplantation can seriously affect the quality of patients' survival after surgery. In China, nearly 20% of patients survive less than three years after heart transplantation, and there is an urgent clinical need for other novel treatments.

Cardiac regenerative therapy, represented by hiPSC technology, certainly offers new hope for patients with end-stage heart failure. This new study, published in Circulation, adds to the evidence of cardiac regeneration therapy. It is believed that with the increasing maturity of hiPSC-related technologies and the advancement of preclinical and clinical studies of cell therapy in China and abroad, more comprehensive data on the efficacy and safety of cardiac myocardial spectrum cells differentiated based on hiPSCs for the treatment of heart failure will be available, which will play a great role in the development of new myocardial regeneration therapies for ischemic heart disease and heart failure.

This article is reprinted from 36kr.com

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Reference

1.WHO. World health statistics 2020: monitoring health for the SDGs, sustainable development goals. https://www.who.int/publications/i/item/9789240005105.

2.Li Q, Wang J, Wu Q, et al. Perspective on human pluripotent stem cell-derived cardiomyocytes in heart disease modeling and repair. Stem Cells Transl Med, 2020;9:1121-1128.3.

3.Weinberger F, Eschenhagen T. Cardiac regeneration: new hope for an old dream. Annu Rev Physiol. 2021;83:59-81. doi: 10.1146/annurev-physiol-031120-103629. Epub 2020 Oct 16.

4.ClinicalTrials.gov. Treating Heart Failure With hPSC-CMs (HEAL-CHF). https://clinicaltrials.gov/ct2/show/NCT03763136?cond=NCT03763136&draw=1&rank=1

5.ClinicalTrials.gov. Treating Congestive HF With hiPSC-CMs Through Endocardial Injection. https://clinicaltrials.gov/ct2/show/NCT04982081?term=iPSC&cntry=CN&draw=2&rank=3

6.Miyagawa S, Kainuma S, Kawamura T, et al. Case report: Transplantation of human induced pluri8potent stem cell-derived cardiomyocyte patches for ischemic cardiomyopathy. Front Cardiovasc Med. 16 August 2022. https://doi.org/10.3389/fcvm.2022.950829

7.ClinicalTrials.gov. A Study of iPS Cell-derived Cardiomyocyte Spheroids (HS-001) in Patients With Heart Failure (LAPiS Study) (LAPiS)https://www.clinicaltrials.gov/ct2/show/NCT04945018?term=LAPiS&draw=2&rank=1

8.ClinicalTrials.gov. Safety and Efficacy of Induced Pluripotent Stem Cell-derived Engineered Human Myocardium as Biological Ventricular Assist Tissue in Terminal Heart Failure (BioVAT-HF) https://www.clinicaltrials.gov/ct2/show/NCT04396899?term=safety+and+efficacy+induced+pluripotent+stem+cells&draw=2&rank=1

9.Stüdemann T, Rössinger J, Manthey C, Geertz B, Srikantharajah R, von Bibra C, Shibamiya A, Köhne M, Wiehler A, Wiegert JS, Eschenhagen T, Weinberger F. Contractile Force of Transplanted Cardiomyocytes Actively Supports Heart Function After Injury. Circulation. 2022；146:1159-1169 8. PMID: 36073365. DOI: 10.1161/CIRCULATIONAHA.122.060124