**2.4. Substances synthesized by C cells**

54 Thyroid Hormone

thyroid gland. 200x.

and cats [17].

colloid by the cytoplasm of follicular cells and the basal aspects of C cells are usually in contact with follicular basal lamina. Occasionally, C cells emit cytoplasmic processes that surround adjacent follicular cells (see Figure 3). At ultrastructural level, many dense

**Figure 2.** Visualization of C cells using an immunohistochemical method for calcitonin. (A) Human thyroid gland; (B) Rat thyroid gland. C cells are more abundant in rat in comparison with the human

**Figure 3.** Immunohistochemical demonstration of C cells in the normal rat thyroid gland. (A) Immunostaining for calcitonin followed by the PAS method for carbohydrates. (B) Double

them are also immunopositive for somatostatin. This somatostatin-positive C cell exhibits a

cytoplasmatic process surrounding neighbouring follicular cells. (x500).

immunostaining for calcitonin (red) and somatostatin (brown). In Fig.A, the "parafollicular" ubication of C cells can be observed. In Fig. B, all C cells are immunostained for calcitonin but only very few of

The distribution of C cells within the thyroid lobes has also been reported to vary among species. In most species, C cells are located primarily in the centre of thyroid lobes, including humans [15, 16], mice [17], rats [18] and rabbits [17]. The area where C cells predominate has been termed as 'C-cell region' [19], which is also the place where the mostactive follicles of the gland predominate [20]. In general, portions of the thyroid containing the highest concentration of C cells correspond to the typical fusion sites of between the UBB and the medial thyroid anlage. As another reminder of their embryonic origin, C cells could also be located within the parathyroid gland and thymus in some species, such as rabbits

secretory granules are observed in the cytoplasm of C cells [13, 14].

The C cells share with other neuroendocrine cells the expression of different characteristic neuroendocrine markers, such as chromogranin, synaptophysin and NSE, with chromogranin A as the most reliable marker generally used to characterize cells of DNES (see Figure 4). Most of those neuroendocrine markers are shared with different populations of nervous cells (Table 1).


**Table 1.** Characteristic substances identified in different neuroendocrine cells, including C cells, according to a chronological order.

In addition to calcitonin, C cells may also contain many other regulatory peptides (Table 2), such as calcitonin gene-related peptide (CGRP) [30], katacalcin [31] or GRP [32]. Somatostatin has also been identified within C cells of most species. In the adult rabbits, bats and guinea pigs, most calcitonin-positive cells also contain somatostatin; however, in adult human and rat thyroid glands, only a small proportion of the calcitonin-positive cells are also somatostatin positive [33]. Similarly, peptides including neuromedin U [34] and helodermin-like peptide [35], have been demonstrated to colocalize with CT in normal C cells. Lately, a new generation of regulatory peptides, similar to those characteristically found in some hypothalamic nuclei, such as TRH [36], CART [37] or ghrelin [38], has increased the long list of substances synthesized by C cells.

Paracrine Regulation of Thyroid-Hormone Synthesis by C Cells 57

Rat Braas et al., 1992 [52]

Rat Darlington et al., 1997 [54]

2000 [55]

Kameda et al., 2007 [10, 53]

Martín-Lacave and Utrilla,

In addition to the regulatory peptide products, C cells also contain a variety of biologically active amines including serotonin [41] and melatonin [45] (see Table 2). Additionally, C cells are also implicated in the synthesis of many other different substances, such as tetranectin

**CEA (***Carcinoembryonic Antigen***)** Human Kodama et al., 1980 [51] **Tetranectin** Human Christensen et al., 1987 [50]

**E-cadherin** Rat Nishiyama et al., 1996 [10, 53];

guinea pig

Apart from their role in calcium homeostasis, C cells are also probably involved in the intrathyroidal regulation of follicular cells. This hypothesis is supported by different features, such as their characteristic 'parafollicular' position, their predominance in the central region of the thyroid lobe – the so-called "C-cell region" [19]– where the most-active follicles of the gland predominate [20], and their implication in the secretion of many different regulatory factors [1, 46, 56]. Some of these regulatory peptides display an inhibiting action on thyroid hormone secretion, such as calcitonin, calcitonin gene-related peptide (CGRP) and somatostatin [1], whereas others act as local stimulators of thyroid hormone synthesis, such as gastrin-releasing peptide (GRP), helodermin, and serotonin [35, 57, 58]. For any of those peptides, a requirement to exert an effective paracrine regulation of follicular cells is the presence of their specific receptors in this endocrine cell population. At this point, the existence of some of those receptors on follicular cells, such as somatostatin or serotonin receptors, has already been described [58, 59]. Furthermore, we have recently

There is additional evidence that C cells and follicular cells somehow interact functionally. Thus, C cells, in the normal-appearing thyroid tissue adjacent to follicular tumours, have been reported to display reactive changes. These changes may include the development of a C cell hyperplasia [61] or the presence of an increased percentage of immunopositive C cells for GRP [32] or somatostatin [62], being the latter a potent inhibitor of TSH-enhanced mitotic activity and T3 and T4 synthesis by follicular cells. Moreover, we have found hyperplastic changes in the C-cell population of rat thyroid glands in a model of non-hypercalcemic hypothyroidism induced by propylthiouracil administration [63]. As we have recently

**NCAM (***Neural Cell Adhesion Molecule***)** Rat Nishiyama et al., 1996 [53]

**Table 3.** Other substances synthesized by C cells, according to a chronological order.

demonstrated the expression of TRH-receptor on follicular cells [60].

**Other substances Species Authors**

[50] or CEA [51] (see Table 3).

*Monooxygenase***)** 

*Protein 18***)** 

**PAM (***Peptidylglycine Alpha-amidating* 

**RESP18 (***Regulated Endocrine-Specific* 

**2.5. Paracrine role played by C cells** 

**c-erbB-2-like product** Human,

**Figure 4.** Immunohistochemical demonstration of chromogranin A (A), calcitonin (B) and CGRP (C) in consecutive sections of the rat thyroid gland. All C cells express the different markers, being slightly less intense CGRP-positive C cells. (x400).


**Table 2.** Regulatory factors identified in the cytoplasm of C cells, according to a chronological order.

In addition to the regulatory peptide products, C cells also contain a variety of biologically active amines including serotonin [41] and melatonin [45] (see Table 2). Additionally, C cells are also implicated in the synthesis of many other different substances, such as tetranectin [50] or CEA [51] (see Table 3).


**Table 3.** Other substances synthesized by C cells, according to a chronological order.
