Decrease of parafollicular thyroid C-cells in experimental esophageal atresia: further evidence of a neural crest pathogenic pathway

Abstract

Adriamycin-induced experimental esophageal atresia (EA) is often associated with malformations of neural crest (NC) origin, such as abnormal pharyngeal pouch derivatives like the thymus and the parathyroids. The aim of the present study was to examine whether NC-derived thyroid C-cells were abnormal in a rat model. Pregnant rats received intraperitoneally either 2 mg/kg Adriamycin (EA) or vehicle (controls) on days 8 and 9 of gestation. Fetuses were recovered on day 21, and blocks including the trachea and thyroid were fixed in formalin, coronally sectioned at 3-mum widths, and stained with standard hematoxylin and eosin until the largest area of thyroid was reached. From this point on, the 1st, 10th, and 20th slices were immunohistochemically stained with anti-calcitonin antibody. Positively-stained cells in each section of the gland were counted using a computer-assisted image analysis method, and the results were averaged. The distribution of the cells within the gland was assessed as well. Comparisons between EA and control rats were made by nonparametric tests with a significance threshold of p<0.05. The number of C-cells was dramatically reduced in EA animals compared with controls (32.4+/-36 vs. 92.3+/-60.5, p<0.001). Histology of the thyroid was similar in both groups, but the distribution of positive C-cells within the gland followed an abnormal pattern in EA rats. Adriamycin causes a pattern of NC-derived malformations, including a severe decrease in thyroid C-cells accompanied by abnormal distribution or migration patterns. These results represent further evidence of the involvement of NC organogenic control dysregulation in the pathogenesis of EA and its associated malformations. The similarities between the rat model and the clinical picture strongly support investigating other subclinical NC-derived anomalies in patients with EA.

Tenascin C in medullary thyroid microcarcinoma and C-cell hyperplasia

“…No correlation was seen between intracellular Tn-C expression with any of the investigated clinicopathologic parameters and stromal Tn-C expression. Due to the expression of tenascin in neural crest cells, the expression in C cells may be an incidental phenomenon due to its neurocrest origin [36][37][38][39].…”

Parafollicular C-Cells of the Thyroid are Decreased in Patients with Congenital Diaphragmatic Hernia

“…The scarcity of thyroid CC in infants with CDH represents the fi rst evidence of yet another neural crest signaling anomaly in CDH patients, mediated very likely by similar dysfunctions in embryogenic control. It should be pointed out that CC scarcity has been found in other human conditions where NC signaling was defi cient such as DiGeorge syndrome or conotruncal cardiac defects [10,11] , and also in a rat model of esophageal atresia where elements of NC control dysfunction are present as well [33] .…”

The neural crest in pediatric surgery

“…In the experimental setting, it has been shown that rats exposed in utero to adriamycin have EA-TEF and very high proportions of absence, hypoplasia or ectopy of the thymus, and parathyroids [81]. We recently investigated the C-cells of the thyroid in this rat model and found that they were drastically reduced in animals with EA-TEF [82]. We do not know whether this happens in patients with EA-TEF, but there is some evidence pointing in that direction: the autopsies of 11 cases of Di George syndrome from our own institution (several of which had EA-TEF) showed decreased number of C-cells in their thyroids [83], and similar findings were reported for patients with conotruncal heart malformations that are frequently associated to EA-TEF [84].…”