The reactivation of a gene called Lin28a, which is active in embryonic stem cells, can regrow hair and repair cartilage, bone, skin, and other soft tissues in mice.
This study comes from scientists at the Stem Cell Program at Boston Children’s Hospital who found that the Lin28a promotes tissue repair by enhancing metabolism in mitochondria, which are the energy-producing engines in cells. These data suggest that upregulation of common “housekeeping” functions might provide new ways to develop regenerative treatments.
George Q. Daley, the director of Boston Children’s Hospital Stem Cell Transplantation Program, said, “Efforts to improve wound healing and tissue repair have mostly failed, but altering metabolism provides a new strategy which we hope will prove successful.”
One of the first authors of this paper, Shyh-Chang Ng, added, “Most people would naturally think that growth factors are the major players in wound healing, but we found that the core metabolism of cells is rate-limiting in terms of tissue repair. The enhanced metabolic rate we saw when we reactivated Lin28a is typical of embryos during their rapid growth phase.”
Lin28a was first discovered in worms, but the Lin28a gene is found in all animals. It is abundantly expressed in embryonic stem cells and during early embryonic development. Stem cell scientists have even used Lin28a to help reprogram adult cells into induced pluripotent stem cells. Lin28a encodes an RNA-binding protein that regulates the translation of messenger RNAs into protein.
To express more of this protein in mice, Daley and his colleagues attached the Lin28a gene to a piece of DNA that would drive expression when the mice were fed the drug doxycycline. Ng and others noticed that one of the targets of Lin28a was a small RNA molecule called Let-7, which is known to promote aging and cell maturation. Let-7 is a member of a class of non-coding RNA molecules called micro-RNAs that bind to messenger RNAs and prevent their translation. Let-7 is made as a larger precursor molecule that is processed to a smaller molecule that is functional. LIN28 binds specifically to the primary and precursor forms of Let-7, and inhibits Let-7 processing.
Ng said, “We were confident that Let-7 would be the mechanism, but there was something else involved.”
Let-28a is known to activate the translation of several different genes that play a role in basic energy metabolism (e.g., Pfkp, Pdha1, Idh3b, Sdha, Ndufb3, and Ndufb8), Activation of these genes enhances oxidative metabolism and promotes an embryonic bioenergetic state.
In their Lin28a transgenic mice, Daley, Ng and others noticed that Lin28a definitively enhanced the production of metabolic enzymes in mitochondria, and that these “revved up” the mitochondria so that they generated the energy needed to stimulate and grow new tissues.
“We already know that accumulated defects in mitochondria can lead to aging in many cells and tissues,” said Ng. We are showing the converse: enhancement of mitochondrial metabolism can boost tissue repair and regeneration, recapturing the remarkable repair capacity of juvenile animals. ”
Further experiments showed that bypassing Lin28a and directly activating mitochondrial metabolism with small molecules had the same effect on wound healing. This suggests that pharmaceuticals might induce regeneration and enhance tissue repair.
“Since Lin28 itself is difficult to introduce into cells, the fact that we were able to activate mitochondrial metabolism pharmacologically gives us hope,” said Ng.
Lin28a did not cause universal regeneration of all tissues. Heart tissue, for example, was poorly aided by Lin28a. Also, Lin28a induced the regeneration of severed finger tips in newborn mice, but not in adult mice.
Nevertheless, Lin28a could be a key factor in constituting a kind of healing cocktail, in combination with other embryonic factors yet to be found.