An Increase in Chromogranin A-Positive, Hormone-Negative Endocrine Cells in Pancreas in Cystic Fibrosis

Abstract

We sought to establish whether an increase in chromogranin A-positive, hormone-negative (CPHN) endocrine cells occurs in the pancreas of patients with cystic fibrosis (CF), as potential evidence of neogenesis. Pancreata were obtained at autopsy from nondiabetic patients with CF (n = 12) and age-matched nondiabetic control subject (CS) individuals without CF (n = 12). In addition, pancreas from three diabetic patients with CF was obtained. Pancreas sections were stained for chromogranin A, insulin, and a cocktail of glucagon, somatostatin, pancreatic polypeptide, and ghrelin and evaluated for the frequency of CPHN cells. There was a higher frequency of CPHN cells in islets of the patients with CF compared with the CS group. Moreover, CPHN cells occurring as single cells or clusters scattered in the exocrine pancreas were also more frequent in patients with CF. The increased frequency of CPHN cells in pancreas of patients with CF may indicate an attempt at endocrine cell regeneration.

Keywords: cystic fibrosis; inflammation; β cell.

Figure 1.

Islet endocrine compositions and frequency of CPHN cells in patients with CF and CF-D compared with the CS group. There was no change in islet composition in nondiabetic CF in terms of the total number of (A) endocrine cells per islet cross section (45.7 ± 5.7 vs 40.8 ± 5.1 vs 50.5 ± 4.4 total endocrine cells/islet section, CF-D vs CF vs CS, P = NS) and (B) endocrine cocktail cells (23.6 ± 4.8 vs 18.6 ± 3.1 vs 21.2 ± 2.4 endocrine cocktail cells/islet cross section, CF-D vs CF vs CS, P = NS). (C) There was, however, a decrease in the number of β cells per islet cross section in both diabetic and nondiabetic patients with CF (19.2 ± 2.1 vs 28.0 ± 2.7 β-cells/islet cross section, CF vs CS, P < 0.01 and 18.2 ± 2.6 vs 28.0 ± 2.7 β-cells/islet cross section, CF-D vs CS, P < 0.05). *P < 0.05, n = 12 (for CS and CF) and n = 3 (for CF-D).

Figure 2.

Example of a CPHN cell in the pancreas from (A) a nondiabetic CS and (B) a patient with CF. Individual layers, stained for insulin (white), endocrine cocktail (glucagon, somatostatin, pancreatic polypeptide, and ghrelin) (green), chromogranin A (red), and 4′,6-diamidino-2-phenylindole (DAPI) (blue), are shown along with the merged image. Insets show magnified images of the desired area (indicated by yellow squares) of low-power images to clearly locate the CPHN cells. Yellow arrows indicate the additional CPHN cells in CF cases. Scale bars, 50 μm. (C) The frequency of CPHN cells was increased in islets in patients with CF-D or CF compared with the nondiabetic CS group (0.4 ± 0.1 vs 0.1 ± 0.04 CPHN cells/islet section, CF vs CS, P < 0.05 and 0.5 ± 0.1 vs 0.1 ± 0.04 CPHN cells/islet section, CF-D vs CS, P < 0.05). The frequency of CPHN cells was also increased as (D) clustered cells (4.3 ± 1.0 vs 1.1 ± 0.2 clustered CPHN cells/mm², CF vs CS, P < 0.01 and 3.2 ± 1.8 vs 1.1 ± 0.2 cluster CPHN cells/mm², CF-D vs CS, P < 0.05) or as (E) single cells (3.6 ± 0.9 vs 1.0 ± 0.2 single CPHN cells/mm², CF vs CS, P < 0.01 and 3.2 ± 1.8 vs 0.9 ± 0.2 single CPHN cells/mm², CF-D vs CS, P < 0.05). *P < 0.05. **P < 0.01, n = 12 (for CS and CF) and n = 3 (for CF-D).