Abstract
Background and Aims: An interactive regulatory network assembled through the induction and downregulation of distinct transcription factors governs acinar cell maturation. Understanding how this network is built is relevant for protocols of directed pancreatic acinar differentiation. The murine transcription factor Prox1 is highly expressed in multipotent pancreatic progenitors and in various mature pancreatic cell types except for acinar cells. In this study, we investigated when is Prox1 expression terminated in developing acinar cells and the potential involvement of its activity in acinar cell specification/differentiation. We also investigated the effects of sustained Prox1 expression in acinar maturation and maintenance. Methods: Prox1 acinar expression was analyzed by immunofluorescence and confocal microscopy. Prox1-null embryos (Prox1GFPCre/Δ), Prox1AcOE transgenic mice, histologic and immunostaining methods, transmission electron microscopy, functional assays, and quantitative RNA and RNA-sequencing methods were used to investigate the effects of Prox1 functional deficiency and sustained Prox1 expression in acinar maturation and homeostasis. Results: Immunostaining results reveal transient Prox1 expression in newly committed embryonic acinar cells. RNA-sequencing demonstrate precocious expression of multiple “late” acinar genes in the pancreas of Prox1GFPCre/Δ embryos. Prox1AcOE transgenic mice carrying sustained Prox1 acinar expression have relatively normal pancreas development. In contrast, Prox1AcOE adult mice have severe pancreatic alterations involving reduced acinar gene expression, abnormal acinar secretory granules, acinar atrophy, increased endoplasmic reticulum stress, and mild chronic inflammation. Conclusion: Prox1 transient expression in early acinar cells is necessary for correct sequential gene expression. Prox1 expression is terminated in developing acinar cells to complete maturation and to preserve homeostasis.
Original language | English (US) |
---|---|
Pages (from-to) | 807-823 |
Number of pages | 17 |
Journal | Gastro Hep Advances |
Volume | 1 |
Issue number | 5 |
DOIs | |
State | Published - Jan 2022 |
Funding
Funding: This study was funded by Northwestern University Feinberg Medical School, National Institutes of Health / National Institute of Diabetes and Digestive and Kidney Diseases grant RO1 DK106266 (BS-P), and Northwestern University's Center for Advanced Microscopy/Cancer Center Support Grant ( NCI CA060553 ).
Keywords
- Acinar Cell
- Maturation
- Prox1
ASJC Scopus subject areas
- Medicine (miscellaneous)
- Gastroenterology
- Hepatology