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

Georg Leinenkugel; Bo Kong; Susanne Raulefs; Katharina Miller; Susanne Roth; Hongdie Jiang; Rouzanna Istvánffy; Hanna Heikenwälder; Nadja Maeritz; Ivonne Regel; Ivane Abiatari; Jörg Kleeff; Christoph W Michalski; Simon Rieder

doi:10.1016/j.pan.2022.01.006

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

Pancreatology. 2022 Mar;22(2):294-303. doi: 10.1016/j.pan.2022.01.006. Epub 2022 Jan 13.

Authors

Affiliations

¹ Department of Gastroenterology and Hepatology, University Hospital Zurich, Switzerland. Electronic address: georg.leinenkugel@usz.ch.
² Department of General and Gastrointestinal Surgery, Ulm University Hospital, Ulm, Germany.
³ Department of Surgery, University Hospital of the Technical University, Munich, Germany.
⁴ Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany.
⁵ Department of Medicine II, University Hospital, LMU Munich, Munich, Germany.
⁶ Institute of Medical and Public Health Research, Ilia State University, Tbilisi, Georgia.
⁷ Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Hospital, Halle (Saale), Germany.

PMID: 35120820
DOI: 10.1016/j.pan.2022.01.006

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 μm² ± 4.9 SEM) and in early inflammation-mediated carcinogenic lesions of the pancreas of Kras^G12D mice (35.8/100 μm² ± SEM 1.9) compared to controls (3.6/100 μm² ± 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.

Keywords: Interferon; Lin(-)Sca-1(+) hematopoietic stem cells; Pancreatic progenitor cells; Sca-1.

MeSH terms

Acute Disease
Animals
Antigens, Ly / analysis
Antigens, Ly / genetics
Antigens, Ly / metabolism
Cell Plasticity*
Epithelial Cells
Humans
Membrane Proteins / genetics
Mice
Mice, Inbred C57BL
Pancreas / pathology
Pancreatitis* / chemically induced
Pancreatitis* / genetics
Pancreatitis* / pathology

Substances

Antigens, Ly
Membrane Proteins