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November 09, 2011

Researchers Create a Pituitary Gland

A research team at Japan's RIKEN Center for Developmental Biology synthesized 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 work brings us closer to being able to bioengineer complex organs for transplant in humans.
Rathke’s pouch development in the mouse embryo.
a, Adenohypophysis originates in the non-neural head ectoderm rostral to the anterior neural plate. dorsal view. b, Immunostaining of mouse Rathke’s pouch. c, Signals from adjacent tissues to Rathke’s pouch. Scale bars, 100 μm (b).


Nature - Self-formation of functional adenohypophysis in three-dimensional culture





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.

The adenohypophysis (anterior pituitary) is a major centre for systemic hormones. At present, no efficient stem-cell culture for its generation is available, partly because of insufficient knowledge about how the pituitary primordium (Rathke’s pouch) is induced in the embryonic head ectoderm. Here we report efficient self-formation of three-dimensional adenohypophysis tissues in an aggregate culture of mouse embryonic stem (ES) cells. ES cells were stimulated to differentiate into non-neural head ectoderm and hypothalamic neuroectoderm in adjacent layers within the aggregate, and treated with hedgehog signalling. Self-organization of Rathke’s-pouch-like three-dimensional structures occurred at the interface of these two epithelia, as seen in vivo, and various endocrine cells including corticotrophs and somatotrophs were subsequently produced. The corticotrophs efficiently secreted adrenocorticotropic hormone in response to corticotrophin releasing hormone and, when grafted in vivo, these cells rescued the systemic glucocorticoid level in hypopituitary mice. Thus, functional anterior pituitary tissue self-forms in ES cell culture, recapitulating local tissue interactions.

Schematic of the SFEBq culture with large cell aggregation for mimicking early
pituitary development. gfCDM, growth factor-free CDM.



14 pages of supplemental material

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