Precursor cells for all components of the heart – except right ventricle – found

Should assist in regenerative medicine

Progenitor cells – undifferentiated cells that later become specified – for all the heart’s components, except for the right ventricle, have been found by Hiroshima University researchers and detailed in a paper published in Nature Communications.

It is hoped this discovery will lead to greater understanding of mechanisms employed during heart development, enable the advancement of induction systems for cardiomyocytes in the lab, and advance heart regeneration therapies.

The Heart is composed of two kinds muscle cells: working cardiomyocytes – involved in the heart’s contraction contraction, and special cardiomyocytes – involved in the heart’s conduction system. The heart’s individual components of right, and left ventricles, atria, outflow tract, and sinus venosus all have a unique role and are composed of these defined cardiomyocytes.

Researchers need to find each specific cardiomyocyte progenitor if they are to induce required tissues in lab. The HU team, lead by Associate Professor Hiroki Kokubo, have found them, for all but one of these regions through studying expression of the Sfrp5 protein by cells in the embryonic heart.

That so much about the heart has remained a mystery until now might seem surprising. It is known that the heart is the first organ to form in the embryo and that it starts off as a crescent shape of heart primordium, composed of mesoderm, that migrates from the posterior to the anterior of embryo. This “heart crescent”, containing progenitor cells, gradually differentiates in stages forming the “heart tube” – essentially a primitive single-circulation heart, like that found in fish. The heart tube in the mammalian embryo continues to elongate and loops itself to form four chambers, generating two independent circulation systems – the pulmonary, and the systemic circulation systems we are familiar with.

While it has been believed that the heart crescent forms from a single tissue source that goes on to form the entire organ, a recent study indicated that another mesodermal layer is involved –  located in the medial side of the former in the cardiac crescent.

This newly found layer has been termed the second heart field (SHF). It is formed from undifferentiated splanchnic mesoderm, and later gives rise the right ventricle, outflow tract and part of atrium. What was formerly known as the cardiac crescent is thus now called the first heart field (FHF), which is already differentiated, forming the left ventricle and most of the atria. The question remains whether progenitors for this FHF exist.

Progenitors for special cardiomyocytes are implied to exist in the cardiac crescent through cell marking analysis – but until now no marker gene for the progenitors of special cardiomyotytes has been reported.

To address these two issues, the researchers at HU have focused on “Wnt signalling”  – as this signalling is known to regulate the proliferation and differentiation of cardiomyotytes – and selected the Sfrp5 gene to investigate in detail.

The research from HU has subsequently found the progenitor cells for the FHF, which give rise to ① the left ventricle and atria, ② forms the splanchnic mesoderm, expressing the SHF marker, that goes on to become the outflow tract, and ③ which differentiates into special cardiomyotyes in the sinus venosus – but not in the right ventricle.

Sfrp5 expression was observed to begin at the lateral sides of the formerly named heart crescent, and its expression ceased in the differentiated components of the left ventricle, atria, and outflow tract, but continued in the sinus venous.

This research provides new insight into how progenitors contribute to each component of the heart during its developmental process and could contribute towards treatments for heart disease. Heart disease is a major cause of death in much of the world and when cardiomyocytes are injured – they aren’t regenerated. Their death can cause serious heart failure, potentially leading to sudden death.

For this reason the HU researchers want to develop stem cell treatments, using the information gleaned from this latest research, so that tissues can be developed for transplant, and necessary progenitors grown for introduction into injured hearts. Sfrp5’s observed role in inducing progenitor proliferation also has potential to be exploited.

The insight gained into the development of the sinus venous is of particular interest due to it being the location of the sinoatrial node – the body’s inbuilt pacemaker.

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