Most damaged tissues or organs, especially in adult mammals, do not possess the ability to regenerate and are instead replaced by a dense scar through fibrosis. But in recent years, researchers have shown that spiny mice (acomys) can heal severe skin wounds along with a network of newly formed blood vessels, cartilage, muscle, and nerve fibers occupying the regenerated region, all without a scar.
Now, in a recent study, a team of researchers at the University of Washington and Seattle Children's Research Institute have discovered that spiny mice can also regenerate severely damaged internal organs that, in other mice, would lead to fatal organ failure. The findings in spiny mice are the first to show kidney regeneration in an adult mammal. This study was published in the November 3, 2021 edition of iScience.
Previous studies have demonstrated that post injury, the spiny mice can regenerate different tissue types, such as cardiac and skeletal muscle tissue. However, there has been no previous report of regeneration of a fully functional organ. Senior author Mark Majesky told BioWorld Science that "renal fibrosis, a hallmark of chronic kidney disease, is a debilitating complication that affects millions of people worldwide. Currently, patients with advanced kidney disease must undergo routine dialysis or receive organ transplantation, both of which are inaccessible for many patients. Chronic fibrosis can ultimately lead to organ failure and death. Annually, millions of people worldwide lose their lives to fibrosis."
Majesky is a principal investigator at Seattle Children's Research Institute and professor of pediatrics at the University of Washington. His group uses various molecular, biological and developmental genetic approaches to study organ development and regeneration.
The team's goal was to "determine whether or not scarless, regenerative wound healing observed in spiny mice skin extended to critical internal organs," Majesky said.
The authors demonstrated a near complete absence of fibrosis and a rapid regeneration of nephron function in spiny mice using two aggressive models of kidney disease, namely, unilateral ureteral obstruction (UUO) and ischemia reperfusion injury (IRI). The authors obstructed urine flow into the kidney (UUO) and directly damaged nephrotic tissue (IRI), then monitored to see whether organ structure and function returned. In contrast, the mouse model (Mus musculus) developed severe kidney fibrosis that rapidly progressed to complete renal failure.
The authors showed that, although spiny mice suffered the same degree of tissue injury initially, they were nevertheless able to completely heal. To understand the mechanism of organ regeneration, the researchers took a comprehensive look at the genes they expressed. Their studies suggest that the spiny mice genome is primed at the time of injury to launch a rapid, scarless regenerative response in surviving kidney cells.
The analysis uncovered differences between spiny mice and Mus musculus in the activity of 843 genes in 6 unique clusters. Among the differentially regulated genes, there were genes involved in cell cycle control, DNA damage response and checkpoint regulation. This was accompanied by a selective upregulation of nephrogenic genes in spiny mice.
The authors also reported a delayed response by macrophages, which are known to play a role in fibrosis. Interestingly, the researchers found almost no collagen build-up in the spiny mice after injury which, according to the authors, indicated that the mice were healing without forming scars.
The significance of this study, according to Majesky, lies in the fact that "it demonstrates 'functional regeneration' of the kidney because spiny mice sustain severe kidney injury initially but then completely restore kidney function within 2 weeks. This differs from fibrotic repair, which is accompanied by variable degrees of loss of organ function."Majesky believes that this study will not only open new opportunities in the development of possible therapies for chronic kidney disease, but that may also apply to other organs that similarly exhibit loss of function due to progressive tissue fibrosis. Finally, Majesky and his team's goal is to learn to understand the mechanisms involved in the evolution of a mammalian genome that heals tissue injury by regeneration without fibrotic scarring and apply the lessons learned to the development of new therapies for kidney disease and other fibrotic disorders in humans. Their future studies will include exploring if similar results of scarless tissue healing can be demonstrated in other spiny mice organs.