Regenerating pituitary endocrine cells

03 October 2013

NIMR researchers have characterized a population of pituitary stem cells in mice, and shown that these cells display regenerative potential. The research is published in Cell Stem Cell.

A central goal of regenerative medicine is to be able to instruct resident tissue stem cells to repair a deficient organ. We therefore need to know how organ-specific tissue stem cells function under normal physiological situations, and whether it is possible to stimulate their regenerative potential. The pituitary is the master endocrine gland, involved in maintaining body homeostasis and controlling physiological processes, such as reproductive maturation and function. It does so by secreting hormones under control of the hypothalamus, within the brain, which acts to centralize peripheral information. Pituitary hormone deficiencies can be congenital or acquired, in particular after traumatic brain injury. These diseases cause significant morbidity with Growth Hormone deficiency being the most frequent (1 in 3500-1000 births). Being able to regenerate missing endocrine cells would represent a significant improvement over the current replacement hormone therapies used to treat these deficiencies, which do not recapitulate endogenous secretion patterns and are costly.

It has been proposed that a population of adult progenitor/stem cells may be present in the pituitary. A few years ago, Iain Robinson’s and Robin Lovell-Badge’s teams, and several other labs, have characterized different, but likely overlapping, populations of adult pituitary progenitors. These cells were shown to express the HMG box transcription factors SOX2 and SOX9 in vivo, and to be able to form stem cell like sphere cultures in vitro.

Karine Rizzoti (pictured), in Robin Lovell Badge’s lab in NIMR’s Division of Stem Cell Biology and Developmental Genetics, has demonstrated that SOX2+ve and SOX9+ve progenitors are the sphere forming cells. She then used genetic lineage tracing tools to show that both SOX2 and SOX9-expressing progenitors can self-renew and give rise to endocrine cells in vivo, in the embryo and the adult, showing that these cells represent tissue stem cells. In the adult the stem cells mostly self-renew but she showed that in response to physiological challenge, they can become mobilized, proliferate and differentiate into the appropriate endocrine cell types.

This study represents the first in vivo demonstration of the existence of adult pituitary stem cells and shows that they can make a significant contribution to the pool of new endocrine cells generated in response to physiological demand. This represents a first step toward the use of pituitary stem cells to modulate endocrine output and treat deficits.

The ability to control the activity of such progenitors in vivo, or to use them in regenerative or cell transplant therapies, could be used to manipulate physiological states, or to treat congenital or acquired pituitary hormone deficiencies, which are associated with significant morbidity. This could also alleviate both the side-effects and cost of current hormone replacement and substitution therapies.

Karine Rizzoti

Our study shows that the adult pituitary is a useful model to study the behavior of adult tissue stem cells in response to physiological demands. The target organ ablation model we have used here will now allow us to dissect the mechanisms underlining this stem cell mobilization, in order to potentially direct new endocrine cell generation, particularly in pathological situations. While congenital defects are rare, post-traumatic hypopituitarism (PTHP) is increasingly being recognised as a common cause of problems in recovery after head injuries.

Robin Lovell-Badge

Click image to view at full-size

SOX9 (pictured) and SOX2 positive cells can self-renew and give rise to all endocrine cell types in the anterior pituitary.

Original article

Karine Rizzoti, Haruhiko Akiyama and Robin Lovell-Badge (2013)

Mobilized adult pituitary stem cells contribute to endocrine regeneration in response to physiological demand.

Cell Stem Cell 13, 419-423 Article fulltext.

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