June 16, 2008
Bioengineered Stem Cells Rejuvenate Muscles In Mice

Think that if only we could create youthful stem cells and then inject them into various parts of the our aging bodies the youthful stem cells would repair us? I've previously reported on work by Thomas Rando's group at Stanford that found something in old blood suppresses stem cells and prevents them from creating new cells for repair. That's a huge obstacle in the of way of use of stem cells for rejuvenation and repair. But a new report from Berkeley (from a team that not coincidentally includes a person who used to work with Rando at Stanford) attempts to genetically engineer stem cells to basically ignore the signals that old bodies use to tell stem cells not to do repairs.

Berkeley - Old muscle got a shot of youthful vigor in a stem cell experiment by bioengineers at the University of California, Berkeley, setting the path for research on new treatments for age-related degenerative conditions such as muscle atrophy or Alzheimer's and Parkinson's diseases.

In a new study to be published June 15 in an advanced online issue of the journal Nature, researchers identified two key regulatory pathways that control how well adult stem cells repair and replace damaged tissue. They then tweaked how those stem cells reacted to those biochemical signals to revive the ability of muscle tissue in old mice to repair itself nearly as well as the muscle in the mice's much younger counterparts.

Irina Conboy, an assistant professor of bioengineering and an investigator at the Berkeley Stem Cell Center and at the California Institute for Quantitative Biosciences (QB3), led the research team conducting this study.

There's a big problem with ignoring those signals that suppress cell division: When cells totally ignore signals that inhibit growth those cells are called cancer cells. We need growth regulation. But not too much or too little or at the wrong time.

The Berkeley researchers are trying to deal with the problem of old blood suppressing repair by younger cells. But that old blood contains cell division suppressor molecules

"We don't realize it, but as we grow our bodies are constantly being remodeled," said Conboy. "We are constantly falling apart, but we don't notice it much when we're young because we're always being restored. As we age, our stem cells are prevented, through chemical signals, from doing their jobs."

The good news, the researchers said, is that the stem cells in old tissue are still ready and able to perform their regenerative function if they receive the appropriate chemical signals. Studies have shown that when old tissue is placed in an environment of young blood, the stem cells behave as if they are young again.

"Conversely, we have found in a study published last year that even young stem cells rapidly age when placed among blood and tissue from old mice," said Carlson, who will stay on at UC Berkeley to expand his work on stem cell engineering either as a QB3 fellow or a postdoctoral researcher. He will be supervised by Conboy; Tom Alber, professor of biochemistry; and David Schaffer, associate director of the Berkeley Stem Cell Center and professor of chemical engineering.

Thomas Rando at Stanford and Irina Conboy (who was at Stanford working with Rando) have been working on the problem of what causes stem cells to stop doing repairs in old body. Rando is looking at a molecule called Wnt as a suppressor of old stem cells. This latest report from Conboy builds in years of work trying to puzzle out why our repair capabilities decline with age.

In this latest round of work the researchers blocked a pathway of cellular growth inhibition. As we age the concentration of a growth-promoting molecule called notch declines while a growth inhibiting molecule called TGF-beta goes up in concentration. So they lowered concentration of the molecule pSmad3 which TGF-beta promotes. By lowering pSmad3 they got excellent muscle tissue repair in the mice.

But what would happen if researchers blocked the adult stem cells in old tissues from reacting to those TGF-beta signals? The researchers put that question to the test in a living organism by comparing the muscle regeneration capacity of old, 2-year-old mice, comparable in age to a 75- to 80-year-old human, with that of 2-month-old mice, similar in age to a 20- to 25-year-old human.

For a group of the old mice, the researchers disabled the "aging pathway" that tells stem cells to stop dividing by using an established method of RNA interference that reduced levels of pSmad3. The researchers then examined the muscle of the different groups of mice one to five days after injury to compare how well the tissue repaired itself.

As expected, the researchers found that muscle tissue in the young mice easily replaced damaged cells with new, healthy cells. In contrast, the areas of damaged muscle in the control group of old mice were characterized by fibroblasts and scar tissue.

However, muscles in the old mice whose stem cell "aging pathway" had been dampened showed levels of cellular regeneration that were comparable to their much younger peers, and that were 3 to 4 times greater than those of the group of "untreated" old mice.

The researchers cautioned that shutting down the TGF-beta/pSmad3 pathway altogether by turning off the gene that controls it could lead to many health problems. The ability to suppress cell division is critical in controlling the development of tumors, for instance.

This report does not outline a solution to the problem of growth inhibition of stem cells in aging bodies. Blocking the suppressor molecules will enhance growth of stem cells needed for repair. But the effect will be too widespread. Cells that ought not divide will get activated. Some of those activated cells might be cancerous.

These researchers are working on a hard problem. The pathways for cellular growth control are complex. The bloodstream in older bodies carries growth inhibiting compounds that deliver a net benefit by reducing cancer risk. If we had great cures for cancer then we might be able to block those inhibiting compounds. But absent those great cures for cancer we need ways to selectively inhibit old stem cells but not younger stem cells.

Share |      Randall Parker, 2008 June 16 12:39 AM  Biotech Stem Cells


Comments
Brett Bellmore said at June 16, 2008 6:10 PM:

Well, here's a suggestion: Generate a set of viruses which encode the "don't divide" signal blocker together with a large variety of apoptosis triggers. They infect and alter the stem cells, which start rejuvenating you. Because any given cancer is going to originate from a particular stem cell, which got a particular trigger out of the many, once the cancer is detected, you can identify and deliver it's trigger, and all of that particular cancer dies, along with any other tissue that was generated by stem cells with that particular trigger. Which is a small price, because each trigger only accounts for a tiny fraction of your tissue.

You could potentially couple each of the triggers with a signaling chemical specific to that trigger, so that a simple blood test would alert you to the fact that the proportion of cells in the body with a specific trigger was rising, warning you that trigger was probably involved in a tumor.

Clearly setting up such a system isn't going to be simple, but I think it's the sort of thing that could do the job.

Fly said at June 16, 2008 6:47 PM:

Great news!

On the related topic of cell growth and tissues producing signaling molecules...

Yesterday I watch a lecture on angiogenesis. The principle concept is that systemic factors are in play. Tissue produces angiogenensis factors that promote blood vessel incursion. Blood platelets contain compartments with angiogenesis factors and compartments with anti-angiogenesis factors. In the presence of wounds or infections the angiogenesis factors are released and blood vessels proliferate helping wound healing and fighting infection. Otherwise, the anti-angiogenesis factors are released that work in opposition to the angiogenesis factors produced by the tissues. With too few blood vessels, the high concentration of angiogenesis factors from the tissue causes blood vessel growth. With more blood, the anti-angiogenesis factors from the blood platelets balance the angiogenesis factors from the tissue and blood vessel growth stops.

Different tissues produce different quantities of angiogenesis factors and so have different blood vessel densities. Some tissues produce anti-angiogenesis factors so blood vessels don't invade those tissues. As the body ages, those tissues may produce fewer anti-angiogenesis factors and there is excessive blood vessel growth. (E.g., macular degeneration.

Throughout an old body there are many small (less than a millimeter in diameter) sites with uncontrolled cell division. Usually the resulting cells have insufficient blood supply and die as fast as they divide. Occasionally the cells mutate to produce higher levels of angiogenesis factors so that blood vessel growth is stimulated. The tumor can then rapidly grow beyond the one millimeter size. The large tumor releases large amounts of angiogenesis factors into the blood. As a result blood vessels start growing at sites that were previously too small to generate a sufficiently large signal to stimulate blood vessel growth. Thus one large tumor can stimulate multiple cancers throughout the body.

Fly said at June 16, 2008 7:00 PM:

Brett,

Yes, I think using stem cells with engineered self destruction signals is a promising approach.

Each decade you supply your body with the latest stem cell version. At the same time you send the suicide signal that kills dividing cells from the older version. Your body gets the latest biotech improvements while avoiding cancer.

Hopefully Anonymous said at June 16, 2008 7:25 PM:

Fly,
I never noticed you in the blogosphere before, but now I see you're making smart and helpful comments all over the place. Like I said in overcomingbias, please get a blog and start blogging.

Garson O'Toole said at June 16, 2008 10:47 PM:

Randall Parker said “The Berkeley researchers are trying to deal with the problem of old blood suppressing repair by younger cells.”

Here is a simple idea for an experiment. Take an older mouse and give it a series of blood transfusions from a collection of mice that are substantially younger. The younger mice are selected so that they are genetically identical to the older mouse so that there is no chance of rejection. This is possible using strains of mice that are bred to be genetically identical. The overall goal is to attempt to replace large amounts of “older” blood with “younger” blood. At the time of the transfusions the experimenter may wish to remove some of the “older” blood while infusing the “younger” blood.

Will this increase the duration of life of the older mouse? If there are signals emanating from older blood cells that are harmful then it is natural to wonder if it is possible to dilute and overwhelm these signals by multiple transfusions of blood from younger mice. This seems to be an easy experiment to perform so perhaps it has already been conducted. Perhaps some blog reader knows about the results.

Of course the blood that is newly created within the older animal will still come from the older stem cells present within the older animal. But these older stem cells will be bathed in “younger” blood and might receive superior signals. All the tissue that is supplied by arteries containing the “younger” blood might be getting superior signals. Also some “younger” stem cells from the infused blood may successfully implant in the body of the older animal.

Brett Bellmore said at June 17, 2008 6:03 AM:

If the donor mice are genetically identical to the old mice, maybe bone marrow transplant would be a more sensible option. I'm guessing that doing blood transfusions on mice is a tricky business, just from a mechanical standpoint.

Garson O'Toole said at June 17, 2008 8:33 AM:

Experimentalists do perform transfusions on mice. An example can be found in the paper “Blood Transfusion Alters the Course and Outcome of Plasmodium chabaudi AS Infection in Mice”:

Blood was obtained from noninfected donors (same strain and sex as recipients) by cardiac puncture with heparinized syringes. Pooled blood cells were washed twice and resuspended in saline. Blood transfusions were done by intraperitoneal injection of washed blood cells (0.7 x 109 to 0.9 x 109 RBC in 1 ml of saline per mouse).
Another example paper is “Transfusion with xenogeneic erythrocytes into SCID mice and their clearance from the circulation.”
We have previously demonstrated that the red blood cells (RBCs) in the blood circulation of SCID mice could be almost completely substituted with bovine RBCs by means of repeated transfusions. … Following the intravenous injection these RBCs were cleared from the circulation at various rates
However, I do not know how “traumatic” the procedure is to the recipient mouse. One paper above uses intraperitoneal injections and another paper uses intravenous injections. If these types of procedures inadvertently harm the animal then the creature might have a shorter life span instead of longer one.

Brett Bellmore’s idea of investigating the possibility of bone marrow transplants is excellent I think.

The same schema for experiments could be performed on other animals (perhaps larger animals). The main precondition is the ready availability of genetically identical animals at different life stages. Plus approval by an ethics review. (I am a computer scientist, so of course these ideas might be off base.)

Fly said at June 17, 2008 2:10 PM:

Garson: "Take an older mouse and give it a series of blood transfusions from a collection of mice that are substantially younger."

A similar experiment has been done. The vascular network of an old mouse was connected to that of a young mouse from the same inbred line. The old mouse stayed old and the young mouse stayed young. Later experiments showed that both the young and old circulating stem cells can aid wound repair in young mice but not in old mice. These are the type of experiments that led to the discovery of notch/delta and wnt signaling described in the article. (Young stem cells have better regenerative power than old stem cells but with the proper tissue signaling the old stem cells can still do the job.)

Whether multiple dilutions of old blood by new blood would work seems doubtful since the old tissues would still be cranking out the bad signals. (Scientists have searched for "aging compounds" in the blood since the 1980's. Lab mice with their thyroid gland removed lived longer so scientists looked for the "death hormone" that the gland released.)

Fly said at June 17, 2008 2:17 PM:

HA: " I never noticed you in the blogosphere before"

I've used the handle "Fly", as in fly-on-the-wall, for several years. Rarely I bzzz, mostly I lurk.

I tried blogging at GNXP a few times but the reward for the effort was too low. Making comments deep in a thread is more fun. The blogger has done the heavy lifting and established a background context. (Thanks Randall.) I write to organize my own thoughts and over 90% of what I write I delete without posting. I comment only when it will push the conversation in an interesting direction. (Or when I'm directly responding to a comment.)

Allan said at June 17, 2008 2:46 PM:

From the article, it also said at the end: In addition to their work on adult stem cells, Carlson and Conboy have also discovered that human embryonic stem cells can actually neutralize the effects of aging.

But didn't give anymore details. Any thought?

Hey Fly ... not being a biologist, I had to read your comments twice to understand ... I think ... what you said. I like your idea of using stem cells with engineered self-destruction signals ... any research you can link to on this topic?

I wonder how this affects people's thoughts on blood donations? Think about it. I wonder how much the blood is processed and what is removed. My brother and I donated for my father. He did seem to have a little more pep in his step after a transfusion but that could have been due to many things. But if you know that younger blood helps an older person but older blood hurts a younger person, then I would want to donate for my parents but would be hesitant to donate for my son unless absolute necessary.

Then that brings up another idea. What if I make a regular donation to my father and my son makes a regular donation to me? It brings up all sorts of possibilities.

Of course, the real question is whether or not it cause the hair on my head to grow back! lol

The folks to watch are those doing the research for the military. They are already attempting to grow a solder's finger back using salamander cells. ... anything to speed up the healing and regenerative processes for soldiers.

Fly said at June 17, 2008 5:15 PM:

Allan: "I like your idea of using stem cells with engineered self-destruction signals ... any research you can link to on this topic?"

Brett was the one who suggested apoptosis signals.

A similar idea is used in genetics research: You want to know the what a specific gene does in a specific tissue during a specific stage of life. You insert a "trigger" that is only expressed in the desired tissue. The trigger is activated by a specific compound, e.g., an antibiotic. When the animal is at the desired age, you supply the antibiotic and the target gene is deactivated in the target tissue. (Perhaps using RNA interference.) You then see what happens to tissue function when the target gene is turned off. The genetic engineering is done on a fertilized mouse egg. The offspring are crossbred until you get a mouse homozygous in the engineered genes.

For our purpose you would genetically engineer a stem cell by inserting a trigger that would be expressed whenever a cell divides. The target might be an apoptosis gene. Ingest the suicide signal and all the dividing cells with the trigger die. Multiple triggers might be used for redundancy. As I've suggested comparable genetic engineering is already being done routinely with mice. (The engineered stem cell would then be grown in culture to produce the desired quantity of cells.)

Stem cells might be engineered so that that would be universally compatible with all humans. Or you might develop immune compatible stem cell lines for people of a specific immune type. In either case, once you had good stem cell line you could supply an unlimited number of people. (Carefully monitoring the culture so as to retain genetic quality.) I think companies will compete by developing stem cell lines optimized for specific traits. You not only rejuvenate your tissues but also improve them.

Fly said at June 17, 2008 5:46 PM:

Allan: "...if you know that younger blood helps an older person but older blood hurts a younger person..."

Remember that with normal stem cells, it is the age of the tissue, not the blood, that primarily affects wound healing. So old blood in a young body works fine. (The article describes stem cells that were genetically modified to ignore the "don't divide" signals sent out by the old muscle tissue.) Also different blood components can be separated and used for different purposes.

Don't be misled by fanciful speculation about ESC's making the mother young. Or bone marrow transplants rejuvenating old people. Tissue rejuvenation isn't that easy.

It is possible that embryonic stem cells could also renew old tissue. However when directly injected they tend to form tetranomas where the cells fail to differentiate into the desired tissue. ESC's are useful for growing specific tissues in a lab culture where the right growth factors can be supplied and the properly differentiated cells can be extracted. Those differentiated cells could then be injected or used to grow an organ that could be used for a transplant.

Randall Parker said at June 17, 2008 6:07 PM:

Guys,

We can certainly find ways to program stem cells to die out at some point. Aubrey de Grey already proposes something close to that with his suggestion for telomerase enzyme deletion. The idea is that if telomerase is deleted then the telomeres wear down and if a cell goes cancerous it can't regain the ability to fix its telomeres and so its number of divisions is limited. I did a post on this technique called Whole-body Interdiction of Lengthening of Telomeres (WILT).

But there's some research suggesting other purposes for telomerase. It might not be that easy.

As for techniques to get around the problem of suppressor molecule concentrations rising with age: As I keep saying every time I write a post about this problem, it does not lend itself to easy solutions. One big reason why: the some suppressor molecules that go up too high in concentration when you age serve smaller scale local purposes. Genetically reengineering a stem cell line to ignore, say, TGF-beta will cause undesirable side effects. I do not know exactly what those side effects will be. But count on them happening.

Now, we take lots of drugs and other medical treatments that have undesirable side effects. But it is hard to intervene in the regulatory systems for cellular growth and get only more cells where we need them but not too much and not any where we do not need them.

These folks at Stanford and Berkeley are doing very important work on this problem. I'm glad you are all excited about it. I think this is a really key important problem that needs to be addressed to make stem cells optimally useful (as compared to just moderately useful) for rejuvenation. But it is a hard problem. Just how hard it is will become clear as these and other scientists elucidate all the pathways for controlling cell growth.

What might be the ideal solution: find great cures for cancer. Then we could lower system-wide blood TGF-beta and other suppressors in old folks and not worry about any resulting cancers. Any cancer that pops up as a result could then be killed. Even better, find ways to kill all seriously damaged cells whether cancerous or not. Leave aside brain cells and perhaps heart cells in such treatments since one might die or get brain damaged if all tired cells in our hearts and brains suddenly died.

Brett Bellmore said at June 17, 2008 6:22 PM:

"Brett was the one who suggested apoptosis signals."

The idea has been kicking around for many years, in cryonics and life extensionist circles. I'm not sure who originated it.

Fly said at June 17, 2008 6:23 PM:

"Carlson and Conboy have also discovered that human embryonic stem cells can actually neutralize the effects of aging."

I followed up on that quote. I believe it refers to a paper on how human embryonic stem cells interact with the stem cell niche to control regeneration.

Here is a short description of the paper, http://ouroboros.wordpress.com/2007/06/12/babes-in-the-woods-embryonic-stem-cells-lose-regenerative-potential-in-aged-microenvironments/


The researchers concluded that young stem cells regenerated better than old stem cells but that the age of the stem cell niche was a dominating factor. I.e., a young stem cell in an old niche acted pretty much like an old stem cell in an old niche. Rejuvenation of old tissue by hESC's would be a minor effect.

Randall Parker said at June 17, 2008 7:34 PM:

Fly,

The biggest initial advantage of replacing older stem cells with younger stem cells might be from the reduction in cancer risk.

Yes, younger stem cells in older environments act almost like older stem cells. When I first learned about this it was the most depressing news about rejuvenation research I'd come across. Well, it still is.

However, I still expect some benefit from younger stem cells in situations where the older stem cells have been up against extended periods of stress and damage. Then the older cells might well lose their ability to divide and go senescent. We certainly see that in some types of immune cells.

Again, this problem of old environments suppressing cells from dividing is a huge problem for rejuvenation therapies. The reason for this suppression is very likely to reduce risk of cancer. Natural selection traded off cancer risk against repairability.

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