Potential New Drug Directs Stem Cells to Mature into Heart Muscle

Cardiac disease researchers have identified a low molecular weight compound that directs embryonic stem cells (ESCs) to differentiate specifically into cardiomyocytes.

Investigators at the Sanford-Burnham Medical Research Institute (La Jolla, CA, USA) employed an advanced high-throughput screening system to identify compounds that would induce mouse and human ESCs to differentiate. They reported in the August 3, 2012, issue of the journal Cell Stem Cell that the 1,4-dihydropyridine compound ITD-1 (inducer of type II TGF-beta receptor (TGFBR2) degradation-1) had the desired effect. Further study showed that ITD-1 acted by triggering the destruction of the TGF-beta receptor, which blocked the entire TGF pathway.

This pathway, named for the cytokine transforming growth factor-beta, controls proliferation, cellular differentiation, and other functions in most cells. It plays a role in immunity, cancer, heart disease, and diabetes. TGF-beta acts as an antiproliferative factor in normal epithelial cells and at early stages of cancer development. In normal cells, TGF-beta, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. When a cell is transformed into a cancer cell, parts of the TGF-beta signaling pathway are mutated, and TGF-beta no longer controls the cell. These cancer cells and surrounding stromal cells (fibroblasts) begin to proliferate. Both types of cell increase their production of TGF-beta. This TGF-beta acts on the surrounding stromal cells, immune cells, endothelial, and smooth muscle cells. It causes immunosuppression and angiogenesis, which makes the cancer more invasive. TGF-beta also converts effector T-cells, which normally attack cancer with an inflammatory reaction, into regulatory (suppressor) T-cells, which turn off the inflammatory reaction.

Acting on a population of ESCs, ITD-1 selectively enhanced the differentiation of uncommitted mesoderm to cardiomyocytes, but not to vascular smooth muscle or endothelial cells. ITD-1 proved to be a highly selective TGF-beta inhibitor and revealed an unexpected role for TGF-beta signaling in controlling cardiomyocyte differentiation from multipotent cardiovascular precursors.

"Heart disease is the leading cause of death in this country. Because we cannot replace lost cardiac muscle, the condition irreversibly leads to a decline in heart function and ultimately death. The only way to effectively replace lost heart muscle cells—called cardiomyocytes—is to transplant the entire heart," said senior author Dr. Mark Mercola, director of the muscle development and regeneration program at Sanford-Burnham Medical Research Institute. "Using a drug to create new heart muscle from stem cells would be far more appealing than heart transplantation."

The investigators are collaborating with the biotech company ChemRegen, Inc. (San Diego, CA, USA) to transform ITD-1 into a drug that one day might be used clinically.


Related Links:
Sanford-Burnham Medical Research Institute
ChemRegen, Inc.