So how could this new cell elude scientists and doctors for so long? In a way, it wasn’t like that. Plikus and his graduate student combed through centuries of scientific papers looking for any missing traces of fatty cartilage. They found a clue in an 1854 German book by Franz Leydig, a contemporary of Charles Darwin. “Anything he could put under the microscope, he did,” Plikus says. Leydig’s book described fat-like cells in a sample of cartilage from rat ears. But the tools of the 19th century could not go beyond that observation, and realizing that a more precise census of skeletal tissue could be valuable for medicine, Plikus decided to solve the case.
His team began their research by looking at the cartilage found between thin layers of mouse ear skin. A green dye that preferentially stains fat molecules revealed a network of soft spots. They isolated these lipid-filled cells and analyzed their contents. All your cells contain the same library of genes, but those genes are not always turned on. What genes did these cells express? What proteins accumulate inside? Those data revealed that lipochondrocytes actually look very different, molecularly, from fat cells.
They then questioned how lipochondrocytes behave. Fat cells have an unmistakable function in the body: storing energy. When your body stores energy, cellular lipid stores swell; When your body burns fat, cells shrink. It turned out that lipochondrocytes do no such thing. The researchers studied ears of mice placed on high-fat diets versus calorie-restricted diets. Despite rapidly gaining or losing weight, the lipochondrocytes in the ears did not change.
“That immediately suggested that they must have a completely different role that has nothing to do with metabolism,” Plikus says. “It has to be structural.”
Lipochondrocytes are like balloons filled with vegetable oil. They are soft and amorphous but still resist compression. This contributes significantly to the structural properties of cartilage. According to rodent data, cartilage tensile strength, resilience, and stiffness increased between 77 and 360 percent when comparing cartilage tissue with and without lipochondrocytes, suggesting that these cells make cartilage more flexible.
And structural gifts seem to benefit all types of species. In the outer ear of the Pallas’ long-tongued bat, for example, lipocartilage underlies a series of folds that scientists believe tune them to precise wavelengths of sound.
The team also discovered lipochondrocytes in human fetal cartilage. And Lee says this discovery seems to finally explain something that reconstructive surgeons commonly observe: “Cartilage is always a little slippery,” he says, especially in young children. “You can feel it, you can see it. It’s very obvious.”
The new findings suggest that lipochondrocytes fine-tune the biomechanics of some of our cartilage. A rigid structure of lipid-free cartilage proteins is more durable and is used to form weight-bearing joints in the neck, back and, yes, you got it, the ribs, one of the traditional sources of cartilage for implants. “But when it comes to more complex things that really need to be flexible, elastic, and bouncy—the ears, the tip of the nose, the larynx,” Plikus says, that’s where lipocartilage shines.
For procedures that involve modifying these body parts, Plikus envisions one day growing lipocartilage organoids in a dish and 3D printing them into any desired shape. Lee, however, advises caution: “Despite 30 or 40 years of study, we’re not very good at producing complex tissues,” he says.
Although such an operation is far away, the study suggests that it is feasible to grow lipochondrocytes from embryonic stem cells and safely isolate them for transplant. Lee assumes regulators wouldn’t give the green light to using embryonic cells to grow tissue for a non-life-threatening condition, but says he would be more optimistic if researchers could grow transplantable tissue from adult cells derived from patients. (Plikus says a new patent application he has filed covers the use of stem cells from adult tissue.)
Lipochondrocytes update our understanding of what cartilage should look and feel like, and why. “When we try to build, say, the nose, sometimes we can use the (lipid-filled cells) as a bit of filler.” Lee says. Lipocartilage could one day fill that gap as a culturable and transplantable tissue, or it could inspire better biomimetic materials. “It could be both,” he says. “It’s exciting to think about it. Maybe that’s something we’ve been missing.”