Reawakening the Body Builders

Stem cells could rejuvenate old or ailing tissues. But we might not need to find a wellspring of vigorous young stem cells to replace our aging body parts. Recent research suggests that the key to regeneration might lie in reviving the elderly stem cells we already have.

In the past 5 years or so, many people have become smitten by the potential of stem cells to cure disease and delay old age. Stem cells from embryos or umbilical cords might seed new organs wholesale; stem cells from adults might be extracted and grown in mass quantities to replace weather-beaten tissues.

But by focusing solely on stem cells, scientists might be missing an important part of the picture: Although stem cells do keep tissues such as skin healthy, the surrounding cells and tissues, it turns out, heavily influence how and when stem cells do their job. These observations could shift attention from therapies that rely on harvesting stem cells to those that manipulate stem cell environments in the body.

Since scientists discovered that stem cells serve as the source of different types of cells, they've tried to learn how to control what, where, and when new cells get made. The findings, they hoped, would not only reveal insights into how organisms develop but also lead to tissue-restoration therapies. Stem cells, researchers imagined, could be removed from the body and encouraged to produce a surfeit of the desired cell type, which could then be returned to the ailing organ. Many groups, for example, have been trying to regrow the nerve cells trashed in patients with Parkinson's disease by injecting stem cells into the damaged areas of the brain.

But that picture is likely to be "oversimplistic," says biologist David Fisher of the Dana-Farber Cancer Institute in Boston. In particular, he notes, "there's been a bit of an overemphasis on [the independence] of stem cells." What's now becoming clear from work on muscle, blood, and other tissues is that stem cells can't do their job unless their resident organ--and maybe the whole organism--is willing and able to help.

Old bodies, it appears, lose their penchant to assist. Elderly muscles, for example, don't heal properly--and sometimes don't heal at all. But when cell biologist Thomas Rando of Stanford University in Palo Alto, California, and colleagues infiltrated old mice with some young blood, the elderly muscles regained their youthful ability to repair themselves. And the power came from the old muscles' stem cells: Rando's team tagged the juvenile stem cells with a glowing protein and saw that the bright young cells did not infiltrate the old muscle, indicating that the resident senior cells had handled the job. Similarly, Rando has also found that young blood helps old livers regenerate, an ability these organs lose over time. Together, these findings suggest that a factor in blood tells stem cells when to repair or replace old cells.

Rando's work shows that "the stem cells are still there in old age; they just seem to be quiescent," says molecular geneticist Michael Rudnicki of the Ottawa Health Research Institute in Ontario, Canada. Identifying such factors, he adds, is "the next huge area in stem cell research."

The place to start looking for agents that motivate the body builders is the region in tissues where each stem cell lives and works. Take, for example, the hair follicle. In mouse and human hair follicles, stem cells pump out pigment cells that color the hair. But as the follicles age, the stem cells malfunction and turn into pigment cells, which have a life span of only a few weeks. The old stem cells even switch on genes that are normally active only in pigment cells. Fisher suspects that the local environment might send these impressionable stem cells the wrong signal late in life, fueling the inappropriate behavior. Identifying those misguided missives might save us from going gray--and help researchers understand what types of compounds control stem cells generally.

Other researchers are looking to bone marrow transplantation, the only stem cell therapy that currently works, to find such stimulatory signals. Bone marrow contains the stem cells that generate red blood cells and the menagerie of immune system cells present in healthy blood. Some pharmaceutical companies, says Rudnicki, are developing drugs based on stem cell stimulating factors, such as the hormone made in the kidney that goads red blood cell production, which would have immediate therapeutic use in increasing marrow output.

Such "factors" might even turn out to be other cells. Recent work in mice fingers a bone-building cell called an osteoblast that prompts blood stem cells to manufacture more blood. Hematologist David Scadden of Harvard Medical School in Boston irradiated mice to clear out their resident blood stem cells and then gave them bone marrow transplants. When he stimulated the osteoblasts in these mice with a particular hormone, all of the animals survived the first month after the operation, compared to 27% of the mice that received the bone marrow without the extra push. The experiment, he says, is proof that researchers can manipulate the stem cell environment to improve the function of its residents. Initial human safety studies using the hormone--which occurs naturally in people--are under way.

The key to learning more about such hormones and stimulatory factors lies in developing better tools for finding and studying stem cell residences, says stem cell biologist Sean Morrison of the University of Michigan, Ann Arbor. In a study published this month, Morrison identified proteins on blood stem cells that will allow researchers to locate stem cells in bone marrow with far greater accuracy than ever before—and to get a handle on their interactions with other cells, he says.

For tissues that already know how to regenerate, such as blood, skin, and gut, coaxing the resident stem cells to perform might be fairly easy, says Scadden. However, other tissues such as the brain don't have as much innate regenerative capacity and will require somehow training the stem cells to surmount that shortcoming.

Fisher says it's important for the general public to understand that outside influences dramatically affect stem cells to avoid overly optimistic outlooks about using stem cells therapeutically. Even if researchers could locate and extract the stem cells that give rise to a particular organ, they probably won't be able to deploy the cells clinically until they understand--and can mimic--the contributions made by the environment, says Fisher. So after researchers delineate the orchestra of signals that guide stem cells, perhaps we'll no longer have to cover our gray. We'll be able to use stem cells to put the bounce and shine back into tissues in addition to our hair.

Mary Beckman is a writer in southeast Idaho who fantasizes about the stem cells that could keep her from having to dye.