Researchers at the University of Wisconsin-Madison led by cardiologist Timothy J. Kamp have genetically reprogrammed the most common type of cell found in mammalian connective tissue called fibroblasts into primitive master heart cells known as induced cardiac progenitor cells- from which the developing heart originates.
Published in the journal Cell Stem Cell, the team says the technology could permit a scalable method for making an almost unlimited supply of the three major types of cells in the heart. If replicated in human cells, the feat could one day fuel drug discovery, powerful new models for heart disease and the raw material for treating diseased hearts.
The lead author, Pratik A. Lalit identified over 11 genes that play a central role in the embryonic development of heart and further shortlisted the ‘essential five genes’ which could be used to reprogram the fibroblasts. The group also found out the conditions necessary for the cells to be transformed and cultured in the laboratory.
With this information in hand, Lalit, Kamp and the team could push the fibroblast cells back in developmental time to become the cardiac progenitor cells that make cardiomyocytes, smooth muscle cells and endothelial cells — the trio of workhorse cells that make up the organ.
This means billions of the critical heart cells can be made in a laboratory dish providing ample material to study heart disease, drug screening and ultimately replacing the diseased heart cells of a person with the healthy ones.
“Because the reprogrammed cells are actively dividing, we can generate billions of cells with relative ease,” says Kamp, who also co-directs the UW-Madison Stem Cell and Regenerative Medicine Center.
Video: Induced cardiac progenitor cells (iCPCs) can develop in a dish into contracting heart muscle cells (green) when grown together with other contracting heart muscle cells. These cells could potentially be used for modelling heart diseases as well as testing drugs.
What is awesome about it?
It is literally like an exercise in reverse engineering! “What does it take to make a normal heart? We’re learning from what happens in the embryo during cardiac development,”says Lalit. By knowing what are the genetic factors needed for the heart to develop from embryo stage, they can direct the fibroblasts down the cardiac developmental lineage too.
A key desired feature that is present in the team’s engineered cardiac progenitor cells is that the cells which grow from the induced progenitor cells made from fibroblasts are faithful only to the cardiac lineage i.e. they become only heart cells. Unlike other all-purpose pluripotent stem cells which can become any of the 220 different kinds of cells in the human body!
Why is it important? A potential drawback of cell transplants derived from all-purpose stem cells is the small but very real possibility of creating a teratoma, a tumor from tissue other than the intended cell lineage.
“With cardiac progenitor cells, you can reduce the risk of tumor formation as they are more committed to the heart lineages and are unlikely to form a tumor,” says Kamp, a professor of medicine in the UW School of Medicine and Public Health.
A good disease model?
Heart attacks lead to cell death and the team experimentally induced one in mice. They injected the new engineered cells in to the damaged hearts of mice and observed that these cells migrated to the damaged part of the heart making new cardiomyocytes- the heart cells that contract to underpin the beating of the heart — as well as smooth muscle and endothelial cells, key cells that form blood vessels. This led to better survival chances in the mice.