Single Cell Peptide Heterogeneity of Rat Islets of Langerhans

Measuring
the chemical composition of individual cells in mammalian
organs can provide critical insights toward understanding the mechanisms
leading to their normal and pathological function. In this work, single
cell heterogeneity of islets of Langerhans is characterized with high
throughput by microscopy-guided single cell matrix-assisted laser
desorption/ionization mass spectrometry. Two levels of chemical heterogeneity
were observed from the analysis of more than 3000 individual cells.
Within a single islet, cellular heterogeneity was evident from the
exclusive expression of the canonical biomarkers glucagon, insulin,
pancreatic polypeptide (PP), and somatostatin within α-, β-,
γ-, and δ-cells, respectively. We localized the neuropeptide
WE-14, a known cell-to-cell signaling molecule, to individual δ-cells.
Moreover, several unreported endogenous peptides generated by dibasic
site cleavages of PP were detected within individual γ-cells.
Of these, PP(27–36) was previously shown to activate the human
Y4 receptor, suggesting it has a signaling role in vivo. Heterogeneity in cell composition was also observed between islets
as evidenced by a 50-fold larger α-cell population in islets
of the dorsal pancreas compared to the ventral-derived pancreatic
islets. Finally, PP(27–36) was more abundant in γ-cells
from the ventral region of the pancreas, indicating differences in
the extent of PP-prohormone processing in the two regions of the pancreas.