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

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 mu m(2) +/- 4.9 SEM) and in early inflammation-mediated carcinogenic lesions of the pancreas of Kras(G12D) mice (35.8/100 mu m(2) +/- SEM 1.9) compared to controls (3.6/100 mu m(2) +/- 1.3 SEM). Pancreatic Lin(-)Sca-1(+) cells displayed a small population of 1.46% +/- 0.12 SEM in FACS. In IFN-beta 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. (C) 2022 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC.