S T A N F O R D M E D I C I N E
19 Number 1 Winter 2002
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Michael Longaker, Karl Sylvester and Peter Lorenz want your fat.
They covet the lumpy, bumpy layers of the stuff many of us have bulging out of our jeans. While the vision of jars of human fat lined up like homemade preserves along lab benches and shelves might make most of us queasy, these researchers see instead a mother lode of unusually talented cells waiting to be harvested.
"Its like liquid gold," says Longaker, MD, co-director of the Transplant and Tissue Engineering Center at Lucile Packard Childrens Hospital. Like modern-day alchemists, the centers physicians plan to convert a portion of this much-maligned substance into something a bit more useful like, say, a liver.
As implausible as this may seem, these researchers arent indulging in flights of fancy. Recent research at UCLA, co-headed by Lorenz prior to his arrival at Packard last November, has shown that a certain type of cell isolated from human fat can be coaxed in the laboratory to assume the characteristics of other, non-fat cells such as cartilage, bone and muscle. Previously these so-called multi-potential cells were only known to exist in the bone marrow. Now the Stanford centers researchers have joined forces with faculty members in the engineering and developmental biology departments to put these cells through their paces. Can they with the right encouragement, also become the tissues that make up the liver, kidney and pancreas? What about brain? Or skin?
If the research outcomes are positive, the implications are staggering. Dysfunctions of cells and tissues including those damaged by heart attack, stroke or degenerative diseases account for about half of the total funds spent on health care in this country, says Longaker, professor of surgery at Stanford University School of Medicine. Identifying a readily available, plentiful source of cells that can be harvested, programmed to pinch-hit for the cell of choice and replaced in the body to home in on the site of injury or damage would be a therapeutic leap beyond what most scientists or physicians could have imagined less than a decade ago.
Until recently, scientists thought that only embryos possessed a special type of cell, known as a pluripotent stem cell, capable of both renewing itself and giving rise to all the cells, tissues and organs in the body. Most adult stem cells are mere shadows of their powerful ancestors, capable of regenerating only their own specific tissue types. Skin stem cells can give rise only to more skin cells, and muscle only to muscle. Renegades that could flip-flop between cell or tissue types were not thought possible.
Its appropriate that the newly found multi-potential cells debuted in the bone marrow, which already houses the most versatile type of adult stem cell that scientists have fully characterized. These well-known cells, called hematopoetic stem cells, constantly regenerate all the different types of blood and immune cells needed to carry oxygen and fight infection throughout the body.
But even these dependable workhorses are restricted to careers in the blood lineage. In contrast, the multi-potential cells represent another population of stem cells in the bone marrow, called mesenchymal stem cells. This group of cells can morph into other cell types such as bone, muscle, cartilage and fat at least within the confines of a Petri dish. Even more tantalizing is the real possibility that these cells may be free of certain surface markers that can trigger an immune response, possibly reducing the chances of rejection if the cells are transferred between individuals.
The question now: Can they perform this feat within the body, and, if so, is it possible to harness this ability to treat patients who could benefit from a jot of new heart muscle or a tad bit more bone growth? Preliminary results in mice and rats are promising but further experiments to understand whether this happens with human cells require a reliable, plentiful source of raw material.
"Not all of these cells will be able to be coaxed, cajoled or prodded down our pathway of choice," says Longaker. "Thats why we need to start with lots of cells."
But until the UCLA research showed the presence of multi-potential cells in the fat, bone marrow was the only resource for these cells in humans. And in the numbers game, bone marrow strikes out. Only a small number of the cells can be isolated from a standard marrow donation, which requires anesthetizing the donor and puncturing the pelvic bone with a needle to withdraw about a liter of marrow not everyones choice for a fun way to fill a few hours.
In contrast, liposuction leftovers represent a rich and easily obtainable source of the changelings: Longaker speculates there may be as many as 1 billion in each liter of the creamy, golden fat, which is usually discarded. "Hundreds of thousands of Americans had liposuction last year, and at the end of the procedure the fat was thrown out," says Longaker.
"Theres an abundance of these types of cells in fat," agrees Lorenz, associate professor of plastic surgery at Packard. The researchers plan to tap fat harvested from local Stanford-affiliated plastic surgeons, transferring it to the lab for processing the day of the surgery. Patients will be asked to sign a consent form that explains the study and the probable fate of their fat cells before their tissue is used.
Scientists arent sure why fat has so many of these cells or where they originated. On the surface they look an awful lot like the mesenchymal stem cells in the marrow so much so that they might be the same cells that have just wandered into a handier hangout.
"Weve learned a lot from studies of the various populations of cells in the bone marrow," says Sylvester, a Stanford assistant professor and surgeon at Packard. "The cells found in fat seem to behave similarly, if not identically, to the marrows mesenchymal stem cells. They may just be more accessible and more numerous." The researchers speculate that the fat may serve as a kind of backstage area for these cells, waiting for a cue of injury or needed growth to begin their performance as the tissue "du jour," which might even be fat itself.
"They may function as a source of new fat cells," says Lorenz.
Fats main function in the body is one of storage. Although unlovely to look at, it plays an important role as an energy repository. Fat tissue is made up primarily of adipocytes, a specialized type of cell plumped up by a big globule of fat. The adipocytes are loosely bound together by connective tissue known as stroma and blood vessels. Its from this stromal vascular fraction that Lorenz and the other UCLA investigators isolated the multi-potential cells. Although it seems at first glance to have little in common with bone marrow, this part of fat tissue shares the same developmental pathway: Both are derived from the embryonic mesoderm, one of three layers of cells in an embryo along with endoderm and ectoderm that eventually form every organ and tissue in a newborns body.
Given that mesoderm is also the ancestor for bone, cartilage, muscle and fat its somewhat understandable that the multi-potential cells have been shown to develop into these tissues in vitro. Like Shakespearean actors familiar with many of the Bards plays, these cells can apparently slip into the roles of different mesoderm-derived tissues with relative ease. But recent research by Helen Blau, PhD, director of Stanfords Baxter Laboratory for Genetic Pharmacology, and others showed that an unknown population of cells from the bone marrow can even migrate to the brain and assume some characteristics of ectodermally derived neurons. This suggests that multi-potential cells found in fat might be even better actors than previously suspected and vastly widens the horizon of targets for tissue engineering.
"Were hoping that the cells found in fat have the same potential," says Sylvester. "Can a fat cell become something other than those mesodermally derived lineages that it became in vitro? Can it also become the endodermal cells that make up the pancreas and liver? Thats a huge jump, but we and others have preliminary data that suggest this is possible." In fact, recent, unpublished research by Lorenz has shown that the multi-potential cells can be coaxed into becoming quite neuron-like in vitro. The cells develop the appearance of neurons and express neuron markers consistent with neuronal stem cells.
Harnessing this suspected capacity for what the scientists call transdifferentiation is essential for the researchers plan to use these cells to rejuvenate faltering or missing organs, and requires an understanding of the signals that guide a cells development. In an embryo, local environmental signals are particularly important.
"If Im an embryonic stem cell and I migrate to the chest as the embryo is forming, Im going to get signals to become lung, heart, trachea or esophagus," says Longaker. "Im not going to become the foot or the liver or the brain. Like water confined to a glass, the shape and function of the contents are determined by the container."
Longaker and Sylvester will take their cues from previous research on embryonic developmental biology as they attempt to decipher the external and internal signals driving the cells down one pathway or another.
"We plan to examine how these cells behave in these animal models of human diseases to see if they will go to the appropriate organ and start performing the functions of that organ," Sylvester says. "If that occurs, then well go backwards from there and ask what were the signals both in the environment and on the gene level that allowed this cell to reprogram itself from a cell that may be hanging out in fat doing nothing to a functioning component of an organ."
Reconstructing a whole organ in the lab presents an additional structural challenge. Not only do many different types of cells have to assemble in the correct three-dimensional orientation, the resulting organ must have access to a blood supply to deliver nutrients and remove waste.
"These are really complicated things," says Longaker, emphasizing that the involvement of faculty members in the School of Engineering will be critical at this stage of the research. "We should know within the next three to five years whether were right about the potential of these cells." Because certain tissues like cartilage do not require a blood supply, Longaker suspects that they will be the first to yield to growth in the lab.
"It will be great if we can get a liver or a pancreas," he says. "But were not biased. Well take whatever we can get."
The researchers have less lofty yet equally important goals for the near future. Both Longaker and Sylvester point out that tissue engineering could alleviate disease without going so far as to replace an entire organ. If the multi-potential cells can be coaxed to differentiate into the correct type of tissue and to express genes that stimulate growth or fill in for a genetic deficiency, they may be able to supplement the function of a damaged or dysfunctional organ.
"Much of the liver function is not found in the whole liver. Liver disease is sometimes due to a deficiency in a single enzyme," says Longaker. "If Dr. Sylvester, working with gene therapy experts here at Stanford, can get the gene for that enzyme into the cell and he can then inject a billion of those cells and they home to the liver and function, it doesnt matter that you havent replaced the whole organ. Youve replaced what that child or adult needs."
"You can take advantage of the liver as it already exists by using it as a scaffold on which to hang the genetically modified cells," concurs Sylvester. "In this way the cells can serve as a shuttle for a single gene."
In addition to generating or supplementing organ function, Lorenz is also interested in investigating whether the cells can be used to promote quicker, perhaps even scarless, wound healing. "If these cells can produce skin like fetal cells can, maybe we can get skin to heal with less scarring," he says.
Although their plans may seem suited for science fiction, the physicians emphasize that their goals are within reach thanks to the collaborative spirit among faculty at Stanfords schools of engineering and medicine.
"If you believe, as we firmly do, that this type of research is going to revolutionize the way that children and adults are treated, then this is the place where you can best make that dream happen," says Longaker.
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