Further strides in ES cell organogenesis
Posted by Paul O'Neill, on 13 November 2011
A new Nature study has again demonstrated the power of ES cells as a model system for recapitulating developmental processes in vitro. Following on from the amazing self-assembly of differentiated optic-cups reported earlier this year, Yoshiki Sasai’s latest work has resulted in the generation of functional pituitary gland tissue from mouse ES cells.
Using a modification of their 3D floating aggregate culture protocol (which can generate complex patterned neural structures), Sasai’s group, from RIKEN CDB in Kobe, Japan, observed the generation of small ectodermal pouches, which expressed markers typical of adenohypophysis (anterior pituitary) maturation.
During embryogenesis, adenohypophysis development is dependent on the interaction of two distinct neural tissues: Pitx1-positive rostral head ectoderm, and Rx-positive rostral hypothalamic neuroectoderm. By using greater cell numbers to establish ES-cell aggregates than in their previous reports, both of these tissue types were generated together. Pitx1-positive ectoderm formed an outer layer, with sheets of Rx-positive tissues within. Regions of Pitx1-positive ectoderm were then observed to express the adenohypophysis marker Lim3, invaginate, and bud, forming vesicles in a manner consistent with normal pituitary development.
Reprinted by permission from Macmillan Publishers Ltd: Nature doi:10.1038/nature10637, copyright (2011)
By manipulating the culture conditions, the immature pituitary vesicles were encouraged to differentiate each of the mature cell types associated with the mature adenohypophysis. Blocking Notch signalling for example, promoted production of ACTH synthesising cells, whereas activating the Wnt pathway resulted in GH and prolactin precursor cells. The efficacy of the ES-cell-derived glands was also confirmed by transplantation of the tissues into mice in which the pituitary had been surgically removed. This resulted in a rise of blood glucocorticoid levels, an increase in locomotor activity, and prolonged life expectancy in the treated animals.
The mechanisms underlying adenohypophysis induction by the neuroectoderm remain unclear, but this methodology provides an excellent system to address this issue. Moreover, the generation of inductive and responsive tissues in the same dish is an exciting progression in the quest to accurately emulate complex tissue formation in vitro.
Reference:
Suga, H., Kadoshima, T., Minaguchi, M., Ohgushi, M., Soen, M., Nakano, T., Takata, N., Wataya, T., Muguruma, K., Miyoshi, H., Yonemura, S., Oiso, Y., & Sasai, Y. (2011). Self-formation of functional adenohypophysis in three-dimensional culture Nature, 480 (7375), 57-62 DOI: 10.1038/nature10637
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