Recent Insights into the Cell Biology of Thyroid Angiofollicular Units

Abstract

In thyrocytes, cell polarity is of crucial importance for proper thyroid function. Many intrinsic mechanisms of self-regulation control how the key players involved in thyroid hormone (TH) biosynthesis interact in apical microvilli, so that hazardous biochemical processes may occur without detriment to the cell. In some pathological conditions, this enzymatic complex is disrupted, with some components abnormally activated into the cytoplasm, which can lead to further morphological and functional breakdown. When iodine intake is altered, autoregulatory mechanisms outside the thyrocytes are activated. They involve adjacent capillaries that, together with thyrocytes, form the angiofollicular units (AFUs) that can be considered as the functional and morphological units of the thyroid. In response to iodine shortage, a rapid expansion of the microvasculature occurs, which, in addition to nutrients and oxygen, optimizes iodide supply. These changes are triggered by angiogenic signals released from thyrocytes via a reactive oxygen species/hypoxia-inducible factor/vascular endothelial growth factor pathway. When intra- and extrathyrocyte autoregulation fails, other forms of adaptation arise, such as euthyroid goiters. From onset, goiters are morphologically and functionally heterogeneous due to the polyclonal nature of the cells, with nodules distributed around areas of quiescent AFUs containing globules of compact thyroglobulin (Tg) and surrounded by a hypotrophic microvasculature. Upon TSH stimulation, quiescent AFUs are activated with Tg globules undergoing fragmentation into soluble Tg, proteins involved in TH biosynthesis being expressed and the local microvascular network extending. Over time and depending on physiological needs, AFUs may undergo repetitive phases of high, moderate, or low cell and tissue activity, which may ultimately culminate in multinodular goiters.

Comprehensive Review of Thyroid Embryology, Anatomy, Histology, and Physiology for Surgeons

“…The pituitary portal system then delivers TRH to the anterior pituitary gland, where TSH (also Thyroid hormones (T4 and T3) wield a negative feedback effect on this step as well. Once it is released from the anterior pituitary gland, TSH binds to TSH receptors (TSHR) on the basal membrane of the thyroid follicular cells, which activates an intracellular cascade, including the activation of adenylate cyclase [64] [92] [93]. The subsequent increase in cyclic adenosine monophosphate (cAMP) fuels nearly every step in thyroid hormone synthesis, including iodine uptake, synthesis of thyroglobulin, organification and coupling, and follicular cell uptake of thyroglobulin from the colloid [93].…”

Thyroid follicle development requires Smad1/Smad5- and endothelial-dependent basement membrane assembly

“…In the mature thyroid, a dense network of blood vessels surrounds each follicle. Together, they form angiofollicular units responsible for T 3 and T 4 thyroid hormone synthesis and storage within luminal Tg, and then hormone secretion into the bloodstream (Colin et al, 2013;Nilsson and Fagman, 2013). A limited number of transcription factors (Nkx2.1, Pax8, Foxe1 and Hhex) and signaling molecules are known to control thyroid development (Fagman and Nilsson, 2010), but the molecular and subcellular morphogenetic machineries regulating follicle formation remain essentially unknown.…”

Timing of Thyroxine Dose Adjustment in Hypothyroid Patients: When are TSH Levels Stable?

“…In addition, TSH exerts its action at the transcription level and influences the hypertrophy and hyperplasia of follicular cells. These adaptive responses result in a prolonged elevation of TSH levels, so that the full effect of thyroid hormone replacement on TSH does not become apparent for a number of weeks [10,11].…”