THE NEW GOLD MINE?
Courtesy of Macropore
Adipose-derived stem cells stained with FITC conjugated CD90 (Thyl) antibody.
Embryonic stem cell research is proceeding apace in many nations but continues to face political and economic hurdles in the United States, despite California voters' approval of a $3 billion war chest for stem cell research conducted in that state. The reelection of President George W. Bush at the same time suggests that limitations on stem cell availability and research funds, at least from the US federal government, are likely to remain.
With many unknowns about both embryonic and adult stem cells, a potentially new type of stem cell, easily isolated from overly abundant fat tissue, may move the field ahead more quickly both in the United States and abroad. A handful of labs and biotechnology companies are working to exploit the potential of these adipose-derived stem cells (ASCs).
One company, San Diego-based Macropore Biosurgery, is developing a system to allow for extraction and immediate reinfusion of the ASCs without culturing or manipulation, which could be useful for treating myocardial infarction. Others are looking at treatments for Crohn disease and applications in cosmetic surgery.
Many questions remain, however, as to whether the cells are truly stem cells and if they will be therapeutically useful. What's more, it's not clear that a company can create a patentable product that provides recurring revenues because the therapy would involve removing cells and reinfusing them into the same patient without any alterations.
What is known is that ASCs offer an irony of sorts. Every year in the United States, 567,810 liters of fat are removed for cosmetic or health purposes, and this unwanted tissue may actually contain health-improving cells. It is also clear that fat is easily accessible and easily removed. It can even be done under local anesthesia, making harvest much more feasible and attractive than trying to cull hematopoietic stem cells from bone marrow. And, fat is a renewable resource, especially in the United States. Some of the ASC researchers, many of whom are plastic surgeons, look at it as killing two birds with one stone. "If we have the opportunity to serve both health and beauty, we would not object to that," says Keith March, director of the Indiana Center for Vascular Biology and Medicine at Indiana University School of Medicine, Indianapolis.
ASCs WEAR MANY HATS
In 2001, scientists at University of California, Los Angeles, and University of Pittsburgh reported that fat tissue extracted during liposuction is a rich source of what they characterized as stem cells.1 In October of this year, attendees of the second annual gathering of the International Fat Applied Technology Society (IFATS) in Pittsburgh agreed that the cells should be called adipose-derived stem cells. They also agreed that concerted efforts should be made to better characterize ASCs, create animal models, and focus clinical research on three key areas: cardiovascular disease, bone defect repair, and reversal of ischemia in peripheral vascular disease.
At the Pittsburgh meeting, Damian Garcia-Olmo of La Paz University Hospital in Madrid, Spain, reported results of a Phase I study using ASCs to close Crohn disease-related fistulas. Garcia-Olmo is collaborating with the Madrid-based biotechnology company Genetrix on a 50-patient Phase II study, which began in September.
The five patients in the Spanish trial had failed to respond to any previous surgical or medical treatment. They all had a minimally invasive liposuction process to harvest the ASCs, which were then cultured and infused into the fistular internal openings. Eight weeks later, six of nine treated fistulas were covered with epithelium and considered cured, says Garcia-Olmo. The stem cells would not likely be a long-term solution, he says, because Crohn fistulas tend to recur, but they would offer a less invasive therapy and likely eliminate the need for multiple surgeries.
A group led by Kotaro Yoshimura at the University of Tokyo is testing an ASC-boosted fat tissue mixture's ability to regrow fat tissue in the breast. Currently, it's being tested on women undergoing cosmetic breast augmentation, but the procedure could have future potential for reconstructive surgery.
Keith March's group at Indiana University School of Medicine is planning a Phase I study in which ASCs will be used to treat peripheral vascular disease in critical limb ischemia. He and his colleagues have been in discussion with the Food and Drug Administration about how to proceed. Though the university has no design for commercializing the therapy, says March, the FDA has advised that ASCs are subject to the agency's regulation because they are being used in a way that is different from their intended biological function. Commercialization might be desirable, but there's no clear path to market, March says. "Our thought is we'll protect certain elements of our intellectual property, which we've done, and we'll try to see if it works."
Macropore is betting there is a market opportunity for ASCs. Marc Hedrick, a UCLA researcher who contributed to the first published paper describing ASCs and who founded the company in 1996, says the first indication for ASCs could be post-myocardial infarction. The aim is to make it possible for cardiologists to extract ASCs and then quickly reinfuse them, in the hope that substantial damage to heart tissue will be prevented. Hedrick notes that the literature indicates that putting adult stems cells into the heart can make the organ pump better. "We happen to think the adipose-derived cells will be the best source for healing and regenerating the heart," he says.
Macropore has licensed a patent on the use of ASCs for therapeutic purposes to the University of California. Whether that patent is defensible is another issue. Because ASCs occur naturally in the body, anyone who licenses the patent would be required to show that they have created a specific therapeutic use for the cells, which may be difficult.
Regardless, Macropore aims to conduct human trials within two years, says Hedrick. The company also runs a small operation that banks fat tissue, and it sells spinal implants based on its biomaterials platform. "We think our business model makes sense, and we think the investment community is going to reward us," says Hedrick.
MORE DATA NEEDED
Others are less certain. While all agree ASCs seem like a good idea, the field has engaged in only three to four years of solid inquiry, which may make investors wary. The notion that stem cells can be harvested from fat is "a neat claim, a neat idea," says Curt Civin, a stem cell researcher at Johns Hopkins University. But Civin, the Samuelson Professor of Cancer Research at Hopkins' Kimmel Cancer Center, says he's looking for more data on just what the cells are and how they behave.
Civin is not alone; many in the field acknowledge that much is yet undiscovered. "We're still learning about what these cells can do and what role they're going to have in clinical regenerative medicine," says J. Peter Rubin, an assistant professor of plastic and reconstructive surgery, and president of IFATS.
Courtesy of Macropore
exist in high quantity within adipose tissue (body fat). Adipose tissue is the richest known source for regenerative cells, which consist of adult stem cells, endothelial progenitor cells and growth factor producing cells.
Even the cells' basic function in adipose tissue is unclear. With fat deposits existing everywhere in the body, researchers are exploring whether the cells taken from various regions are different, and whether a patient's age affects the quality of the cells. Early research has shown that the cells can differentiate into other cell types. Duke scientists have reported that they've coaxed ASCs to form chondrocytes, and nerve and bone cells.2 At Louisiana State University's Pennington Biomedical Research Center in Baton Rouge, Jeffrey Gimble and colleagues also have reported the ability to transform the cells into bone and muscle cells.3 At Tulane University in New Orleans, Kai Pinkernell converted ASCs to heart muscle cells. And UCLA researchers submitted an abstract at the IFATS meeting suggesting that they had been able to derive smooth muscle cells from ASCs.
So far, it looks as if only a percentage of ASCs may be defined as true stem cells. It would not be surprising that few of the ASCs fit the classic definition of a stem cell, because stem cells by nature are rare in the body, Civin says. Another question is whether the ASCs are a new class of stem cell, or if they simply are a mesenchymal stem cell or hematopoietic stem cell that's been carried by the blood to the fat, he adds.
Adam Katz, who discovered ASCs when he was a surgical resident at the University of Pittsburgh, says he pursued the fat-derived cells because they looked so similar to the mesenchymal cells he'd been studying. After coaxing them to differentiate and observing self-renewal, he thought they were a new class of stem cell. But now Katz, an assistant professor of plastic surgery at the University of Virginia Health System in Charlottesville, says he's not as convinced.
Despite the doubt, the cells could still prove useful, Katz says, "Even if they may not meet the most rigorous definition of stem cells, I do think that the literature really suggests that there might be therapeutic benefits." Like others, Katz has shown that the cells' secrete anti-inflammatory and pro-angiogenic signals. His lab is pursuing at least five projects with ASCs, including the basic characterization and isolation of the cells, and using them in mice to regenerate heart tissue after myocardial infarction. Katz is also working on experiments in rats, using ASCs after stroke and to regenerate bone.
March, whose Indiana University lab is studying the basic biology of ASCs, says the cells are likely to play a larger role in assisting healing rather than becoming bone or organ tissue. "We think they're very smart in terms of secreting materials that have important therapeutic or repair potential," he says.
The first hurdle for ASCs going into trials may be safety. Since the cells promote blood vessel growth, a big issue is whether infusing them in large numbers might fuel existing tumors or give rise to new tumors. March says the potential was discussed at the IFATS meeting, with some scientists agreeing that it should be explored, while others say it is not likely since the cells occur naturally in the body.
"The short answer is, it's a great question," says March. But he says he feels that initial ASC-derived therapies, which will be autologous, will be generally safe since the cells will be put back in the body with little manipulation. Some may question the rush into human studies when many of the basic science questions are unresolved. But Civin says it's not unreasonable to attempt "appropriate" clinical studies in patients who are seriously ill and have no other options.
Research into ASCs is still a relatively small field, says Civin, noting that a journal he edits,