Yuzuru Ishimura

The undifferentiated cell zone is a stem cell zone in adult rat adrenal cortex

The adrenal cortex of mammals has been known to consist of three morphologically and functionally distinct zones, i.e. the zona glomerulosa (zG), the zona fasciculata (zF) and the zona reticularis (zR), each of which secretes a specific corticosteroid different from those produced by the other two zones. We found previously, however, that an additional zone existed between zG and zF of adult rat adrenal cortex and that the cells in that zone were in a functionally undifferentiated state as an adrenocortical cell [Endocrinology 135, (1994) 431]: they were incapable of synthesizing highly active forms of corticosteroids, such as aldosterone and corticosterone, although they could produce their precursors. Hence, we named the zone as the undifferentiated cell zone (zU) of the adrenal cortex. Here we show that zU and its surroundings, i.e. the innermost portion of zG and the outermost portion of zF are the sites for cell replication in adult rat adrenal cortex and that the cells raised there migrate to other regions. Such cell replications in this region occur regardless of physiological conditions, such as the rise and fall of hormonal stimuli and circadian fluctuation of adrenocortical activities. On the bases of these and other findings previously described, we propose that zU is the stem cell zone of the adult rat adrenal cortex. Our recent success in isolating novel cell lines, which display an undifferentiated phenotype similar to that of zU cells, could facilitate the exploration of molecular mechanisms for the differentiation and development of the adrenocortical cells.

Steroid monooxygenases as markers for studying functional zonation in the adrenal cortex

Abstract Aldosterone synthase cytochrome P450 (P450aldo) and corticosteroid 11β hydroxylase (P45011β) are the monooxygenases which localize in the zona glomerulosa and the zonae fasciculata–reticularis of the adrenal cortex, respectively. The former enzyme catalyzes the formation of the strongest mineralocorticoid, aldosterone, and the latter synthesizes the two major glucocorticoids, corticosterone and cortisol, from their respective precursors. Employing these two monooxygenases as markers for each adrenocortical zone, we investigated the molecular basis for the functional zonation and developmental processes of rat adrenal cortex. The results indicated that the specific function of each zone in rats as well as in humans is attributable to the expression of three monooxygenases, P450aldo, P45011β and steroid 17α-hydroxylase (P45017α,lyase) in the component cells. This is in contrast with the fact that the specific functions of the zona glomerulosa and the zona fasciculata are determined by a protein–protein interaction between P450scc and P45011β in bovine adrenal cortex [S. Ikushiro et al., J. Biol. Chem. 267 (1992) 1464]. Furthermore, we found the presence of the fourth zone between the zona glomerulosa and the zona fasciculata in rat adrenal cortex and named it the undifferentiated cell zone; it turned out to be the stem cell zone which replenishes cells to each zone of adult rat adrenal cortex. Analyses of the developmental processes from fetal to adulthood and of the regeneration process of the enucleated adrenal cortex were also described.