ReviewAdrenocortical stem and progenitor cells: Unifying model of two proposed origins
Introduction
Dr. Keith Parker serendipitously became a pioneer in the molecular study of adrenal gland development and organogenesis when he cloned the gene for steroidogenic factor 1 (Sf1) as a transcriptional regulator of genes encoding steroidogenic enzymes (Luo et al., 1994). Dr. Parker's work occurred concurrently with studies emerging from the Morohashi laboratory on the steroidogenic transcription factor Ad4BP, which turned out to be identical to Sf1 (Hatano et al., 1996). Together, these studies surprisingly found that the adrenal glands did not form in mice with a genetically modified null allele of Sf1. Studies of Sf1 for over two decades have provided the molecular framework for the emerging field of adrenocortical stem and progenitor biology. The current research in the emerging field of adrenal organogenesis and data supporting the presence of adrenocortical stem/progenitor cells was recently reviewed (Kim et al., 2009). The current summary herein highlights a working model of adrenocortical stem/progenitor cell biology and the proposed stem cell niche and includes the emerging data supporting the hypothesis.
Section snippets
Adrenal anatomy
The adrenal glands are formed from two embryologically distinct tissues. The inner adrenal medulla is derived from neural crest cells of the neuroectoderm lineage and synthesizes catecholamines essential for the “fight-or-flight” response. The cortex is derived from cells of the intermediate mesoderm and is responsible for secretion of steroid hormones. The cortex is organized into three concentric zones, each with a discrete function, the synthesis and secretion of steroid hormones: (1) zona
Organogenesis
Adrenal gland organogenesis is orchestrated in discrete histological phases (Fig. 1; reviewed in Else and Hammer, 2005, Keegan and Hammer, 2002, Uotila, 1940). In the initial phase (4th week of gestation in humans, embryonic day (E) 9.0 in mice), the adrenogonadal primordium (AGP) is first distinguished and expresses the essential transcription factor SF1/Sf1 (Hatano et al., 1996, Luo et al., 1994). In the second phase (8th week gestation in humans, E10.5 in mice), the AGP separates into two
Evidence that the fetal cortex is the source of adrenocortical precursor cells
Sf1 expression is critical for proper adrenal organogenesis and is required for steroidogenic function in both the fetal and the adult cortex. As addressed by work of Zubair et al. (2006), the differential activity and regulation of Sf1 in the development and function of these two cell populations (fetal and adult cortex), is emerging as an essential mediator of adrenal gland organogenesis. These investigators identified a Fetal Adrenal Enhancer (FAdE) that directs Sf1 expression solely in the
Mediators of adrenal stem/progenitor cell maintenance, proliferation, and differentiation
As anticipated, a multitude of signaling pathways and transcription factors are emerging as critical mediators of adrenocortical growth and differentiation, including the regulation of adrenocortical stem/progenitor cells. The transcriptional mediators, β-catenin and Dax1, have drawn particular interest due to their role in human disease and their demonstrated regulation of Sf1 activity.
Conclusion
Since the inception of Keith Parker's groundbreaking work, much progress has been made to define the development and the signaling pathways involved in the maintenance and differentiation of the adrenal gland. In this review, data have been highlighted which support two different models for the source of adrenal stem/progenitor cells: the fetal adrenal and the adrenal capsule. Further studies are required to support or refute a unifying model whereby proposed transient cells arise from the
Acknowledgements
The authors thank Joanne H. Heaton for critical review and editing of this manuscript. This work was supported by National Institutes of Health (NIH) Grant DK062027 from National Institute of Diabetes and Digestive and Kidney Diseases (to G.D.H.) and Grant CA134606 from the National Cancer Institute (to G.D.H.); M.A.W was supported, by NIH Grant T32 DK07245 from theTraining Program in Endocrinology at the University of Michigan.
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