Beer gut, spare tire, saddle bags. To most people, excess fat is unsightly and useless. Americans spend between $500 million and $900 million per year to have doctors extract it via liposuction procedures—after which the tissue is simply discarded as medical waste. But Michael Longaker sees a goldmine in this maligned material. Fat contains stem cells that can be coaxed into performing amazing therapeutic feats, such as growing new bone.
"Fat is a great natural resource. It's easy to obtain; it's yourself; and it's renewable," says Longaker, who is professor of plastic and reconstructive surgery and co-director of the Institute of Stem Cell Biology and Regenerative Medicine. Using cells harvested from liposuction waste, Longaker has repaired mouse skull defects that would not heal on their own. He has also reprogrammed the cells so that they can potentially regrow any tissue in the body.
"I'm a plastic surgeon in a stem cell scientist's body, or the other way around," Longaker says. As a physician, he fixes skeletal defects in children injured by trauma or born with congenital defects, such as cleft lip and palate. Large defects require bone grafts: Longaker takes bone from a healthy part of the skeleton (such as the hip bone) to fill in the damaged area. However, bone grafts are painful and complicated, and often there isn't enough spare bone for the job. Longaker hopes instead to grow new bone from stem cells.
Stem cells come in two main types: "pluripotent" cells, which can become any cell type in the body, and "multipotent" cells, which have a limited number of potential fates. Pluripotent stem cells are present only in the embryo (and using them raises ethical issues), but multipotent stem cells are present in all of us. Bone marrow, for example, contains stem cells that can become bone, blood, muscle, cartilage or fat. However, these cells are painful to extract from inside the bone and relatively scarce. About a decade ago, researchers discovered that adipose tissue—abundant and easy to access—harbors similar stem cells in higher concentrations.
In 2004, Longaker and colleagues first showed that stem cells from mouse fat can repair skull defects in mice that are too large to heal spontaneously. When transplanted on a sponge-like scaffold, the cells repaired a 4-millimeter hole in the bone in 12 weeks. In 2010, Longaker's team showed that human stem cells from liposuction waste can heal mouse skull defects even faster—in just eight weeks. Importantly, the procedure used freshly isolated cells without the need to cultivate or modify them in a laboratory. This suggests that a surgeon could harvest a patient's fat, extract the relevant cells, and transplant them back into the patient all within a single operation.
"The idea that you can do the whole procedure within one operative setting is very attractive for someone who is doing clinical work," says James P. Bradley, professor of plastic surgery at UCLA Medical Center, who specializes in pediatric craniofacial surgery. The technology may only be five to seven years away from clinical use, Longaker says.
In the longer term, fat-derived stem cells may have an even greater therapeutic potential. In 2006, Japanese researcher Shinya Yamanaka figured out how to turn back the clock on adult cells, reprogramming them into a pluripotent state. Like embryonic stem cells, these "induced" pluripotent cells, or iPS cells, can be coaxed into making any tissue in the body—such as heart muscle, nerve cells or intestines. (The discovery nabbed Yamanaka the 2012 Nobel Prize.) Many researchers have focused on making iPS cells from skin cells, which are easy to collect. But Longaker has shown that it's twice as fast and 20 times more efficient to start with fat-derived stem cells. Unlike skin cells, fat-derived stem cells are already multipotent and thus "much more efficient to back all the way up," he says. Plus, you can harvest many more of them at once.
Longaker and colleagues are helping to tackle several key issues that need to be solved before iPS cells can be used therapeutically. In Yamanaka's method, viruses randomly insert reprogramming genes into a cell's DNA, which carries the risk of turning the cell cancerous. But in 2010 Longaker and two collaborators—Mark Kay, professor of pediatrics and genetics, and Joseph Wu, professor of cardiovascular medicine—introduced a safer, nonviral method of making iPS cells that doesn't mess with the cell's DNA.
The versatility of iPS cells is also a double-edged sword. When transplanted into the body, iPS cells can form benign tumors called teratomas: unorganized masses of miscellaneous tissue. "It's not a cancerous tumor, but it's not what you want in your brain or heart," Longaker says. In a 2012 paper in PNAS, Longaker's team showed how to avoid teratomas by providing the right growth environment. They seeded iPS cells (made from liposuction fat) or embryonic stem cells onto a scaffold coated in bone mineral and engineered to release a protein that strongly promotes bone growth. "All these things scream: You need to become a bone cell," Longaker says. Then they placed the scaffolds into mouse skull defects—which provide a macro-environment that also signals bone growth. The skeletal defects healed in eight weeks and no teratomas formed in 27 mice treated with iPS cells. (Two formed in 15 mice treated with embryonic stem cells.)
"We're getting much closer to actually being able to use these cells," Bradley says. "As clinicians, we're skeptical; 20 years ago, we heard about tissue engineering techniques that never came to fruition. But then we see breakthroughs like this and we realize this has the potential to change the way we do things."
Kristin Sainani, MS '99, PhD '02, is a clinical assistant professor in the department of health research and policy and a freelance writer.
