Research could lead to a topical treatment for burns or baldness in humans

Researchers at Boston Children's Hospital's Stem Cell Program and Harvard University's Medical School (HMS) have made an exciting discovery, discovering two ways by which a special gene family found in mice and humans alike can trigger tissue regeneration.  

The study shows that the key repair protein produced from this gene family can not only inhibit aging/maturation proteins that slow down healing, but also directly kick-start mitochondria, a cell's power plants.  This second mechanism helps to produce the energy required for vigorous healing.  And even better, the study shows that small molecules can mimic this protein activity, raising the hope of developing sprays or creams that stimulate healing via boosting cellular metabolism, with potential for treating limb injuries in young children, fighting baldness in adults, and even treating severe burns.

I. Meet LIN28 -- a Super-Gene

The secret lies in the family of genes LIN28, which were first discovered in earthworms.  LIN28-family genes have since been found in all "advanced" organism, including mice and humans, which express homologue A of the gene (which is hence dubbed LIN28A).

Researchers began to suspect LIN28 genes played a role in tissue growth and/or regeneration, after noticing they were abundantly expressed [abstract] in embryonic stem cells from humans and other organisms.  Much of the research to date on LIN28 has focused on using it to "trick" cells from mature tissues such as living skin cells into becoming stem cells, that offer similar healing potential to traditional stem cells from embryonic stem cells, albeith with a higher cancer risk.  This approach may produce less carcinogenic resulting stem cells, versus approaches that uses other genes, including Oct3/4, Sox2, Klf4, and c-Myc.  
A new study shows just why LIN28 homologue A (LIN28A) is so crucial for promoting regenerative capabilities in stem cells -- it both promotes expression of other regenerative factors like LET-7, and boost mitochondrial metabolism to produce energy for healing. [Image Source: EMW/Wikimedia Commons]

Specifically, a 2007 paper [abstract] from the Univ. of Wisconsin-Madison reported that by swamping -- Klf4 and c-Myc -- so called "oncogenes", whose overexpression can cause cancer -- for LIN28 and NANOG, can not only improve conversion efficiency in induced pluripotent stem-cells, but also may result in a less tumorigenic line.

Now this new research demonstrates that even outside of inducing pluripotency, there may be therapeutic potential for tricking cells into producing LIN28A.  The researchers damaged various tissues in mice then induced LIN28A expression.  Some, but not all tissues showed a remarkable regenerative capability.

For example, "finger" tips that were clipped in newborn mice, grew to a healthy state.  LIN28A was also shown to heal broken/damaged cartilage and bones, to regrow hair, and heal soft tissues (such as skin and subcutaneous fat layers).

The middle and index fingertips did not regrow in an untreated mouse (top), but in a baby mouse treated with LIN28 induction therapy, they regrew like they were never injured. [Image Source: HMS/Cell]

By triggering LIN28A expression in skin tissue on the back of mice, the researchers were able to trigger hair regrowth, even in cases where follicles were removed via waxing.  This raises hope that LIN28A could be used in humans as a cure for baldness.

The work also shows potential for treating serious limb or digit injuries in children, which may show similar gains if the injury occurs and is treated while the child is very young.

II. Cells Need Lots of Energy to Heal -- and LIN28A Boosts Energy

The new work was performed by the Harvard Medical School's Daley Lab, which is led by Dr. George Q. Daley.  Singapore native Shyh-Chang Ng, a Harvard Medical School Ph.D. candidate coauthored the work with a post-doc, Dr. Hao Zhu.

Mr. Shyh-Chang explains the recent experiments commenting:

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 could be a key factor in constituting a healing cocktail, but there are other embryonic factors that remain to be found.

The researchers already knew that LIN28A's actions were in part driven by it attaching to RNA and enhancing the rate of transcription for certain proteins that stimulated growth and healing.  They focused their initial investigation on LET-7, which is known to promote cell maturation and aging.  Inhibiting LET-7 expression and/or action was shown to be a key mechanism of LIN28A rejuvenatory action in past studies, such as this 2011 work [abstract] from Dr. Richard Gregory's group (another Harvard Medical School group studying stem cells).

LET-7's link to LIN28A
Interactions between LIN28A and LET-7 translation. [Image Source: HMS/Cell]

But the researchers found that the LIN28A proteins also were localized in the cell's mitochondria, a place where little LET-7 was found.  This suggested that an additional effect might be at play.  Upon closer investigation the researchers were able to show that the protein also boosted the expression of certain mitochondrial genes, bumping the cell's metabolism in order to crank up its biochemical power levels in preparation for healing.

Mr. Shyh-Change explains:

We were confident that LET-7 would be the mechanism, but there was something else involved.  We already know that accumulated defects in mitochondrial metabolism can lead to aging in many cells and tissues.  We are showing the converse -- that enhancement of mitochondrial metabolism can boost tissue repair and regeneration, recapturing the remarkable repair capacity of juvenile animals.

The study was not without its disappointments. Getting even tisssues in mice to express the key LIN28A gene was admittedly difficult.  And even when they could get sufficient expression levels, some adult tissues -- e.g. heart tissue and adult "finger" tips -- showed no regeneration.

LIN28A was shown to act not just via LET-7 inhibitory interactions (left), but also by boosting mitochondrial metabolism. [Image Source: Cell/HMS] 

However, the researchers also offered a potential roadmap to short term therapeutic approaches by using small synthetic biomolecules to mimic the action of LIN28A on mitochondrial DNA and trick tissues to increase their metabolism, enhancing healing rate.  Even without LIN28A present, this approach was able to offer many of the same benefits.

Mr. Shyh-Chang concludes:

Since LIN28 itself is difficult to introduce into cells, the fact that we were able to activate mitochondrial metabolism pharmacologically gives us hope.

Grad student Shyh-Chang Ng (left); Harvard professors Drs. George Daley (bottom middle) and Richard Gregory (far right), along with grad student Srinivas Viswanathan (top, right) [Image Source: HMS]

Dr. Daley, the lab leader and senior author of the study on the work adds:

Efforts to improve wound healing and tissue repair have mostly failed, but altering metabolism provides a new strategy which we hope will prove successful.

The paper was published in the prestigious peer-reviewed journal Cell.  The team plans to next examine other critical genes that grant stem cells their marvelous regenerative abilities and to investigate whether the small-molecule metabolism booster could be applicable to boosting wound healing in human soft tissues.

Sources: Cell [abstract], Eurekalert [press release]

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