Somatotroph to thyrotroph cell transdifferentiation during experimental hypothyroidism ‐ a light and electron‐microscopy study

Abstract

Somatotroph and thyrotroph pituitary cells share a common precursor cell expressing the transcription factor Pit1 in ontogeny. Cells expressing both thyrotropin (TSH) and growth-hormone (GH) are found in adult rat pituitary and in human pituitary adenomas in acromegaly, and these tumors contain both thyrotropin-releasing hormone (TRH) and the TRH receptors (TRHR). It has been shown that stimulation of TSH expression in primary hypothyroidism promotes changes suggestive of somatotroph to thyrotroph cell transdifferentiation. We tested this hypothesis and the role of TRH in experimental primary hypothyroidism in rats. Adult female Long-Evans rats, 6 months old, were administered the antithyroid drug methimazole (0,1% w/v) in the drinking water for 42 days. Animals were sacrificed by perfusion fixation under anaesthesia at weekly intervals and pituitary tissue processed in acrylic resin for immunofluorescence and immuno-electronmicroscopy for TSH, GH and TRHR. In the hypothyroid rat pituitary immunofluorescent somatotrophs were greatly reduced in number and gradually replaced by thyrotrophs during methimazole administration. Colocalization of GH and TSH in the same cell was noted. Immunoelectronmicroscopy demonstrated the development of enlarged thyrotrophs with dilated rough endoplasmic reticulum containing an electron-dense material and intracisternal granules, both of which are immunoreactive for TSH ('thyroidectomy cells'). The somatotrophs showed reduced GH immunoreactivity and also the presence of TSH-type, small-size secretory granules. This suggests that the greatly increased number of TSH-cells in methimazole-induced-hypothyroidism is due, at least partially, to the transdifferentiation of somatotroph into thyrotroph cells. TRHR immunofluorescence was expressed in many somatotrophs in normal rat pituitary and unlike immunoreactive GH, its expression was enhanced during hypothyroidism. The number of TRHR-immunoreactive cells increased in parallel with the number of TSH-immunoreactive cells. This indicates a role for TRH stimulation in the transdifferentiation process. Taken together, these data suggest that, in addition to the cell mutation mechanism involving an early totipotential progenitor cell, transdifferentiation of existing somatotroph cells also plays a part in the pathogenesis of multihormonal GH-secreting adenomas.

FOXL2 versus SOX9: A lifelong “battle of the sexes”

“…Co-expression of GH and TSH in the same cell and a reduction of GH signal in somatotrophs suggest that the increased number of TSH cells results, at least in part, from the transdifferentiation of somatotrophs. [45] Conversion of lactotrophs into somatotrophs (which also share the same precursors) has also been reported. [43] The rapidity of the transdifferentiation process of follicle cells is also worth noting.…”

“…It would be interesting to explore the transcriptome (and, more interestingly, the proteome) of follicular cells in the period when neither Foxl2 nor Sox9 are expressed, in order to assess whether these cells are temporarily ''bifunctional,'' as proposed in cases of transdifferentiation in the context of pituitary cell lineages. [43][44][45] This would still be compatible with the idea of toggle switch, because a proteomic switch should take some time (i.e., synthesis of new proteins and decay of old ones). Transdifferentiation has been proposed to occur in the pituitary.…”

Central Hypothyroidism in Children

“…Actually transient CCH is described in children born from mothers with gestational hyperthyroidism. Transiency of this phenotype and the recovery of thyrotrope numbers after cessation of T 4 excess points towards a relevant plasticity of the pituitary tissue, which may involve transdifferentiation between different pituitary cell types when necessary, in this particular case from somatotropes towards thyrotropes [42,43].…”

Neuronal Differentiation and Expression of Neural Epitopes in Pituitary Adenomas

“…Diethylstilbestrol increases lactotrophs by transdifferentiation of gonadotrophic cells (Shukuwa et al 2006). Somatotroph conversion into thyrotrophs after experimental production of a hypothyroid state has also been described (Radian et al 2003). Adenoma cell transdifferentiation into neurons has not been established, but adenoma cells are known to express some neuronal epitopes, particularly synaptophysin (Pierret et al 2006), and may have that potential.…”