Differentiation and Regeneration of Adrenal Tissues: An Initial Step toward Regeneration Therapy for Steroid Insufficiency

Abstract

Abstract. In animal experiments, adrenal cortical tissue has been successfully regenerated through xenotransplantation of cloned adrenocortical cells, suggesting that the intraadrenal stem cells required for such tissue formation may be present in the adrenal cortex. Stable expression of Ad4BP/SF-1, a key factor for adrenal and gonadal development and steroidogenesis, has been shown to direct embryonic stem cells toward the steroidogenic lineage. However, this steroidogenic capacity was very limited since progesterone was only produced in the presence of an exogenous substrate. Bone marrow mesenchymal cells are thought to contain pluripotent progenitor cells, which differentiate into multiple lineages. We have demonstrated that adenovirus-mediated forced expression of SF-1 in long-term cultured bone marrow cells can produce steroidogenic cells with the capacity for de novo synthesis of various steroid hormones in response to ACTH. This discovery may represent the first step in autologous cell transplantation therapy for patients with steroid hormone deficiency.

Steroidogenic factor 1/adrenal 4 binding protein transforms human bone marrow mesenchymal cells into steroidogenic cells

“…As in mouse cells (Gondo et al 2004), the steroid profile of cultured human BMCs showed a mixed pattern of adrenal and gonadal steroidogenesis, namely the simultaneous production of cortisol and sex steroids. This finding matches well an established concept that common precursor cells divide into two distinct characteristic cell types, designated adrenal precursor cells and bipotential gonadal precursor cells, and finally develop into the adrenal cortex or testes and ovaries, respectively, under the regulation of many transcriptional factors, including SF-1 (Yanase et al 2006).…”

“…In humans, sex-determining region Y (SRY) initiates the testis-determining pathway by inducing the expression of a series of downstream factors, including SF-1, WT1, DAX-1, SRY-related genes HMG-box 9, and several other factors, thus resulting in a male phenotype (Yanase et al 2006). In this pathway, SF-1 has been considered to be a master regulator that controls the overall stream of the developmental mechanism.…”

“…Our finding that only SF-1 among SF-1, WT1, DAX-1, PBX-1, CITED2, and WNT4 could transform human BMCs into steroidogenic cells suggested that SF-1 is truly a master regulator, even for the production of steroidogenic cells from human mesenchymal BMCs. However, it is also important to test the functional relationship between SF-1 and other factors involved in steroidogenesis by multiple transfections, because sexual differentiation takes place in a series of cascades of various factors (Yanase et al 2006). Such detailed experiments are currently underway in our laboratory.…”

Regulation of Steroidogenesis, Development, and Cell Differentiation by Steroidogenic Factor-1 and Liver Receptor Homolog-1

“…This method can also differentiate human BM-MSCs into cortisol-producing cells in response to adrenocorticotropic hormone stimulation, which are similar to the zona fasciculata cells of the adrenal gland. Additionally, BM-MSCs transform to steroidogenic cells by adenovirus-mediated transient expression of SF-1 Tanaka et al, 2007;Wei et al, 2012;Yanase et al, 2006). These studies are consistent with the concept that SF-1 is a master regulator for steroidogenesis.…”

Adrenarche: a cell biological perspective

“…Some evidence that MSCs could differentiate to steroidogenic cells was obtained via transplantation of bone marrow MSCs into the testis (Yazawa et al 2006). Human and mouse MSCs, derived from bone marrow or fat, become capable of expressing steroidogenic genes and of synthesizing several steroids following forced expression of SF-1 or LRH-1 (NR5A2; Yanase et al 2006, Tanaka et al 2007, Gondo et al 2008, Yazawa et al 2009). Importantly, forced expression of SF-1 in mesenchymal cells produced cells capable of secreting DHEA as well as other adrenocortical steroids (Tanaka et al 2007, Gondo et al 2008.…”