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Creating functional, three-dimensional tissue and organs from pluripotent cells such as embryonic stem cells (EScs) or induced pluripotent stem cells (iPScs), is one of the grand challenges of stem cell research. It is also the fundamental goal of the emerging field of regenerative medicine.
Stem cell differentiation can be stimulated to follow a given path by culturing the cells in environments when embryogenesis normally occurs. Recent work has shown that when EScs are cultured under the appropriate conditions, they will self-organize into complex, three-dimensional tissue-like structures closely resembling their physiological counterparts.
Hidetaka Suga of the Division of Human Stem Cell Technology, and Yoshiki Sasai, Group Director of the Laboratory for Organogenesis and Neurogenesis, along with team members have steered mouse ESCs to give rise to tissue closely resembling the pituitary, in vitro.
Conducted in collaboration with Yutaka Oiso at the Nagoya University Graduate School of Medicine, their work was published in the journal Nature.
The Sasai group has made these achievements in differentiation using an ES cell culture technique dubbed SFEBq (shorthand for "serum-free floating culture of embryoid body-like aggregates with quick re-aggregation").
In recent years, refinements of this approach have enabled the development of pluripotent stem cells, giving rise to multi-cell-type populations of cortical and retinal neurons that spontaneously self-organize into tissue nearly identical to that of the developing embryo, including the differentiation of dopaminergic, cerebral cortex, cerebellar Purkinje, and other neuronal cell types.
Suga then wanted to use SFEBq to derive the secretory component of the pituitary from mouse ES cells. In embryonic development, the pituitary emerges from a region of the non-neural (rostral) head ectoderm, adjacent to the anterior neural plate. This region forms an indentation, known as Rathke's pouch, in the predecessor of the roof of the mouth, and eventually gives rise to the anterior section of the pituitary, which is the source of hormones involved in growth, reproduction and modulating a physiological response to stress.
The Sasai lab had previously reported how a modified version of the SFEBq approach could spur ES cells to give rise to hypothalamic neurons. Building on his finding, Suga found by tweaking the conditions he could steer populations of stem cells to differentiate simultaneously into the neighboring rostral head ectoderm and hypothalamic neuroectoderm. To test whether co-culture of this ectoderm with hypothalamic tissue would lead to the formation of Rathke's pouch-like structures, Suga added the signaling factor Sonic hedgehog, and was able to induce formation of the vesicular tissue.
Previous research had also suggested that Notch signaling interferes with the development of ACTH (adenocorticotropic hormone)-secreting cells, so the group added a Notch blocker to the culture medium. Following a similar principle, they then adding Wnt, glucocorticoid and insulin to the culture at appropriate doses and stages, and obtained growth hormone-secreting cells in quantity. By varying the recipe of the growth factor cocktail, the researchers were able to induce other pituitary hormones as well. Critically, the group was able to show that in vitro hormone secretion would respond to requisite signals and engage in regulatory feedback just as found normally in the body.
In a final series of experiments, Suga's team transplanted ESC-derived ACTH-secreting tissue into the kidneys of adult mice whose own pituitary glands had been made disfunctional. Within a week of transplantation, these mice showed strong overall survival, a marked rise in ACTH levels and an increase in corticosterone (a glucocorticoid hormone stimulated by ACTH) over those of untransplanted control groups, which uniformly weakened and died within eight weeks of hypophysectomy.
Yoshiki Sasai, leader of the study, commented on this most recent demonstration of the remarkable self-organizing capabilities of embryonic stem cells in vitro. "We have previously shown how ES cells can give rise to self-organized, three-dimensional neuronal and sensory tissues, and in this report we describe for the first time how this principle can be used to generate to an endocrine tissue, suggesting our approach is of general applicability."
Suga, himself an endocrinologist, remarks, "We currently treat pituitary deficiencies by hormone replacement, but achieving the correct dosage is not a straightforward problem, given the naturally fluctuating levels secreted within the body. I am hopeful that this new finding will lead to further advances in regenerative medicine in the endocrine system."
Original article: http://www.eurekalert.org/pub_releases/2011-11/r-spt111411.php