Young animals are known to repair their tissues effortlessly, but can this capacity be recaptured in adults? A new study from researchers at the Stem Cell Program at Boston Children’s Hospital suggests that it can. By reactivating a dormant gene called Lin28a, which is active in embryonic stem cells, researchers were able to regrow hair and repair cartilage, bone, skin and other soft tissues in a mouse model.
The study also found that Lin28a promotes tissue repair in part by enhancing metabolism in mitochondria—the energy-producing engines in cells—suggesting that a mundane cellular “housekeeping” function could open new avenues for developing regenerative treatments.
“Efforts to improve wound healing and tissue repair have mostly failed, but altering metabolism provides a new strategy which we hope will prove successful,” says the study’s senior investigator George Q. Daley, MD, PhD, director of Boston Children’s Stem Cell Transplantation Program and an investigator with the Howard Hughes Medical Institute.
To better understand how Lin28a promotes tissue repair, the researchers systematically looked at what specific RNAs it binds to. They initially had their sights on a tiny RNA called Let-7, which is known to promote cell maturation and aging.
“We were confident that Let-7 would be the mechanism,” says Shyh-Chang. “But there was something else involved.”
Specifically, the researchers found that Lin28a also enhances the production of metabolic enzymes in mitochondria, the structures that produce energy for the cell. By revving up a cell’s bioenergetics, they found, Lin28a helps generate the energy needed to stimulate and grow new tissues.
Further experiments showed that bypassing Lin28a and directly activating mitochondrial metabolism with a small-molecule compound also had the effect of enhancing wound healing. This suggests the possibility of inducing regeneration and promoting tissue repair with drugs.
Lin28A didn’t universally induce regeneration in all tissues. Heart tissue showed little effect, and while the researchers were able to enhance the regrowth of finger tips in newborn mice, they could not in adults.
“Lin28a could be a key factor in constituting a healing cocktail,” says Shyh-Chang, “but there are other embryonic factors that remain to be found.”
The power of Lin28a appeared to only extend so far. When mice were no longer babies—at five weeks—the scientists were not able to regenerate their limbs, even if the gene was stimulated. And mice with Lin28a activation were never able to repair damage to the heart, suggesting that the protein is not equally effective everywhere in the body. One factor that may limit the regeneration is the size of the organs involved, says Yui Suzuki, a developmental biologist at Wellesley College who was not involved with the work. Perhaps the mice can regenerate small organs, such as immature toes, but not larger ones, such as full-size digits or the heart, but the jury is still out.
Scientists have long pursued the goal of human limb regeneration, but uncovering how to kick-start the necessary biological processes or identify the needed pathway for humans to regenerate body parts the way salamanders or starfish do has remained elusive.
Humans do have some regenerative capacities—for example, regrowing fingertips if a sizable portion of the fingernail remains. That process depends on the presence of stem cells tucked in the epithelium underneath the nail, which is a luxury not available throughout the body. The new research, however, could potentially open a way to expand our regenerative playbook by manipulating the activity of genes such as Lin28a or mimicking their effects.
A combination of gene activation and stem cell therapy could enable regeneration of larger organs.