Stem Cells, Self-Renewal, and Lineage Commitment in the Endocrine System

Abstract

The endocrine system coordinates a wide array of body functions mainly through secretion of hormones and their actions on target tissues. Over the last decades, a collective effort between developmental biologists, geneticists, and stem cell biologists has generated a wealth of knowledge related to the contribution of stem/progenitor cells to both organogenesis and self-renewal of endocrine organs. This review provides an up-to-date and comprehensive overview of the role of tissue stem cells in the development and self-renewal of endocrine organs. Pathways governing crucial steps in both development and stemness maintenance, and that are known to be frequently altered in a wide array of endocrine disorders, including cancer, are also described. Crucially, this plethora of information is being channeled into the development of potential new cell-based treatment modalities for endocrine-related illnesses, some of which have made it through clinical trials.

Keywords: development; plasticity; regenerative medicine; self-renewal; stem cells.

Figure 1

Morphogenesis of the mouse pituitary gland. Abbreviations: AL, anterior lobe; ANR, anterior neural ridge; IL, intermediate lobe; Inf, infundibulum; MZ, marginal zone; PL, posterior lobe; RP, Rathke's Pouch; VD, ventral diencephalon.

Figure 2

Molecular regulation of pituitary gland development. A succession of transcription factors (black) and signaling molecules (blue) determine the establishment of RP and the subsequent lineage specification and differentiation in the progenitor cells of the developing pituitary hormone-secreting cell types characteristic of the mature anterior pituitary gland: corticotrophs (ACTH), gonadotrophs (FSH and LH), thyrotrophs (TSH), somatotrophs (GH), and lactotrophs (PRL). The key lineage commitment makers are highlighted in red. Arrows indicate upstream relationships in molecular signaling pathways, not necessarily direct activation. Red T-bar arrows denote repressive relationships. Abbreviations: ACTH, adrenocorticotropic hormone; AL, anterior lobe; FSH, follicle-stimulating hormone; GH, growth hormone; IL, intermediate lobe; LH, luteinizing hormone; MZ, marginal zone; PL, posterior lobe; PRL, prolactin; RP, Rathke's pouch, VD; Ventral diencephalon.

Figure 3

Schematic representation of adrenal gland development. Cells from the adrenogonadal primordium (agp) form the adrenal and gonadal anlage. The adrenal anlage is invaded by migrating medullary progenitors who derive from early migrating neural crest-derived cells (NCCs, a minority in mice) and from late migrating Schwann cell precursors (SCPs). Concomitantly, the adrenal is encapsulated by mesenchymal cells. During late embryogenesis, definitive adrenal cells appears and will substitute fetal adrenal cells. IML: intermediolateral column (IML); NT, neural tube; n, notochord.

Figure 4

Schematic representation of post-natal adrenal cortex centripetal streaming and self-renewal in mice. Gli1⁺ cells in the capsule can give rise to Sf1⁺/Shh⁺ cortical cells: both are self-renewing adrenocortical progenitor cell populations. Shh⁺ cells can become ZG cells, and ZG cells can lineage convert to ZF cells, which migrate centripetally. Direct differentiation between Shh⁺ cells and ZF is probably occurring in parallel. These differentiation events are governed by pathways mostly active in the capsular/subcapsular region, while apoptotic figures are observed at the cortex/medulla boundary in senescence cells.

Figure 5

Thyroid/Parathyroid development. Follicular thyroid progenitor cells (orange) derive from the midline thyroid anlage (mta), an endodermal tissue in the floor of the pharynx just caudal to the 1st pharyngeal arch. The superior parathyroid glands (green) originate from the 4th brachial pouch while the inferior parathyroid (blue) and the thymus develop from the 3rd brachial pouch. C cells (red) differentiate from the ultimobrachial body, below the 4th brachial pouch.

Figure 6

Schematic representation of testis and ovary development. Cells from the adrenogonadal primordium (agp) form the gonadal anlagen. The gonadal anlagen is invaded by migrating primordial gem cells that derive from the region of the forming hindgut. Expression of Sry/Sox9, and Wnt4/Foxl2 determine gonad differentiation into testis or ovaries, respectively.

Figure 7

Schematic representation of factors affecting self-renewal and differentiation of spermatogonia in mice. Spermatogonia are classified as Asingle (As), Apaired (Apr), and Aaligned (Aal) according to the number of cells contained in a syncytium. In steady-state, a subset of Gfrα1/Nanos2 expressing cells function as stem cells with the ability to self-renew their population. Gfrα1⁺ spermatogonia have the ability to generate cells that lose the expression of Gfrα1 and become Ngn3⁺/Rarγ⁺/Miwi2⁺, which can retain the stem cell potential but mostly become Kit⁺ cells, and therefore are committed to terminal differentiation. In regenerative contexts, Ngn3⁺/Rarγ⁺/Miwi2⁺ can regain Gfrα1 expression contributing to the self-renewing pool.

Figure 8

Schematic representation of ovary development. Primordial germ cells (PGCs) colonize the gonadal primordium and undergo mitotic division with incomplete cytokinesis producing cysts. Subsequently, germ cell cysts undergo breakdown to produce primordial follicles, consisting of a single oocyte surrounded by pre-granulosa cells. During sexual maturation, primordial follicles develop further eventually becoming potential fertilizable eggs at sexual maturity.

Figure 9

Schematic representation of murine pancreatic development. Multipotential Pancreatic Cells (MPC) (pink) and acinar cells (purple) are located at the tip of the pancreatic epithelium. The trunk contains endocrine/ductal bipotent progenitors (light blue) that migrate out of the epithelium and differentiate to endocrine progenitor cells (orange) which give rise to hormone positive cells (green cells). Endocrine commitment is driven by inhibition of Notch, Wnt, Tgf-β, Hippo, and Bmp signaling pathways.