Development of a human cardiac organoid injury model reveals innate regenerative potential

Abstract

The adult human heart possesses a limited regenerative potential following an ischemic event, and undergoes a number of pathological changes in response to injury. While cardiac regeneration has been documented in zebrafish and neonatal mouse hearts, it is currently unknown whether the immature human heart is capable of undergoing complete regeneration. Combined progress in pluripotent stem cell differentiation and tissue engineering has facilitated the development of human cardiac organoids (hCO), which resemble fetal heart tissue and can be used to address this important knowledge gap. This study aimed to characterise the regenerative capacity of immature human heart tissue in response to injury. Following cryoinjury with a dry ice probe, hCO exhibited an endogenous regenerative response with full functional recovery by two weeks following acute injury. Cardiac functional recovery occurred in the absence of pathological fibrosis or cardiomyocyte hypertrophy. Consistent with regenerative organisms and neonatal human hearts, there was a high basal level of cardiomyocyte proliferation, which may be responsible for the regenerative capacity of the hCO. This study suggests that immature human heart tissue has an intrinsic capacity to regenerate.

Three-Dimensional and Biomimetic Technology in Cardiac Injury After Myocardial Infarction: Effect of Acellular Devices on Ventricular Function and Cardiac Remodelling

“…Furthermore, the addition of monocytes in our studies did not have any impact on cardiomyocyte proliferation. This study suggests that immature human heart muscle may possess an intrinsic ability to mount a regenerative response, which occurs even in the absence of inlammation and angiogenesis [77]. Other studies have emerged documenting complete functional recovery of newborn human hearts following MI [63,67,[81][82][83].…”

“…A human cardiac organoid injury model reveals innate regenerative potential [77]. Under normal conditions, the ECM provides structural support for the heart, acts as a reservoir for cytokines and growth factors and provides a connection with surrounding cells that is important for transmission of extracellular cues [27,78].…”

“…This model of study therefore provides an opportunity to interrogate the molecular and cellular mechanism governing regeneration of immature human heart tissue [73,77].…”

“…Thus, evidence has accumulated over the past 20 years to demonstrate that there is some amount of cardiac turnover, both in healthy and injured tissues [63,77], and this has prompted eforts to devise cardiomyocyte replacement therapies by the promotion of endogenous regenerative process [60,62]. Evidence from rodent [86], axolotls, newts, zebraish [77] and human studies challenges the view of the heart as a terminally diferentiated organ and unable to regenerate [67]. The ability of ECM biomaterials to stimulate robust endogenous cardiac regeneration without adding exogenous cells would avoid these issues, today more and more studies show that this utopia is not more the 'holy grail' of heart regeneration.…”

Organoids: a Special Issue

“…With this in mind, Voges et al (2017) report on the generation of heart organoids and use them to investigate the regenerative capacity of human fetal heart tissue in vitro. While the formation of cardiomyocytes has long been possible in 2D, researchers are now tweaking protocols for generating PSC-derived organoids to either improve specification or patterning in 3D, which will have important implications for both drug screening and disease modelling.…”