Inching Closer to Neuregulin-1 as a Target for Regenerative Heart Therapies

Neuregulin-1 (NRG-1) is one of those proteins that shows up in a number of places in research relevant to aging and regeneration, and in a variety of quite different contexts. That suggests it is probably not central to the processes of interest, but rather sufficiently related that manipulating it can alter the operation of multiple systems influential in maintenance of tissues and healing. Biology is very complex indeed, and the fact that any given process of interest can be altered by changing circulating levels of any of a score of proteins makes it a real challenge to determine what is actually going on under the hood.

So we have NRG-1 as a possible suspect in naked mole-rat longevity, based on measured levels in the brains of old individuals versus those of old mice and humans. Levels of NRG-1 in the brain seem to correlate with species longevity, in rodents at least. All of that is quite different from the role of NRG-1 in heart regeneration, however: it was noted some years ago that is possible to spur greater than usual tissue maintenance in heart tissues by artificially raising levels of NRG-1. The heart is lacking in regenerative capacity in comparison to other tissue types, so there is some interest in the medical community in finding ways to safely and temporarily work around that limitation.

That heart tissue research took place back in 2009, which rather underscores the point that medical science is not something that moves at the pace of politics or sports. When we talk about the incredible pace of research today, we mean that sometimes you'll see follow-on papers and new advances two to three years after an initial breakthrough. More commonly, expect five to ten years to elapse between an initially promising result and some more practical implementation, and it may take numerous cycles of a few years of work each to make meaningful progress. This is fast in comparison to the past, but it doesn't fit well with the modern news cycle, or with the short-term memory of the public. Supporting science isn't an easy sell to a world that wants all the answers and all of the shiny things right now, or tomorrow at the very latest. Still, here you have the latest in the story of neuregulin-1 and heart regeneration, another incremental advance towards the goal of building a regenerative therapy based on the mechanisms explored in this paper. That end goal still seems about as far away as it was in 2009, frankly:

Research finds turbo-charging hormone can regrow the heart

Researchers have discovered a way to stimulate muscle regrowth in the heart of a mouse. The animal study found it was possible to regenerate muscle cell numbers in the heart by up to 45%, by 'turbo-charging' a hormone that helped coordinate cell growth. "Unlike blood, hair or skin cells, which can renew themselves throughout life, cell division in the heart virtually comes to a standstill shortly after birth, which means the heart can't fully regenerate if it is damaged later in life. Previous studies have demonstrated that it is possible to coax heart muscle cells to proliferate again, but only at very trivial levels. What the research team has been able to do is boost heart muscle cell numbers by as much as 45% after a heart attack."

The scientists focused on a signalling system in the heart driven by a hormone called 'neuregulin'. By switching the neuregulin pathway to 'turbo charge', the researchers found that heart muscle cells continued to divide in a spectacular way in both the adolescent and adult periods. Stimulating the neuregulin pathway during a heart attack led to replacement of lost muscle. "This big achievement will focus the attention of the field on heart muscle cell replacement as a therapeutic option for ischemic heart disease. The dream is that one day we will be able to regenerate damaged heart tissue, much like a salamander can regrow a new limb if it is bitten off by a predator. Just imagine if the heart could learn to regrow and heal itself. That would be the ultimate prize."

​ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation

The murine neonatal heart can regenerate after injury through cardiomyocyte proliferation, although this capacity markedly diminishes after the first week of life. ​Neuregulin-1 (​NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the ​NRG1 co-receptor ​ERBB2 in cardiac regeneration.

NRG1-induced cardiomyocyte proliferation diminished one week after birth owing to a reduction in ​ERBB2 expression. Cardiomyocyte-specific ​Erbb2 knockout revealed that ​ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ​ERBB2 (ca​ERBB2) in neonatal, juvenile and adult cardiomyocytes resulted in cardiomegaly, characterized by extensive cardiomyocyte hypertrophy, dedifferentiation and proliferation. Transient induction of ca​ERBB2 following myocardial infarction triggered cardiomyocyte dedifferentiation and proliferation followed by redifferentiation and regeneration. Thus, ​ERBB2 is both necessary for CM proliferation and sufficient to reactivate postnatal cardiomyocyte proliferative and regenerative potentials.

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