Print 13 comment(s) - last by Phoque.. on Nov 14 at 8:59 PM

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]

Comments     Threshold

This article is over a month old, voting and posting comments is disabled

By Motoman on 11/11/2013 5:33:39 PM , Rating: 3
Holy FSM people, you can't mess with mitochondria!

Have you never seen Parasite Eve FFS?

RE: :O
By Spookster on 11/11/2013 6:08:25 PM , Rating: 3
As long as Dr. Curt Connors is not working on this project we should be ok.

RE: :O
By Omega215D on 11/11/2013 7:11:23 PM , Rating: 2
Hey, it was a pretty awesome game. Now all we need is a real life Aya Brea...

RE: :O
By JasonMick on 11/12/2013 11:13:56 AM , Rating: 2
RE: :O
By mike66 on 11/11/2013 10:39:22 PM , Rating: 2
Even though you are joking there is a serious issue with this, mitochondria are not only a cells energy source but they also act as the cells policeman, it can detect cellar defects and cause the cell to commit suicide,tumor type cancers turn off the mitochondria in the cell and use alternative energy sources, I used this effect to help cure a brain tumor by turning the mitochondria back on, it was particularly effective with me as I have a high mitochondrial count. If you increase the mitochondrial metabolism then it will be burning the candle at both ends. When Dolly the cloned sheep was born she was considered to be as old as the cell sample taken from the original sheep, that age estimate was the mitochondrial age of the cells. So robbing Peter to pay Paul in this case may produce great looking corpses on a macro scale but very old ones on a micro scale.

I wonder...
By sheh on 11/12/2013 10:58:06 AM , Rating: 2
I wonder what kind of CPU that is, in the third image.

RE: I wonder...
By kwrzesien on 11/12/2013 12:11:34 PM , Rating: 2
I'm not sure how much work Shyh-Chang Ng is getting done, he appears to be watching the Matrix.

RE: I wonder...
By jimhsu on 11/12/2013 12:39:17 PM , Rating: 2
Picture: probably a stock image because real research (excel, word, R, scripting) is just boring to look at. (This from experience)

Research: Quite fascinating (and how Lin-28 is not your typical receptor/kinase/whatever). As a previous poster alluded to, mining the "junk DNA" (which is definitely not junk) that we all have is poised to introduce unfathomable advances in both our understanding of biology, as well as result in uncountably many new leads for treatments.

For the astute observers
By geddarkstorm on 11/11/2013 9:13:06 PM , Rating: 3
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
By BioHazardous on 11/12/2013 10:46:42 AM , Rating: 2
Can you imagine where we'd be if we spent half as much time and resources on this type of research instead of drugs?

By Wazza1234 on 11/12/2013 2:41:53 PM , Rating: 2
I find it quite harsh that in order to make this discovery they had to cut off the fingertips of some baby mice.

RE: Harsh
By rpmrush on 11/13/2013 1:07:35 PM , Rating: 2
U've never been in an animal lab then? I serviced equipment for a very popular college. Under every dorm class building in the basement were animal research labs. They had thousands of rats and mice. When a line is contaminated or a theory is finished with the line...Carbon dioxide and bye-bye hundreds of rodents. A neccessary evil IMHO. They even had HIV Chimps. Dentistry dogs. Rabbits for who knows. With the government shutdown and all the government funded labs...I wonder how many animals were put down.

By Phoque on 11/14/2013 8:59:51 PM , Rating: 2
How long before they find a way to 'naturally' enlarge your penis or boobs with this technology?

"We can't expect users to use common sense. That would eliminate the need for all sorts of legislation, committees, oversight and lawyers." -- Christopher Jennings

Most Popular ArticlesSmartphone Screen Protectors – What To Look For
September 21, 2016, 9:33 AM
UN Meeting to Tackle Antimicrobial Resistance
September 21, 2016, 9:52 AM
Walmart may get "Robot Shopping Carts?"
September 17, 2016, 6:01 AM
5 Cases for iPhone 7 and 7 iPhone Plus
September 18, 2016, 10:08 AM
Update: Problem-Free Galaxy Note7s CPSC Approved
September 22, 2016, 5:30 AM

Copyright 2016 DailyTech LLC. - RSS Feed | Advertise | About Us | Ethics | FAQ | Terms, Conditions & Privacy Information | Kristopher Kubicki