Human engineered cardiac tissues (hECTs) are derived by experimental manipulation of

pluripotent Cell potency is a cell's ability to differentiate into other cell types. The more cell types a cell can differentiate into, the greater its potency. Potency is also described as the gene activation potential within a cell, which like a continuum ...

stem cells, such as

human embryonic stem cells Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist ...

(hESCs) and, more recently, human induced pluripotent stem cells (hiPSCs) to differentiate into human

cardiomyocytes Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...

. Interest in these bioengineered cardiac tissues has risen due to their potential use in cardiovascular research and clinical therapies. These tissues provide a unique

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

model to study cardiac physiology with a species-specific advantage over cultured animal cells in experimental studies. hECTs also have therapeutic potential for

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

regeneration of heart muscle. hECTs provide a valuable resource to reproduce the normal development of human heart tissue, understand the development of human cardiovascular disease (CVD), and may lead to engineered tissue-based therapies for CVD patients.

Generation

hESCs and hiPSCs are the primary cells used to generate hECTs. Human pluripotent stem cells are differentiated into cardiomyocytes (hPSC-CMs) in

culture Culture ( ) is a concept that encompasses the social behavior, institutions, and Social norm, norms found in human societies, as well as the knowledge, beliefs, arts, laws, Social norm, customs, capabilities, Attitude (psychology), attitudes ...

through a milieu containing small-molecule mediators (e.g. cytokines, growth and transcription factors). Transforming hPSC-CMs into hECTs incorporates the use of 3-dimensional (3D) tissue scaffolds to mimic the natural physiological environment of the heart. This 3D scaffold, along with

collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...

– a major component of the cardiac

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...

– provides the appropriate conditions to promote cardiomyocyte organization, growth and differentiation.

Characteristics

At the intracellular level, hECTs exhibit several essential structural features of cardiomyocytes, including organized

sarcomeres A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells (called muscl ...

, gap-junctions, and

sarcoplasmic reticulum The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kep ...

structures; however, the distribution and organization of many of these structures is characteristic of

neonatal In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to Juvenile (orga ...

heart tissue rather than adult human heart muscle. Recently, the combined effects of electrical and dynamic stimulation were found to significantly enhance the functional maturation of hECTs, resulting in improved alignment, structure, and organization, enhanced calcium handling capacity, increased expression of contractile and structural protein genes, and enhanced vascular network formation, closely resembling healthy in vivo conditions. hECTs also express key cardiac genes ( α-MHC, SERCA2a and

ACTC1 ACTC1 encodes cardiac muscle alpha actin. This isoform differs from the alpha actin that is expressed in skeletal muscle, ACTA1. Alpha cardiac actin is the major protein of the thin filament in cardiac sarcomeres, which are responsible for muscle ...

) nearing the levels seen in the adult heart. Analogous to the characteristics of ECTs from animal models, hECTs beat spontaneously and reconstitute many fundamental physiological responses of normal heart muscle, such as the Frank-Starling mechanism and sensitivity to calcium. hECTs show dose-dependent responses to certain drugs, such as morphological changes in action potentials due to

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...

blockers and modulation of contractile properties by

inotropic An inotrope or inotropic is a drug or any substance that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular co ...

and

lusitropic Lusitropy or lucitropy is the rate of myocardial relaxation. The increase in cytosolic calcium of cardiomyocytes via increased uptake leads to increased myocardial contractility (positive inotropic effect), but the myocardial relaxation, or lusitro ...

agents.

Experimental and clinical applications

Even with current technologies, hECT structure and function is more at the level of newborn heart muscle than adult myocardium. Nonetheless, important advances have led to the generation of hECT patches for myocardial repair in animal models and use for in vitro models of drug screening. hECTs can also be used to experimentally model CVD using genetic manipulation and adenoviral-mediated gene transfer. In animal models of

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

(MI), hECT injection into the hearts of rats and mice reduces infarct size and improves heart function and contractility. As a proof of principle, grafts of engineered heart tissues have been implanted in rats following MI with beneficial effects on left ventricular function. The use of hECTs in generating tissue engineered heart valves is also being explored to improve current heart valve constructs for in vivo animal studies. As tissue engineering technology advances to overcome current limitations, hECTs are a promising avenue for experimental drug discovery, screening and disease modelling and in vivo repair.

References

{{reflist, 33em Stem cell research Tissue engineering Muscle tissue Tissue transplants