Human Stem Cells for Cardiac Disease Modeling and Preclinical and Clinical Applications-Are We on the Road to Success?

Abstract

Cardiovascular diseases (CVDs) are pointed out by the World Health Organization (WHO) as the leading cause of death, contributing to a significant and growing global health and economic burden. Despite advancements in clinical approaches, there is a critical need for innovative cardiovascular treatments to improve patient outcomes. Therapies based on adult stem cells (ASCs) and embryonic stem cells (ESCs) have emerged as promising strategies to regenerate damaged cardiac tissue and restore cardiac function. Moreover, the generation of human induced pluripotent stem cells (iPSCs) from somatic cells has opened new avenues for disease modeling, drug discovery, and regenerative medicine applications, with fewer ethical concerns than those associated with ESCs. Herein, we provide a state-of-the-art review on the application of human pluripotent stem cells in CVD research and clinics. We describe the types and sources of stem cells that have been tested in preclinical and clinical trials for the treatment of CVDs as well as the applications of pluripotent stem-cell-derived in vitro systems to mimic disease phenotypes. How human stem-cell-based in vitro systems can overcome the limitations of current toxicological studies is also discussed. Finally, the current state of clinical trials involving stem-cell-based approaches to treat CVDs are presented, and the strengths and weaknesses are critically discussed to assess whether researchers and clinicians are getting closer to success.

Keywords: cardiovascular diseases; cell therapy; disease modeling; human stem cells; iPSC.

Figure 1

Sources and types of human stem cells. (A) Pluripotent cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are obtained from the inner cell mass of the blastocyst and by reprogramming of somatic cells (e.g., collected from dermal skin fibroblasts or peripheral blood), respectively. They can generate cells and tissues derived from the three embryonic germ layers. (B) Several types of multipotent stem cells are found in adult tissues. These have a more restrictive differentiation potential than pluripotent stem cells. Examples of multipotent stem cells currently being used in CVD therapy include (i) mesenchymal stem cells (MSCs), which can be derived from different tissue sources such as bone marrow, fat adipose tissue, and umbilical cord; (ii) bone-marrow-derived mononuclear cells (BMMNCs); (iii) cardiac stem cells (CSCs); (iv) endothelial progenitor cells (EPCs); (v) hematopoietic stem cells (HSCs); and (vi) skeletal myoblasts (SMs). This figure was partially drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/, accessed on 28 May 2023).

Figure 2

Stem cells in disease modeling, toxicity studies, drug discovery, and cell therapy for CVDs: Pluripotent stem cells (A), including ESCs and iPSCs, are often used for the modeling of CVDs. They can be differentiated in cardiac cells both in 2D (B) or 3D cultures (C), which can be supported by the inclusion of different scaffolds and matrices. The differentiated cells can be used for drug discovery and toxicity studies (D) and for cell therapy purposes through transendocardial, intramyocardial, intravenous, or intracoronary delivery (E). This figure was partially drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/, accessed on 6 April 2023).