Biomedical Engineers Grow Human Tissue that Suppress Immune Response

Using patients’ fatty cells, a team of scientists at the Tel Aviv University in Israel grew several tissue transplants that are fully compatible with the patients’ bodies, and won't trigger an immune system response.

Most tissue and organ transplants contain at least some amount of foreign material, whether animal-based or synthetic, provoking the immune system to attack. As a result, patients must take immunosuppressing medications to avoid the body’s rejection of the implant. This is a double-edge sword as the implanted tissue may be spared, but patients become vulnerable to minor infections and can die from something as common as a flu. And while in recent years bioengineers have made great progress in forging tissues from patients’ own cells, these cells still rely on animal or synthetic extracellular scaffolding material.

Extracellular matrix protein (ECM) is a three-dimensional matrix of macromolecules such as collagen, enzymes, and glycoproteins that provide structural and biochemical support to the living cells. ECM acts as a biologically active concrete—it holds the cells together, and provides them with important biological information and a food supply.

“ECM plays many important roles,” Tal Dvir, the study’s lead author, said. “It provides important cues on whether cells need to divide or proliferate, or expand in size, or start some kind of reactions. Without it there would be no tissue.”

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Until now, attempts to create human-derived ECM scaffolding did not succeed, so medics relied on ECM materials derived from pigs. “There are many biomaterials made of pig proteins,” Dvir said, but that triggers an acute immune response, meaning millions of people have to take immunosuppressants and other medications to stop their bodies from rejecting these implanted biomaterials.

To solve this problem, the Israeli team created patient-derived ECM scaffolding and used it to grow the patients’ own cells, thus creating fully personalized or autologous implants, with all components sourced from the same individual.

Bioengineers harvested small bits of omentum, a sheet of fatty tissue stretching over the abdomen. These omentum bits consisted of fatty cells along with the ECM scaffolding that held them together. Using an already established technique, scientists reprogrammed fatty cells into induced pluripotent stem cells (iPSCs), which can then differentiate into any other cells and grow into the corresponding tissue, including heart, brain, spinal cord and others.

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Next, scientists broke the ECM scaffolding into pieces small enough to become water-soluble. When they mixed the ECM fibers with water and heated the blend from room temperature to 37 °C (98.6 °F), the concoction formed a hydrogel. With properties akin to the natural human ECM, the hydrogel was immunologically compatible with the patient from whom it was extracted.

 “The mixture contains small ECM fibers, and when we heat it, they entangle together and they form the hydrogel,” Dvir said.

This hydrogel is essentially a biochemical mimic of the body’s natural ECM, so it creates the same native environment the cells are used to. “It’s a fully personalized hydrogel,” Dvir said. This means that cells can comfortably differentiate into any tissue types. Dvir’s team used this hydrogel to grow heart, spinal cord, and brain cells into functioning tissues.

“The beauty of this approach is that it combines simplicity with effectiveness,” said Gordana Vunjak-Novakovic, head of the laboratory for Stem Cells and Tissue Engineering at Columbia University, who was not involved in the study. “The source of both the cells and the carrier biomaterial is omentum, a highly vascularized membrane that encloses our bowels. The authors show that the cellularized patch derived from omentum can repair a number of tissues, including the heart, motoneurons, and vasculature.”

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After harvesting patients’ immune system cells from their blood samples and used in vitro, researchers compared their reaction to the tissues grown from their own ECM scaffolding versus ECM from other people and from those grown from pigs. Not surprisingly, the immune system’s reaction was the calmest with the patients’ own scaffolding and more elevated with other people’s scaffolding. It mounted the highest response to the pig material. “We see really huge response of activated T-cells when we use pig material,” Dvir said, suggesting these animal implants may not be as safe as previously thought.

The method opens many possibilities of personalized transplants, such as neuronal implants for treating central nervous system diseases or for healing brain lesions. It can also be used for growing tissues for personalized transplants in reconstructive surgery, eliminating the necessity to alter the immune system’s normal functions. “We are currently exploring the implants for Parkinson’s,” Dvir said, adding that the next step would be to establish a company to bring this technology to the clinics.   

“An ideal therapy for a patient would be personalized, with respect to the materials, cells, dosages and regimens of medications,” Vunjak-Novakovic said. “By generating a patch containing therapeutic cells and biomaterial that are both derived from the easily harvested patient’s tissue, this study brings us a step closer to this big goal.”

Lina Zeldovich is an independent writer.

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