generation-high-throughput-screening-biobanking-human-induced

Generation, High-Throughput Screening, and Biobanking of Human-Induced Pluripotent Stem Cell-Derived Cardiac Spheroids

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are of paramount importance for human cardiac disease modeling and therapeutics. We ...

University Medical Center Utrecht

Heart failure (HF) is a leading cause of death worldwide. The most common conditions that lead to HF are coronary artery disease, myocardial infarction, valve disorders, high blood pressure, and cardiomyopathy. Due to the limited regenerative capacity of the heart, the only curative therapy currently available is heart transplantation. Therefore, there is a great need for the development of novel regenerative strategies to repair the injured myocardium, replace damaged valves, and treat occluded coronary arteries. Recent advances in manufacturing technologies have resulted in the precise fabrication of 3D fiber scaffolds with high architectural control that can support and guide new tissue growth, opening exciting new avenues for repair of the human heart. This review discusses the recent advancements in the novel research field of fiber patterning manufacturing technologies for cardiac tissue engineering (cTE) and to what extent these technologies could meet the requirements of the highly organized and structured cardiac tissues. Additionally, future directions of these novel fiber patterning technologies, designs, and applicability to advance cTE are presented.

Fiber Scaffold Patterning for Mending Hearts: 3D Organization Bringing the Next Step.

The circadian clock synchronizes the body into 24-h cycles, thereby anticipating variations in tissue-specific diurnal tasks, such as response to increased cardiac metabolic demand during the active period of the day. As a result, blood pressure, heart rate, cardiac output, and occurrence of fatal cardiovascular events fluctuate in a diurnal manner. The heart contains different cell types that make up and reside in an environment of biochemical, mechanical, and topographical signaling. Cardiac architecture is essential for proper heart development as well as for maintenance of cell homeostasis and tissue repair. In this review, we describe the possibilities of studying circadian rhythmicity in the heart by using advanced in vitro systems that mimic the native cardiac 3D microenvironment which can be tuned in time and space. Harnessing the knowledge that originates from those in vitro models could significantly improve innovative cardiac modeling and regenerative strategies.

Cardiac circadian rhythms in time and space: The future is in 4D.

Worldwide, over 26 million patients suffer from heart failure (HF). One strategy aspiring to prevent or even to reverse HF is based on the transplantation of cardiac tissue-engineered (cTE) constructs. These patient-specific constructs aim to closely resemble the native myocardium and, upon implantation on the diseased tissue, support and restore cardiac function, thereby preventing the development of HF. However, cTE constructs off-the-shelf availability in the clinical arena critically depends on the development of efficient preservation methodologies. Short- and long-term preservation of cTE constructs would enable transportation and direct availability. Herein, currently available methods, from normothermic- to hypothermic- to cryopreservation, for the preservation of cardiomyocytes, whole-heart, and regenerative materials are reviewed. A theoretical foundation and recommendations for future research on developing cTE construct specific preservation methods are provided. Current research suggests that vitrification can be a promising procedure to ensure long-term cryopreservation of cTE constructs, despite the need of high doses of cytotoxic cryoprotective agents. Instead, short-term cTE construct preservation can be achieved at normothermic or hypothermic temperatures by administration of protective additives. With further tuning of these promising methods, it is anticipated that cTE construct therapy can be brought one step closer to the patient.

A Roadmap to Cardiac Tissue-Engineered Construct Preservation: Insights from Cells, Tissues, and Organs.

Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) do not display all hallmarks of mature primary cardiomyocytes, especially the ability to use fatty acids (FA) as an energy source, containing high mitochondrial mass, presenting binucleation and increased DNA content per nuclei (polyploidism), and synchronized electrical conduction. This immaturity represents a bottleneck to their application in (1) disease modelling-as most cardiac (genetic) diseases have a middle-age onset-and (2) clinically relevant models, where integration and functional coupling are key. So far, several methods have been reported to enhance iPSC-CM maturation; however, these protocols are laborious, costly, and not easily scalable. Therefore, we developed a simple, low-cost, and rapid protocol to promote cardiomyocyte maturation using two small molecule activators of the peroxisome proliferator-activated receptor β/δ and gamma coactivator 1-alpha (PPAR/PGC-1α) pathway: asiatic acid (AA) and GW501516 (GW). METHODS AND RESULTS: Monolayers of iPSC-CMs were incubated with AA or GW every other day for ten days resulting in increased expression of FA metabolism-related genes and markers for mitochondrial activity. AA-treated iPSC-CMs responsiveness to the mitochondrial respiratory chain inhibitors increased and exhibited higher flexibility in substrate utilization. Additionally, structural maturity improved after treatment as demonstrated by an increase in mRNA expression of sarcomeric-related genes and higher nuclear polyploidy in AA-treated samples. Furthermore, treatment led to increased ion channel gene expression and protein levels.

Article	Year
Fiber Scaffold Patterning for Mending Hearts: 3D Organization Bringing the Next Step. Advanced healthcare materials\| PubMed ID: 31603288	2020
Cardiac circadian rhythms in time and space: The future is in 4D. Current opinion in pharmacology\| PubMed ID: 33338891	2021
A Roadmap to Cardiac Tissue-Engineered Construct Preservation: Insights from Cells, Tissues, and Organs. Advanced materials (Deerfield Beach, Fla.)\| PubMed ID: 34048090	2021
Small molecule-mediated rapid maturation of human induced pluripotent stem cell-derived cardiomyocytes. Stem cell research & therapy\| PubMed ID: 36575473	2022

Nino Chirico

Biography

JoVE Journal Publications

Other Publications