Mice Regrow Fingertips, Hair With Help of Mitochondria-Boosting Protein
November 11, 2013 5:05 PM
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Research could lead to a topical treatment for burns or baldness in humans
Boston Children's Hospital
Stem Cell Program
(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
, which were first discovered in earthworms.
-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
Researchers began to suspect
genes played a role in tissue growth and/or regeneration, after noticing they were
[abstract] in embryonic stem cells from humans and other organisms. Much of the research to date on
has focused on using it to
"trick" cells from mature tissues
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
A new study shows just why
homologue A (
) is so crucial for promoting regenerative capabilities in stem cells -- it both promotes expression of other regenerative factors like
, and boost mitochondrial metabolism to produce energy for healing. [Image Source: EMW/Wikimedia Commons]
[abstract] from the
Univ. of Wisconsin-Madison
reported that by swamping --
-- so called "oncogenes", whose overexpression can cause cancer -- for
, 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
. The researchers damaged various tissues in mice then induced
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.
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]
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
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
The new work was performed by the Harvard Medical School's
, which is led by Dr. George Q. Daley. Singapore native
, a Harvard Medical School Ph.D. candidate coauthored the work with a post-doc, Dr. Hao Zhu.
Mr. Shyh-Chang explains the recent experiments
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
'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
, which is known to promote cell maturation and aging. Inhibiting
expression and/or action was shown to be a key mechanism of
rejuvenatory action in past studies, such as
this 2011 work
Dr. Richard Gregory
's group (another Harvard Medical School group studying stem cells).
translation. [Image Source: HMS/Cell]
But the researchers found that the
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
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.
was shown to act not just via
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
on mitochondrial DNA and trick tissues to increase their metabolism, enhancing healing rate. Even without
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
in the prestigious peer-reviewed journal
. 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.
Eurekalert [press release]
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For the astute observers
11/11/2013 9:13:06 PM
LET-7 isn't your typical gene; it's a small non-coding RNA that is initiating RNA interference for mitochondrial genes. Lin28a is in turn regulating this small RNA, turning it off, which then increases mitochondrial function and initiates regeneration according to this publication. This is the new frontier in biology starting to show its fruits: that there's more to our genomes than the protein encoding genes we've been focusing on since the 1950s.
The potency of LET-7's effects on our cells really shows how much more advanced our gene regulation systems are than we ever began to imagine until the past few years. Close to 80% of our genetic material appears to be transcribed as these little RNA molecules (junk DNA is NOT junk, but functional), which we are only just starting to look at through brand new techniques like RNAseq (the technique is so new and data rich, we still haven't solved the computational problem of how to analyze the results properly yet).
Be on the lookout for more of these sorts of revolutionary discoveries as we start to dive into the hidden dimension of our genetics that is the world of small, non-coding RNAs.
RE: For the astute observers
11/12/2013 10:46:42 AM
Can you imagine where we'd be if we spent half as much time and resources on this type of research instead of drugs?
"What would I do? I'd shut it down and give the money back to the shareholders." -- Michael Dell, after being asked what to do with Apple Computer in 1997
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