Abstract
Human pluripotent stem cells (hPSCs) constitute a valuable model to study the complexity of early human cardiac development and investigate the molecular mechanisms involved in heart diseases. The differentiation of hPSCs into cardiac lineages in vitro can be achieved by traditional two-dimensional (2D) monolayer approaches or by adopting innovative three-dimensional (3D) cardiac organoid protocols. Human cardiac organoids (hCOs) are complex multicellular aggregates that faithfully recapitulate the cardiac tissue’s transcriptional, functional, and morphological features. In recent years, significant advances in the field have dramatically improved the robustness and efficiency of hCOs derivation and have promoted the application of hCOs for drug screening and heart disease modeling. This review surveys the current differentiation protocols, focusing on the most advanced 3D methods for deriving hCOs from hPSCs. Furthermore, we describe the potential applications of hCOs in the pharmaceutical and tissue bioengineering fields, including their usage to investigate the consequences of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV2) infection in the heart.
Highlights
The knowledge on human cardiogenesis has been based on either post-mortem studies or animal models for a long time
The use of human pluripotent stem cells as an in vitro model to study cardiac development has flourished over the last two decades. hPSCs are suitable for regenerative medicine, tissue engineering, and drug screening applications owing to their unique proliferative capacity and potential to differentiate into virtually all somatic cell types
We emphasize the latest breakthroughs in the fields of cell biology and tissue bioengineering that open the road for the generation of 3D human cardiac organoids
Summary
The knowledge on human cardiogenesis has been based on either post-mortem studies or animal models for a long time. These hCOs have a mid-myocardial layer without chamber-like structures and some epicardial-like cells (septum-transversum-like anlagen) in the outer layer. Since Wnt inhibition promotes heart formation in Xenopus (Marvin et al, 2001), chicks, and mouse embryonic stem cells (Ueno et al, 2007), the second stage relies on Wnt inhibitors, such as DKK-1, IWP2, IWP4, or Wnt-C59 to promote cardiac mesoderm differentiation. The most employed chemicallydefined protocol known as GiWi (GSK-inhibition/Wntinhibition) allows the generation of about 80% of CMs from several hPSC lines This method drives the specification into mesoderm precursors by treating the cells with CHIR99021, a glycogen synthase kinase-3β (GSK-3β) inhibitor that activates the canonical Wnt/β-catenin pathway. The first section will navigate through the “self-assembly” method that
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