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Mending a Broken Heart -- With a Molecule That Turns Stem Cells Into Heart Cells

                   Science Daily  — For years, scientists have been looking for a good source of heart cells that can be used to study cardiac function in the lab, or perhaps even to replace diseased or damaged tissue in heart disease patients. To do this, many are looking to stem cells. Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham), the Human BioMolecular Research Institute, and ChemRegen, Inc. have been searching for molecules that convert stem cells to heart cells for about eight years -- and now they've found one.

"Heart disease is the leading cause of death in this country. Because we can't 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 Mark Mercola, Ph.D., director of Sanford-Burnham's Muscle Development and Regeneration Program and senior author of the study. "Using a drug to create new heart muscle from stem cells would be far more appealing than heart transplantation."Writing in the August 3 issue of Cell Stem Cell, the team describes how they sifted through a large collection of drug-like chemicals and uncovered ITD-1, a molecule that can be used to generate unlimited numbers of new heart cells from stem cells.

Searching for needles in a haystack

Stem cells are important because they do two unique things --

1) self-renew, producing more stem cells and

2) differentiate, becoming other, more specialized cell types.

To obtain a large number of a certain cell type, such as heart cells, the hard part is figuring out the signals that direct them to become the desired cell type.

Mercola's group has been hunting for heart-inducing signals for 15 years -- in embryos and in stem cells. To find a synthetic molecule that might one day lead to a drug therapy to regenerate the heart, they joined forces with a team of medicinal chemists at the Human BioMolecular Research Institute led by John Cashman, Ph.D. With funding from the California Institute for Regenerative Medicine, they used sophisticated robotic technology to methodically test a large collection of drug-like chemicals, looking for that needle in a haystack that, when added to stem cells, results in cardiomyocytes. The winning compound was ITD-1.

Therapeutic applications

There's no shortage of therapeutic possibilities for ITD-1. "This particular molecule could be useful to enhance stem cell differentiation in a damaged heart," explained Erik Willems, Ph.D., postdoctoral researcher in Mercola's lab and first author of the study. "At some point, it could become the basis for a new therapeutic drug for cardiovascular disease -- one that would likely limit scar spreading in heart failure and promote new muscle formation."

Mercola, Willems, and Cashman are now working with San Diego biotech company ChemRegen, Inc. to further develop ITD-1 into a drug that one day might be used to treat patients.

More scientific detail

The researchers discovered that ITD-1 blocks a cellular process known as TGFϐ signaling. TGFϐ (short for transforming growth factor-ϐ) is a protein produced by one cell type to influence others' behaviors, such as proliferation, scarring, and even stem cell differentiation. TGFϐ works from outside the cell, binding to a receptor on the surface of a responding cell to initiate an intracellular signaling cascade that causes genes to be switched on or off, ultimately altering cellular behavior -- in this case making heart muscle.

ITD-1 triggers degradation of the TGFϐ receptor, thus inhibiting the whole process. With TGFϐ signaling turned off, stem cells are set on a course toward cardiogenesis. ITD-1 is the first selective inhibitor of TGFϐ, meaning that it might also have applications in many other processes controlled by TGFϐ.

Embryonic Blood Vessels That Make Blood Stem Cells Can Also Make Beating Heart Muscles

Science Daily — UCLA stem cell researchers have found for the first time a surprising and unexpected plasticity in the embryonic endothelium, the place where blood stem cells are made in early development.

Scientists found that the lack of one transcription factor, a type of gene that controls cell fate by regulating other genes, allows the precursors that normally generate blood stem and progenitor cells in blood forming tissues to become something very unexpected -- beating cardiomyocytes, or heart muscle cells.

The finding is important because it suggests that the endothelium can serve as a source of heart muscle cells. The finding may provide new understanding of how to make cardiac stem cells for use in regenerative medicine, said study senior author Dr. Hanna Mikkola, an associate professor of molecular, cell and developmental biology in Life Sciences and a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

"It was absolutely unbelievable. These findings went beyond anything that we could have imagined," Mikkola said. "The microenvironment in the embryonic vasculature that normally gives rise to blood cells can generate cardiac cells when only one factor, Scl, is removed, essentially converting a hematopoietic organ into a cardiogenic organ."

The two-year study is published Aug. 3, 2012 in the peer-reviewed journal Cell.

The findings were so surprising, in fact, that Mikkola and her team did not want to believe the results until all subsequent assays proved the finding to be true, said Amelie Montel-Hagen, study co-first author and a post-doctoral fellow.

"To make sure we had not switched the samples between blood forming tissues and the heart we ran the experiments again and repeatedly got the same results," Montel-Hagen said. "It turns out Scl acts as a conductor in the orchestra, telling the other genes in the endothelium who should be playing and who shouldn't be playing."

The team used microarray technology to determine which genes were "playing" in embryonic endothelium to generate blood stem and progenitor cells and found that in the absence of Scl, the genes required for making cardiomyocytes were activated instead, said study co-first author Ben Van Handel, a post-doctoral fellow.

The lone difference was that Scl was missing in the process that resulted in the fate switch between blood and heart.

"Scl has a known role as a master regulator of blood development and when we removed it from the equation, no blood cells were made," Van Handel said. "That the removal of Scl resulted in fully functional cardiomyocytes in blood forming tissues was unprecedented."

The team used the yolk sac -- the first tissue where blood cells are made -- from embryos that lacked Scl and within four hours of plating on the culture dish, the tissue had generated beating cardiomyocytes. The team also found similar cardiomyocyte potential in Scl-deficient embryos in the endocardium that lines the heart chambers. They also looked for genetic signatures that would suggest that these endothelial precursors could potentially also make other closely related tissues such as skeletal muscle, bone or kidney, but found no evidence of such plasticity. The default fate of the endothelium was to make cardiomyocytes in the absence of Scl, Mikkola said.

The findings may also have implications in cell reprogramming, which generally calls for adding factors to induce cell fate change, a process that can be problematic. It might be safer to suppress a factor like Scl to nudge cells into a cardiomyocyte fate, Mikkola said.

"This study opens new ways to think about what could be a potential source of cardiac stem cells," she said. "We now have a better understanding of how cardiac progenitor cells can be made and regulated, and this may one day lead us to a way to treat heart attacks by creating new heart muscle cells to replace those that were damaged."

Going forward, Mikkola and her team plan to investigate the developmental and regenerative potential of the endothelium-derived cardiac progenitor cells, and define the mechanisms by which Scl can at the same time activate one fate while suppressing another.

"These results call for future studies to examine the prospect of harnessing the latent cardiogenic potential in the vasculature for use in regenerative medicine, and to investigate whether similar development plasticity exists in other major cell fate decisions in the developing embryo," the study states.