Sca-1 is a marker for cell plasticity in murine pancreatic epithelial cells and induced by IFN-β in vitro

Abstract

BACKGROUND & AIMS: Sca-1 is a surface marker for murine hematopoietic stem cells (HSCs) and type-I interferon is a key regulator for Lin$^{-}$Sca-1$^{+}$ HSCs expansion through Ifnar/Stat-1/Sca-1-signaling. In this study we aimed to characterize the role and regulation of Sca-1$^{+}$ cells in pancreatic regeneration.

METHODS: To characterize Sca-1 in vivo, immunohistochemistry and immunofluorescence staining of Sca-1 was conducted in normal pancreas, in cerulein-mediated acute pancreatitis, and in Kras-triggered cancerous lesions. Ifnar/Stat-1/Sca-1-signaling was studied in type-I IFN-treated epithelial explants of adult wildtype, Ifnar$^{-}$$^{/-}$, and Stat-1$^{-}$$^{/}$$^{-}$ mice. Sca-1 induction was analyzed by gene expression and FACS analysis. After isolation of pancreatic epithelial Lin$^{-}$Sca-1$^{+}$cells, pancreatosphere-formation and immunofluorescence-assays were carried out to investigate self-renewal and differentiation capabilities.

RESULTS: Sca-1$^{+}$ cells were located in periacinar and periductal spaces and showed an enrichment during cerulein-induced acute pancreatitis (23.2/100 μm$^{2}$ ± 4.9 SEM) and in early inflammation-mediated carcinogenic lesions of the pancreas of Kras$^{G12D}$ mice (35.8/100 μm$^{2}$ ± SEM 1.9) compared to controls (3.6/100 μm$^{2}$ ± 1.3 SEM). Pancreatic Lin$^{-}$Sca-1$^{+}$ cells displayed a small population of 1.46% ± 0.12 SEM in FACS. In IFN-β treated pancreatic epithelial explants, Sca-1 expression was increased, and Lin$^{-}$Sca-1$^{+}$ cells were enriched in vitro (from 1.49% ± 0.36 SEM to 3.85% ± 0.78 SEM). Lin$^{-}$Sca-1$^{+}$ cells showed a 12 to 51-fold higher capacity for clonal self-renewal compared to Lin$^{-}$Sca-1$^{-}$ cells and generated cells express markers of the acinar and ductal compartment.

CONCLUSIONS: Pancreatic Sca-1$^{+}$ cells enriched during parenchymal damage showed a significant capacity for cell renewal and in vitro plasticity, suggesting that corresponding to the type I interferon-dependent regulation of Lin$^{-}$Sca-1$^{+}$ hematopoietic stem cells, pancreatic Sca-1$^{+}$ cells also employ type-I-interferon for regulating progenitor-cell-homeostasis.