Cells believed to regenerate heart cells instead create vessels

Wednesday, May 7, 2014

Lillehei Heart Institute researchers from the University of Minnesota have found cardiac stem cells believed to give rise to heart cells are not doing so at the pace required to regenerate heart muscle. Within the scope of their findings, the researchers also unlocked the answer to a key question in cardiovascular medicine when they discovered that the cells may help grow new blood vessels.

C-kit positive cells are currently used in clinical trials outside of the University of Minnesota, with the intention of promoting cardiomyocyte (heart muscle cells) regeneration in patients post heart attack or for people battling heart failure. However the latest Lillehei research, performed in conjunction with Cincinnati Children’s Hospital Medical Center, showed the cells were responsible for limited cardiomyocyte growth. Instead, the cells appear to be forming capillaries, small blood vessels supplying oxygen and nutrients to the heart.

According to the Lillehei research team, the findings, published today by Nature, could have significant therapeutic implications.

“By taking a closer, more critical and rigorous look at these c-kit positive cells, we have answered a major scientific question around the possibilities of these cells,” said lead author Jop van Berlo, M.D., Ph.D., assistant professor of medicine in the University of Minnesota’s Medical School and Lillehei Heart Institute scholar. “In uncovering this question, we have unlocked ten more good questions. Although c-kit positive cells rarely make new cardiomyocytes, we hope to stimulate the rate at which they do this in future studies. The potential for therapies impacting both the heart and other organs is thrilling.”

C-kit is a cell marker long linked to bone marrow and its regenerative properties. However, researchers have more recently been investigating whether the marker could indicate a regenerative property to c-kit positive cells in other organs.

Ongoing clinical trials have tested the theory by applying c-kit positive cells to a heart recovering from incidents of failure after a myocardial infarction (heart attack). In its first phase, the trial showed potential for benefit. However, it was difficult to determine just what about these cells was providing benefit within a human patient.

To take a closer look, van Berlo partnered with colleagues at the Cincinnati Children’s Hospital and Cedars-Sinai Heart Institute and generated a mouse model to track the activity and final destination of the c-kit positive cells as they interacted within the body.

Researchers in the current study worked with two lines of genetically bred mice to see how efficiently c-kit-positive cells would generate cardiomyocytes in the hearts of the animals. The authors measured heart cell regeneration rates during the animals’ embryonic development, during aging and after myocardial infarction (heart attack).

The mice were bred so a fluorescent marker was added to any cell that expressed c-kit, and remained lit as it differentiated into another cell type. Results showed c-kit cells regenerated new cardiomyocytes at an extremely limited rate. 

“Our data suggest any potential benefit from injecting c-kit-positive cells into the hearts of patients is not because they generate new contractile cells called cardiomyocytes,” said Jeffery Molkentin, Ph.D., principal investigator and cardiovascular molecular biologist at the Cincinnati Children’s Heart Institute. “Caution is warranted in further clinical testing of this method until the mechanisms in play here are better defined or we are able to dramatically enhance the potential of these cells to generate cardiomyocytes.”

The next question van Berlo hopes to address is why the c-kit positive cells are differentiating into blood vessels when applied to the heart. He hopes this key knowledge could be applicable to other organs, and could open new therapeutic options.

“This research has given us a whole new look at the way c-kit influences cells in our bodies. The rigorous methods used by van Berlo and his collaborators have used state of the art models to investigate this fundamental question in our field,” said Daniel Garry, M.D., Ph.D., director of the Lillehei Heart Institute and chief of Cardiology at the University of Minnesota’s Medical School. “We are excited about the implications of this research and are thrilled to have on staff at the University of Minnesota the field’s best and brightest up and coming researchers.”

 

Funding for this research was provided by National Institutes of Health grants R00HL112852, HL060562, HL069779, HL105924, HL108806, NS072027, HL083109, HL112852. Funding for Molkentin was also provided through the Howard Hughes Medical Institute.