Researcher scientists from the University of California, Berkeley, and the Gladstone Institutes have successfully developed a template for generating beating cardiac tissue. The unique system, designed using stem cell regeneration, could be used as a drug-screening tool for safer pregnancies, or as a model for assessing cardiac birth defects. Published in the journal Nature Communications, researchers claimed to have used biophysical and biochemical cues to stimulate stem cells into differentiation and self-organization, resulting in micron-scale cardiac tissue with microchambers.

Artificial Cardiac Tissue

The study is a one of its kind, demonstrating how a human heart develops in vitro. It was supported by the National Institutes of Health along with a Siebel Paostdoctoral Fellowship.

Screening Tool For Drug Toxicity

Researchers exposed the system of differentiating cells to thalidomide, a drug widely known to cause severe birth defects. When compared to normal heart tissue, it was seen that normal therapeutic doses of the drug caused abnormalities in the developing microchambers, such as reduced size, improper muscle contractions and decreased beat rates.

Dr. Bruce Conklin, senior investigator at the Gladstone Institute of Cardiovascular Disease and Professor of Medical Genetics and Cellular and Molecular Pharmacology at UC San Francisco explained that every year, almost 280,000 pregnant women suffer from drug-related foetal problems. The most common birth defects involve heart abnormalities, and so the team had decided to use their system to check for drug-induced developmental toxicity.

A New Milestone

Almost four months after the previous findings, Kevin Healy, a UC Berkeley Professor of Bioengineering and co-senior author of the study, along with other UC Berkeley researchers introduced a structure of beating human heart cells inscribed onto a chip as a potential screening system for drug toxicity. However, this heart-on-a-chip device used pre-differentiated cardiac cells that mimicked adult tissues – genetically reprogrammed stem cells from adult skin tissue formed beating heart cells with small chambers.

Conklin’s lab at Gladstone, an independent, non-profit life science research organization affiliated with UC San Francisco, supplied the human-induced pluripotent stem cells.

Differentiation In Terms Of Location

After a period of two weeks, the 2-D configuration of cells took on a 3-D structure of a pulsating microchamber. The cells had spatially self-organized on the basis of their positioning – along the perimeter or in the centre of the colony – as soon as differentiation started.

Compared with cells in the middle, the ones along the perimeter or on the edge underwent greater mechanical stress, resembling fibroblasts which form collagen in connective tissues. The cells in the middle developed into cardiac muscle cells. Moreover, these cells lost the expression of epithelial cadherin (E-cadherin) and octamer-binding transcription factor 4 (OCT4) faster than the cells at the perimeter – a significant factor in the formation of heart tissue.

Used In Place Of Animal Models

Developing a fully functional human heart from preliminary steps is very difficult to achieve in vitro, the study explained. Studies such as these have previously involved dissecting animals at various stages of development, in order to study organ formation and faults in biochemical processes.

“The fact that we used patient-derived human pluripotent stem cells in our work represents a monumental change in the field”, claimed Healy. “Previous studies of cardiac micro tissues primarily used harvested rat cardiomyocytes, which is an imperfect model for accurately studying human disease”.

Other Prospects

Researchers highlighted that this technological achievement can be used to study other organs and their developmental processes and problems as well.

“Our focus here has been on early heart development, but the basic principles of patterning of human pluripotent stem cells, and subsequently differentiating them, can be readily expanded into a broad range of tissues for understanding embryogenesis and tissue morphogenesis”, Healy hopes.