Breakthrough results in early human heart development from stem cells have been achieved by the scientists at the University of California, Berkeley in association with researchers at the Gladstone Institute. The results of the experiment have been published in the Journal of Nature Communications. A template for growing beating cardiac tissue from stem cells has been developed; thus, creating a system that could serve as a model for early heart development and a drug-screening tool to make pregnancies safer. Biochemical and biophysical cues were used by researchers to prompt stem cells to differentiate and self-organize into micron-scale cardiac tissue, including micro chambers.
Kevin Healy, a UC Berkeley professor of bioengineering, and a co-senior author of the study said that it is the first example illustrating the process of a developing human heart chamber in vitro. He is positive about this technology and is hopeful that it would help in quickly screen for drugs that are likely to generate cardiac birth defects, and thereby help doctors in pointing out the drugs that can be potentially dangerous during pregnancy.
In order to test the potential of the system as a drug screening tool, differentiating cells were exposed to thalidomide – a drug that is known to cause severe birth defects. It was found that even at normal therapeutic doses, the drug led abnormalities in the hearts micro chambers like decreased size, problems with muscle contraction and lower beat rates.
Dr. Bruce Conklin, a senior investigator at the Gladstone Institute of Cardiovascular Disease, a professor of medical genetics and cellular and molecular pharmacology at UC San Francisco and a co-author of the study said that drug cardiac developmental toxicity screening was specifically chosen to demonstrate a clinically relevant application of the cardiac micro chambers. He opined that every year about 280,000 pregnant women are exposed to drugs with evidence of potential fetal risk. Birth defects involving the heart are the most common, and that is the reason why drug safety during pregnancy is of utmost importance.
For this new study, the scientists mimicked human tissue formation by starting with stem cells that were genetically reprogrammed from adult skin tissue to form small chambers with beating human heart cells. The undifferentiated stem cells were then placed onto a circular-patterned surface that served to physically regulate cell differentiation and growth. After 2 weeks, the cells that had started on a two-dimensional surface environment started taking on a 3D structure as a pulsating micro chamber. Also, the cells had self-organized based upon whether they were positioned along the perimeter or in the middle of the colony. It was also observed that cells along the edge experienced greater mechanical stress and tension, and appeared more like fibroblasts, which form the collagen of connective tissue as compared to the cells in the center. The center cells on the other hand developed into cardiac muscle cells. This spatial organization was observed as soon as the differentiation started. Center cells lost the expression of octamer-binding transcription factor 4 (OCT4) and epithelial cadherin (E-cadherin) faster than perimeter cells, which are important to the development of heart tissue.
Zhen Ma, a UC Berkeley postdoctoral researcher in bioengineering and study’s lead author said that such spatial differentiation happens in biology naturally, but it was demonstrated by them through this process in vitro. The confined geometric pattern provided biochemical and biophysical cues that directed cardiac differentiation and the formation of a beating micro chamber.
Healy opined that since patient-derived human pluripotent stem cells were used in this experiment, it made a huge difference in the results. Previous similar studies used harvested rat cardiomyocytes, which is not a suitable model for human disease. This technology holds great potential to study other organ development as well.
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