Scientists Regenerate Damaged Heart Tissue Without Using Stem Cells

US scientists have found a way to regenerate damaged heart tissue without using stem cells: using a growth factor called neuregulin1 (NRG1 for
short), they coaxed heart muscle cells to re-enter the cell cycle, thus encouraging already differentiated adult cells to divide and make new and healthy
heart tissue in the hearts of mice and rats who had suffered heart attacks. They hope this method can one day be used as an alternative or a
complement to stem cell therapy as a way to treat failing hearts in humans.


The study was the work of Dr Bernhard KГјhn and colleagues and appears in the 23 July issue of Cell. KГјhn and colleagues are from the
Department of Cardiology at the Children's Hospital, and the Department of Pediatrics at Harvard Medical School, both in Boston,
Massachusetts.


Many organs like the heart rely on stem cells (cells that are not yet differentiated into fully formed adult cells dedicated to particular functions) and
progenitor cells (starting to differentiate and destined rather than dedicated to particular functions) to make new tissue.


But what is not clear, and remains a controversial question, is whether fully differentiated cells can regenerate and replace tissue.


We know that heart muscle cells, also known as cardiomyocytes, proliferate when the baby is still in the womb. But soon after birth, cardiomyocytes
become binucleated, meaning that they have two nuclei, and don't take part in the cell cycle any more, leading us to assume that they have gone beyond
the point of no return and can't be induced to proliferate any more.


But KГјhn told the press that recent research has discovered that adult heart muscle cells turn over at a low rate of around half the cells in the heart
replacing themselves in the course of a lifetime.


This study is further evidence of this turnover ability, and the researchers even captured video footage of the cells doing it, with growth factor
neuregulin1 (NRG1) accelerating the process.


In the study KГјhn and colleagues discovered an underlying molecular mechanism involving NRG1 and its tyrosine kinase receptor, ErbB4, that
enabled them to induce differentiated cardiomyocytes to proliferate and regenerate.


They already knew that NRG1 induced mononucleated, but not binucleated, cardiomyocytes to divide, and that switching off the gene for ErbB4
stopped cardiomyocyte proliferation whereas increasing ErbB4 expression encouraged it.


They had the idea that perhaps there was an inter-cell signal pathway they could activate to spur cardiomyocytes along the line of injury in damaged
tissue to re-enter the cell cycle.


First they tested the ability of various molecules to induce cell division in cultured cardiomyocytes. NRG1 had the strongest effect, inducing the
division of those cardiomyocytes with one nucleus instead of two.















By manipulating the expression of the NRG1 receptor ErbB4, they found they could increase or decrease cardiomyocyte proliferation in living
animals. They also found injecting NRG1 in adult mice kicked off cardiomyocyte cell-cycle activity and the regeneration of heart muscle, leading ot
improved heart muscle function in those animals that had suffered a heart attack (myocardial infarction).


Finally, KГјhn and colleagues managed to prove that the regeneration had not come from undifferentiated progenitor cells.


Thus they concluded that:


"Increasing the activity of the NRG1/ErbB4 signaling pathway may provide a molecular strategy to promote myocardial regeneration."


KГјhn and colleagues wrote they weren't sure if NRG1 was responsible for the natural repair process, but this study shows it can enhance it. They also
commented that although NRG1 and its receptor are to be found in the adult heart, it's not clear if there are enough of them in the right
places.


They noted that:


"Collectively, we have identified the major elements of a new approach to promote myocardial regeneration."


"Many efforts and important advances have been made toward the goal of developing stem-cell based strategies to regenerate damaged tissues in the
heart as well as in other organs. The work presented here suggests that stimulating differentiated cardiomyocytes to proliferate may be a viable
alternative that could be developed into a simple strategy to promote myocardial regeneration in mammals," they added.


KГјhn told the press:


"To my knowledge, this is the first regenerative therapy that may be applicable in a systemic way."


He envisages a future where people with heart tissue damage might be able to just attend a clinic and have daily infusions NRG1 over a period of
weeks.


"In principle, there is nothing to preclude this going into the clinic," said KГјhn.


"Based on all the information we have, this is a promising candidate," he added, but cautioned that further studies would still be needed to make
sure the method was safe before testing on humans.


The team plan to test if manipulating the NRG1/ErbB4 signaling pathway works in pigs: human heart tissue is more like that of pigs than that of mice and rats. Then they will start tests in humans.


The end goal is to provide a useful alternative or complement to therapy that is based on regenerative stem cells, said KГјhn.


"Neuregulin1/ErbB4 Signaling Induces Cardiomyocyte Proliferation and Repair of Heart Injury."

Kevin Bersell, Shima Arab, Bernhard Haring, Bernhard KГјhn.

Cell, Vol 138, Issue 2, pp 257 - 270, 23 July 2009.

doi:10.1016/j.cell.2009.04.060


Sources: Cell Press, Children's Hospital Boston.


Written by: Catharine Paddock, PhD