Newborns with heart complications can rely on their newly developed immune systems to regenerate cardiac tissues, but this isn’t the case in adults. After a heart attack, most adults struggle to regenerate healthy heart tissue, leading to scar tissue buildup and, often, heart failure.
A study in mice by Northwestern Medicine researchers has now identified a critical difference in how immune system macrophages help repair the heart in newborns versus adults after a heart attack. They found that in newborns, macrophages perform a process called efferocytosis, which recognizes and eats dying cells. This process triggers the production of a bioactive lipid called thromboxane, signaling nearby heart muscle cells to divide, and allowing the heart to regenerate damaged heart muscle. In contrast, efferocytosis by adult macrophages ultimately culminates in fibrotic scarring.
The study highlights a fundamental difference in how the immune system drives healing based on age and could point to strategies for improving tissue repair after heart attack in adults.
“Understanding why newborns can regenerate their hearts while adults cannot will open the door to developing treatments that could ‘reprogram’ adult macrophages,” said first and co-corresponding author Connor Lantz, PhD, lead scientist of the bioinformatics core at the Comprehensive Transplant Center at Northwestern University Feinberg School of Medicine.
Lantz, together with co-corresponding author Edward B. Thorp, PhD, professor of experimental pathology at Feinberg, and colleagues, reported on their findings in Immunity, in a paper titled, “Early-age efferocytosis directs macrophage arachidonic acid metabolism for tissue regeneration,” in which they suggest that the pathway identified “… may also be broadly active in other organs after injury.”
The ability to regenerate damaged tissues is “fundamental for survival,” the authors wrote, but this critical function varies across organisms and organ systems. “The diminishment of tissue regeneration often correlates with advancing age,” they continued. The heart is one example of what the team describes as “an age-dependent dichotomy in regenerative potential.” While some vertebrates, including species of salamanders, axolotls, and zebrafish, can naturally regenerate heart tissue throughout adulthood, in mammals, including humans, this cardiac regenerative capacity is lost shortly after birth.
“Tissue regeneration is a tightly coordinated process that involves multiple cell types, including cells of the innate immune system,” the researchers further wrote. For their reported study the team examined how the immune system responds to heart injury in mice of different ages, including newborn mice (one day old) and adult mice (eight weeks old).
They found that engulfment of dying cells by newborn macrophages triggered a chemical chain reaction that produced a molecule called thromboxane A2, which unexpectedly stimulated heart muscle cells to multiply and repair the damage. Additionally, the results indicated that nearby muscle heart cells in newborns are primed to respond to thromboxane A2, leading them to change their metabolism to support their growth and healing. This process did not work the same way in adults, however. In contrast, in adults, after an injury, macrophages did not produce enough thromboxane A2, limiting their ability to regenerate heart tissue. “By mimicking the effects of thromboxane, we might one day improve tissue repair after a heart attack in adults,” Lantz said.
“Collectively, our findings … uncover a dichotomy whereby neonatal macrophages recognize injured cells to initiate intercellular signaling and promote tissue regeneration,” the scientists stated. “By contrast, efferocytosis by adult macrophages culminates in persisting fibrotic scarring.”
The researchers found the ability of macrophages to engulf dying cells was enhanced in newborn mice due to increased expression of MerTK, a receptor that recognizes dying cells. When the scientists blocked this key receptor, newborn mice lost their ability to regenerate their hearts, resembling adult hearts after a heart attack. “By genetically inhibiting efferocytosis signaling through genetic ablation of Mertk, the regenerative response in the neonatal heart is altered to resemble that of adult hearts, both in terms of macrophage phenotype and impaired cardiac function,” they further noted.
“Altogether, our findings uncover an age-defined mechanism by which tissue injury reprograms macrophage metabolism to fuel regeneration … Our findings integrate what appears to be a formative immunometabolism signature with recognition of dying cells as well as production of cell mitogens.”
