Advances in 3D Organoid Models for Stem Cell-Based Cardiac Regeneration

Abstract

The adult human heart cannot regain complete cardiac function following tissue injury, making cardiac regeneration a current clinical unmet need. There are a number of clinical procedures aimed at reducing ischemic damage following injury; however, it has not yet been possible to stimulate adult cardiomyocytes to recover and proliferate. The emergence of pluripotent stem cell technologies and 3D culture systems has revolutionized the field. Specifically, 3D culture systems have enhanced precision medicine through obtaining a more accurate human microenvironmental condition to model disease and/or drug interactions in vitro. In this study, we cover current advances and limitations in stem cell-based cardiac regenerative medicine. Specifically, we discuss the clinical implementation and limitations of stem cell-based technologies and ongoing clinical trials. We then address the advent of 3D culture systems to produce cardiac organoids that may better represent the human heart microenvironment for disease modeling and genetic screening. Finally, we delve into the insights gained from cardiac organoids in relation to cardiac regeneration and further discuss the implications for clinical translation.

Assessment of the Optimal Generation Period and Size of Human iPSC-Derived Cardiac Organoids for Cardiotoxicity Drug Testing

“…The success of the 3D cardiac organoid model relies on an adequate nutrient and oxygen supply. As the size of the organoid increases, there may be challenges in supplying nutrients to the internal cells [49][50][51]. This is because cells within the organoid need to be within a certain distance to receive su cient nutrients and oxygen.…”

Revisiting Cardiac Biology in the Era of Single Cell and Spatial Omics

“…101 Clinical implementation of stem cell-based technologies applied to the heart includes the recent development of 3-dimensional cardiac microtissues engineered from iPSCs harboring human mutations, allowing for rapid testing of potential therapeutics for correction of genetic defects and promotion of cardiac regeneration. 102,103 By guiding cell phenotypes toward desired lineages, these systems provide valuable insight into the cellular mechanisms governing human cardiac cell differentiation and development, and the use of patient-derived iPSCs is useful for understanding pathogenic mechanisms in cells with genetic signatures of disease. However, the ability of these models to faithfully recapitulate in vivo phenotype and behavior is limited; for example, iPSCderived cardiomyocytes display a fetal-like phenotype that restricts their ability to perform when transplanted in vivo.…”

“… 101 Clinical implementation of stem cell-based technologies applied to the heart includes the recent development of 3-dimensional cardiac microtissues engineered from iPSCs harboring human mutations, allowing for rapid testing of potential therapeutics for correction of genetic defects and promotion of cardiac regeneration. 102 , 103 …”

Advances in the Generation of Constructed Cardiac Tissue Derived from Induced Pluripotent Stem Cells for Disease Modeling and Therapeutic Discovery

“…Cardiovascular disease (CVD) causes one-third of all deaths [1][2][3], leading global mortality [4][5][6][7][8][9][10][11][12][13][14][15][16][17], with myocardial infarction (MI) contributing the most among CVDs [6]. Heart failure (HF) is a terminal CVD resulting in irreversible loss of heart function with progression exacerbated by prolonged inflammation [6,15,[18][19][20].…”

“…Limited therapeutic options necessitate reliance on scarce donor organs and immunosuppression [8,[10][11][12]16,[23][24][25][26][27]. Preclinical studies have attempted to remuscularize infarcted hearts by regenerating new cardiomyocytes (CMs) from stem cells and non-CMs or by modulating the proliferation-maturation axis of existing CMs [1,17,[26][27][28][29][30][31], the constituent cells of cardiac muscle [1,31] (Figure 1). Recent studies have also aimed to revascularize damaged tissue or reprogram fibrotic scar tissue into healthy musculature and vasculature [3,6,8,12,15,20,26,27,30,32,33].…”