“The state of the heart”: Recent advances in engineering human cardiac tissue from pluripotent stem cells

Abstract

The pressing need for effective cell therapy for the heart has led to the investigation of suitable cell sources for tissue replacement. In recent years, human pluripotent stem cell research expanded tremendously, in particular since the derivation of human induced pluripotent stem cells. In parallel, bioengineering technologies have led to novel approaches for in vitro cell culture. The combination of these two fields holds potential for in vitro generation of high-fidelity heart tissue, both for basic research and for therapeutic applications. However, this new multidisciplinary science is still at an early stage. Many questions need to be answered and improvements need to be made before clinical applications become a reality. Here we discuss the current status of human stem cell differentiation into cardiomyocytes and the combined use of bioengineering approaches for cardiac tissue formation and maturation in developmental studies, disease modeling, drug testing and regenerative medicine.

Human-Induced Pluripotent Stem Cell Technology and Cardiomyocyte Generation: Progress and Clinical Applications

“…Important advances have been achieved in chemical-based cardiac differentiation, cardiac subtype specification, large-scale suspension culture differentiation, and the development of chemically defined culture conditions. These protocols of hiPSCs require key steps for the differentiation progression that have already been thoroughly reviewed [ 9 , 43 , 44 ].…”

“…In vitro differentiation of hiPSCs into CMs, regardless of the methodological approach, should mimic the sequential steps of in vivo embryonic cardiac development providing temporal administration of molecules that regulate specific signaling cascades: the activation of the canonical Wnt signaling induces the early primitive streak/mesoendoderm stage and the following inhibition of the same pathway at a later stage allows it to achieve the cardiac mesoderm specification [ 9 , 43 , 44 ].…”

Engineering of Mature Human Induced Pluripotent Stem Cell‐Derived Cardiomyocytes Using Substrates with Multiscale Topography

“…Therefore, methods that enhance the maturation of iCMs from iPSCs prior to injection or drug screening tests are crucially needed. It has also been the consensus that the differentiation process suffers from batch‐to‐batch variation and lack of repeatability . Accordingly, it is logical to conclude that the physical cues provided to iPSCs during standard culture conditions do not sufficiently mimic the natural process of differentiation to fully mature CMs.…”

Development of a bio‐MEMS device for electrical and mechanical conditioning and characterization of cell sheets for myocardial repair

“…Engineered tissue replacements for damaged myocardium, such as stacked cellular sheets provide one solution to this problem. Though much research is focused on cell sources and solutions for damaged myocardium, there are multiple remaining design challenges associated with creating safe, functioning cardiac implants that need to be bridged before realizing clinical application (Chiu, Iyer, Reis, Nunes, & Radisic, ; Hecker & Birla, ; Hirt, Hansen, & Eschenhagen, ; Rodrigues, Kaasi, Maciel Filho, Jardini, & Gabriel, ; Sirabella, Cimetta, & Vunjak‐Novakovic, ). Native myocardium is formed from a high density of aligned myocytes and supporting cells that contract synchronously according to electrical signal propagation throughout the tissue (Vunjak‐Novakovic et al, ).…”