Rolling back the clock on muscle disease, aging

Last week CIRM grantees at University of California Berkeley published a follow-up to some of my favorite stem cell research. I'm speaking personally here as a runner who is getting older and would like to turn my race recovery back to what it was in my youth.

Irina Conboy started investigating the slow response of aging muscle stem cells as a postdoctoral fellow in the lab of Thomas Rando at Stanford University (I've written about that work here). What they found is that older muscles in mice don't respond very effectively to muscle damage. But, and this is a big but, if those older mice have younger blood, the muscle stem cells work just fine. Strange, but true.

Since that discovery, Conboy and her lab at Berkeley has been piecing together the story of how and why the younger blood refreshes those old and tired muscle stem cells. In their latest work, which was published in the journal Chemistry & Biology, they show a way using a short-term dose of chemicals to roll back the clock on mature muscle and return it to an earlier state.

A press release from UC Berkeley says:

Building new muscle to replace old or damaged tissue is the routine job of muscle stem cells, or satellite cells. Stationed along the perimeter of adult muscle tissue, they wait for a signal to grow, divide and fuse into new muscle fibers when there’s damage to repair.

But that repair process gets worn out in people with Duchenne muscular dystrophy, a genetic condition in which muscles degenerate because of a defective structural protein and subsequent exhaustion of muscle stem cells. Muscle repair also becomes incapacitated with advancing age.

The group hopes that by turning back the clock, they can return the muscle to a state where it is better able to repair damage. The press release goes on to say:

The researchers say the next steps include testing the process on human muscle tissue and screening for other molecular compounds that could help de-differentiate mature tissue.

“This approach won’t work for all degenerative diseases,” said Conboy. “It might work for some diseases or conditions where we can start with differentiated tissue, such as neurons or liver cells. But patients with type I diabetes, for instance, lack the pancreatic beta-islet cells to produce insulin, so there is no functional differentiated tissue to start with. Our approach is not a replacement for pluripotent cells, but it’s an additional tool in the arsenal of stem cell therapies.”

The group is a long way from marketing the next race recovery beverage. They still have to show that the technique works in human muscle and that those more youthful cells are better able to repair damage.

CIRM Funding: Irina Conboy (RN1-00532-1)
Chemistry & Biology, September 23, 2011


A.A.

Reflecting on muscular dystrophy awareness week

This past week was muscular dystrophy awareness week, which seems like a short amount of time to focus on such a heartbreaking disease. One in every 3500 boys in the US develops that debilitating and fatal Duchenne muscular dystrophy (DMD) - the most common and serious form of muscular dystrophy - and there is no cure.

CIRM funds a few awards to researchers studying the muscle stem cells called satellite cells. These dot the muscle fibers, ready to spring to action when there’s damage. In kids with MD, those satellite cells can’t repair the damage and the muscles eventually waste away.

Here’s a list of CIRM-funded projects that could lead to new insights or therapies for MD. One Early Translational II project to Michele Calos at Stanford University is especially interesting. Starting in mice, she’s proposing to reprogram cells from animals with MD, fix the defective gene, then grow those cells into muscle stem cells that can be transplanted back into the mice. If the technique works, she and her team hope to start working with human cells.

As with all early research there are a lot of unknowns. Can they actually fix the gene? Can they grow up enough muscle stem cells for transplantation? Will those manipulated cells thrive and be able to repair the damaged muscle? And a big question: How on earth do you get those genetically altered cells to all the wasted muscles in the body?

Hopefully in future muscular dystrophy awareness weeks we’ll be able to answer some of those questions, and one day if all goes well we’ll be writing about a cure.

- A.A.

Mighty mice point to stem cell therapy for muscle diseases and aging

The L.A. Times gave it’s rodent of the week designation to a mighty mouse produced by University of Colorado, Boulder researchers.

The group transplanted muscle stem cells from healthy mice into mice with damaged muscles. Not only did the muscle stem cells spring to action, repairing the damaged muscle, but they maintained the mouse in its newly bulked up state for its entire two-year lifespan.

The Telegraph quotes lead author Bradley Olwin as saying:

"We found that the transplanted stem cells are permanently altered and reduce the ageing of the transplanted muscle, maintaining strength and mass."

"With further research we may one day be able to greatly resist the loss of muscle mass, size and strength in humans that accompanies ageing, as well as chronic degenerative diseases like muscular dystrophy."

In their story, the L.A. Times points out that the stem cells came from young mice and were implanted into similarly young mice. Other research by CIRM grantee Irina Conby at University of California, Berkeley has found that the environment in older mice somehow inhibits muscle stem cells from repairing damaged muscle (here's a blog entry on her work). Likewise, bathing muscle stem cells from older mice in the blood of young mice seems to rejuvenate the cell’s ability to repair tissue.

The issue of aging and environment is an important one when looking at transplantation of adult stem cells. Where the cells are implanted could play an important role in how well the cells repair damage. (You can read more about aging and stem cells in this story from Stanford University.)

As a runner prone to muscle damage and whose clock is relentlessly ticking, I'll be watching for researchers to figure out what it is that allows the transplanted stem cells to flourish and prevent aging in mice. And I can only hope the answer is not that I have to remain young for my muscle stem cells to thrive.

A.A.

iPS cells from women create model for muscular dystrophy, X-linked diseases

Reprogrammed skin cells showing inactivated X in red

CIRM grantees at the University of California, Los Angeles have uncovered a feature of reprogrammed iPS cells that make them uniquely excellent for understanding diseases that arise from mutations on the X chromosome.

First some background. Men inherit an X chromosome from their mother, which contains many thousands of genes, and a Y from the father, which does little except confer manhood. Women inherit one X chromosome from each parent. Those female cells overcome their genetic overabundance by shutting down, at random, one of the two X chromosomes, putting the cells at genetic par with male cells.

But the two aren’t really equal. If men inherit a mutation on an X chromosome, it is present in every cell of the body and can cause muscular dystrophy, Rett Syndrome, color-blindness and other disorders. Women who inherit a mutation on an X chromosome from one parent will only show that mutation in half their cells. The other half of the body's cells, with the non-mutated chromosome active, can generally compensate.

So what does this have to do with reprogrammed cells and disease modeling? It turns out that the process of reprogramming skin cells into embryonic-like induced pluripotent stem cells doesn’t overturn the inactivated X. Reprogramming cells from a woman’s skin sample will produce two distinct types of iPS cell lines; half with one X active, and half of with the other X active. If one of those two chromosomes carries a mutation, say, for muscular dystrophy, some of those iPS lines will also display that mutation.

In a press release from UCLA, senior author Kathrin Plath said:

“This non-random pattern of X chromosome inactivation found in iPS cell lines has critical implications for clinical applications and disease modeling and could be exploited for a unique form of gene therapy for X-linked diseases.”

In a publication in Cell Stem Cell, Plath and her colleagues report that they created iPS cell lines from a woman who had inherited one X chromosome carrying a mutation that can cause muscular dystrophy. The other X chromosome had a normal copy of the gene. Scientists can now mature both groups of cells into skeletal muscle and compare the resulting tissue as a way of understanding—and perhaps one day treating—the devastating disease.

Cell Stem Cell: September 3, 2010
CIRM funding: Sean Sherman (TG2-01169), Kathrin Plath (RN1-00564), William Lowry (RS1-00259), Jerome Zack. (RL1-00681)

Muscle stem cells a step closer to treating muscular dystrophy

Stanford scientists have overcome one significant hurdle in developing a therapy for muscle-wasting diseases like muscular dystrophy. Until now, the muscle stem cells that stand at the ready to repair muscle damage couldn’t be grown outside the safe confines of a muscle. Once uprooted from their home and transferred to a laboratory dish, they matured into less useful progenitor cells. That’s a problem because once mature the cells no longer have the potential to be transplanted to repair muscle damaged by injury or disease.

Until Helen Blau, CIRM grantee and Stanford”s Donald E. and Delia B. Baxter Professor, had a good idea, that is. According to a Stanford press release:

The researchers wondered if the way the cells are normally grown in culture could be the problem. After all, as Blau pointed out, cells are used to rubbing shoulders comfortably with their neighbors on all sides rather than being splayed out and anchored on a rigid plastic culture dish that is 100,000-fold less elastic than true muscle.

Blau and her team grew the cells on a hydrogel that mimicked the elasticity of muscle, and voila. In the Stanford press release Blau said:

“Clearly the cells grown on the more-elastic surfaces have better survival and self-renewing properties than those grown on standard tissue culture dishes. We conducted our experiments with muscle stem cells, but I expect this will be true for other types of adult stem cells as well.”

When transplanted into mice, the cells contributed to leg muscles, showing that the cells were not only more numerous but also therapeutically useful. The group said this discovery could pave the way for scientists to grow muscle stem cells in quantities needed for transplantation therapies to treat muscular dystrophy and other muscle diseases.

Science (Express Online) July 15, 2010
CIRM funding: PM Gilbert (TG2-01159); Helen Blau (RT1-01001)

A.A.