Last spring, a research team at Japan’s RIKEN Center for Developmental Biology created retina-like structures from cultured mouse embryonic stem cells. This week, the same group reports that it’s achieved an even more complicated feat—synthesizing a stem-cell-derived pituitary gland.
The pituitary gland is a small organ at the base of the brain that produces many important hormones and is a key part of the body’s endocrine system. It’s especially crucial during early development, so the ability to simulate its formation in the lab could help researchers better understand how these developmental processes work. Disruptions in the pituitary have also been associated with growth disorders, such as gigantism, and vision problems, including blindness.
The study, published in this week’s Nature, moves the medical field even closer to being able to bioengineer complex organs for transplant in humans.
The experiment wouldn’t have been possible without a three-dimensional cell culture. The pituitary gland is an independent organ, but it can’t develop without chemical signals from the hypothalamus, the brain region that sits just above it. With a three-dimensional culture, the researchers could grow both types of tissue together, allowing the stem cells to self-assemble into a mouse pituitary. “Using this method, we could mimic the early mouse development more smoothly, since the embryo develops in 3-D in vivo,” says Yoshiki Sasai, the lead author of the study.
The researchers had a vague sense of the signaling factors needed to form a pituitary gland, but they had to figure out the exact components and sequence through trial and error. The winning combination consisted of two main steps, which required the addition of two growth factors and a drug to stimulate a developmental protein called sonic hedgehog (named after the video game). After about two weeks, the researchers had a structure that resembled a pituitary gland.
Fluorescence staining showed that the cultured pituitary tissue expressed the appropriate biomarkers and secreted the right hormones. The researchers went a step further and tested the functionality of their synthesized organs by transplanting them into mice with pituitary deficits. The transplants were a success, restoring levels of glucocorticoid hormones in the blood and reversing behavioral symptoms, such as lethargy. Mice implanted with stem-cell constructs that hadn’t been treated with the right signaling factors, and therefore weren’t functional pituitary glands, did not improve.
Next, Sasai and his colleagues will attempt the experiment with human stem cells. Sasai suspects it will take them another three years to synthesize human pituitary tissue. Perfecting the transplantation methods in animals will likely take another few years.
Still, researchers in the stem-cell field are impressed with what Sasai’s team has accomplished. “This is just an initial step toward generating viable, transplantable human organs, but it’s both an elegant and illuminating study,” says Michael G. Rosenfeld, a neural stem-cell expert at the University of California, San Diego.