"Long before it's in the papers"
January 28, 2015


A new way to fix a broken heart?

July 24, 2009
Courtesy Cell Press
and World Science staff

Re­search­ers seem to have identified a new way to fix a bro­ken heart, a re­port says. 

The scientists have de­vised a meth­od to co­ax heart mus­cle cells in­to reen­ter­ing the cell cy­cle, al­low­ing the ma­ture adult cells to di­vide and re­gen­er­ate healthy heart tis­sue af­ter a heart at­tack, ac­cord­ing to mouse and rat stud­ies de­scribed in the July 24 is­sue of the jour­nal Cell

The key in­gre­di­ent is a growth fac­tor known as neu­reg­ulin 1. The re­search­ers sug­gest that the fac­tor might one day be used to treat fail­ing hu­man hearts.

“To my knowl­edge, this is the first re­gen­er­a­tive ther­a­py that may be ap­pli­ca­ble in a sys­tem­ic way,” said Bern­hard Kühn of Chil­dren’s Hos­pi­tal Bos­ton and Har­vard Med­i­cal School. For in­stance, he added, peo­ple might one day go to the clin­ic for daily in­fu­sions of the sub­stance over a pe­ri­od of weeks. 

“In prin­ci­ple, there is noth­ing to pre­clude this go­ing in­to the clin­ic. Based on the all the in­forma­t­ion we have, this is a prom­is­ing can­di­date.” He em­pha­sized, how­ev­er, that fur­ther stud­ies would be re­quired to dem­on­strate safe­ty be­fore such treat­ment could be tested in hu­man pa­tients.

The heart had long been con­sid­ered an or­gan largely in­ca­pa­ble of re­pair­ing it­self. Heart mus­cle cells, al­so known as car­diomy­ocytes, do pro­lifer­ate dur­ing pre­na­tal de­vel­op­ment. Soon af­ter birth, how­ev­er, the cells be­come bi­nu­cle­ate, mean­ing that they have two nu­clei, and with­draw from the cell cy­cle, giv­ing rise to the no­tion that adult car­diomy­ocytes are in­ca­pa­ble of fur­ther pro­lifera­t­ion.

How­ev­er, re­cent ev­i­dence has shown that adult heart mus­cle cells can re­place them­selves at some low lev­el, with per­haps half of the cells in the heart turn­ing over in the course of a life­time, Kühn said. The new study of­fers var­i­ous lines of ev­i­dence for this turno­ver abil­ity – in­clud­ing vi­deo of the cells in ac­tion – and in­di­cates neureg­ulin 1 can ramp up the pro­cess.

In the new stu­dy, the re­search­ers first tested the abil­ity of var­i­ous mo­le­cules to spur cell di­vi­sion in cul­tured car­diomy­ocytes. If car­diomy­ocytes are to re­en­ter the cell cy­cle along the bor­der zone of in­ju­ry, the re­search­ers sur­mised that there must be an chem­ical sig­nal that trig­gers the re­sponse, Kühn ex­plained.

They looked to sev­er­al fac­tors known to drive car­diomy­ocyte pro­lifera­t­ion dur­ing pre­na­tal de­vel­op­ment. Of those, neu­reg­ulin 1 had the most sig­nif­i­cant ef­fect, in­duc­ing the di­vi­sion of those car­diomy­ocytes with one nu­cle­us in­stead of two.

By ma­ni­pu­lat­ing neuregulin 1 levels, the scientists said they showed they could in­crease or de­crease car­diomy­ocyte pro­lifera­t­ion in liv­ing an­i­mals. Moreo­ver, in­ject­ing neu­reg­ulin 1 in adult mice sparked car­diomy­ocyte cell-cy­cle ac­ti­vity and pro­mot­ed the re­genera­t­ion of heart mus­cle, lead­ing to im­proved func­tion af­ter the an­i­mals suf­fered a heart at­tack. The re­genera­t­ion could not be traced to pro­gen­i­tor cells, the re­searchers said.

The scientists added that they aren’t sure wheth­er neu­reg­ulin 1 is re­spon­si­ble for the nat­u­ral re­pair pro­cess, but their find­ings show that it clearly can en­hance it. They al­so note that neu­reg­ulin 1 and its re­cep­tor, or mole­cular “gate­way” facil­i­tat­ing its trans­mis­sion and use, are al­ways pre­s­ent in the adult heart, though it is not clear if they are in the right place or in suf­fi­cient quanti­ties.

Be­fore mak­ing the leap to the clin­ic, Küh­n’s group plans to fur­ther ex­plore how the treat­ment works at the fun­da­men­tal lev­el. They will al­so exam­ine the re­sponse in pigs, which have more in com­mon with hu­mans than ro­dents do. Ul­ti­mate­ly, such a treat­ment might serve as a use­ful al­ter­na­tive or com­ple­ment to treat­ments de­signed to seed dam­aged hearts with re­gen­er­a­tive stem cells, Kühn said.

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Researchers seem to have a new way to fix a broken heart, a report said. They have devised a method to coax heart muscle cells into reentering the cell cycle, allowing the mature adult cells to divide and regenerate healthy heart tissue after a heart attack, according to studies in mice and rats reported in the July 24th issue of the journal Cell. The key ingredient is a growth factor known as neuregulin1. The researchers suggest that the factor might one day be used to treat failing human hearts. “To my knowledge, this is the first regenerative therapy that may be applicable in a systemic way,” said Bernhard Kühn of Children’s Hospital Boston and Harvard Medical School. For instance, he added, people might one day go to the clinic for daily infusions of the substance over a period of weeks. “In principle, there is nothing to preclude this going into the clinic. Based on the all the information we have, this is a promising candidate.” He emphasized, however, that further studies would be required to demonstrate safety before such treatment could be tested in human patients. The heart had long been considered an organ largely incapable of repairing itself. Heart muscle cells, also known as cardiomyocytes, do proliferate during prenatal development. Soon after birth, however, the cells become binucleated, meaning that they have two nuclei, and withdraw from the cell cycle, giving rise to the notion that adult cardiomyocytes are terminally differentiated and incapable of further proliferation. However, recent evidence has shown that adult heart muscle cells can replace themselves at some low level, with perhaps half of the cells in the heart turning over in the course of a lifetime, Kühn said. The new study offers various lines of evidence for this turnover ability – including video of the cells in action – and indicates neuregulin1 can ramp up the process. In the new study, the researchers first tested the ability of various molecules to spur cell division in cultured cardiomyocytes. If cardiomyocytes are to reenter the cell cycle along the border zone of injury, the researchers surmised that there must be an extracellular signal that triggers the response, Kühn explained. They looked to several factors known to drive cardiomyocyte proliferation during prenatal development. Of those, NRG1 had the most significant effect, inducing the division of those cardiomyocytes with one nucleus instead of two. By manipulating the NRG1 receptor up or down, the researchers showed they could increase or decrease cardiomyocyte proliferation in living animals. Moreover, injecting NRG1 in adult mice sparked cardiomyocyte cell-cycle activity and promoted the regeneration of heart muscle, leading to improved function after the animals suffered a heart attack. That regeneration could not be traced to undifferentiated progenitor cells, they report. The researchers say they aren’t sure whether NRG1 is responsible for the natural repair process, but their findings show that it clearly can enhance it. They also note that the NRG1 receptor and NRG1 itself are always present in the adult heart, though it is not clear if they are in the right place or in sufficient quantities. “Collectively, we have identified the major elements of a new approach to promote myocardial regeneration,” the researchers wrote.” 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.” Before making the leap to the clinic, Kühn’s group plans to further explore how the treatment works at the fundamental level. They will also characterize the regenerative response in pigs, which have more in common with humans than rodents do, before testing the approach in human patients. Ultimately, such a treatment might serve as a useful alternative or complement to treatments designed to seed damaged hearts with regenerative stem cells, Kühn said.