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SOX9+/PTF1A+ Cells Define the Tip Progenitor Cells of the Human Fetal Pancreas of the Second Trimester

Authors :
Valentina Villani
Matthew E. Thornton
Heather N. Zook
Christiana J. Crook
Brendan H. Grubbs
Giuseppe Orlando
Roger De Filippo
Hsun Teresa Ku
Laura Perin
Source :
Stem Cells Translational Medicine, Vol 8, Iss 12, Pp 1249-1264 (2019)
Publication Year :
2019
Publisher :
Oxford University Press, 2019.

Abstract

Abstract Significant progress has been made in recent years in characterizing human multipotent progenitor cells (hMPCs) of the early pancreas; however, the identity and persistence of these cells during the second trimester, after the initiation of branching morphogenesis, remain elusive. Additionally, studies on hMPCs have been hindered by few isolation methods that allow for the recovery of live cells. Here, we investigated the tip progenitor domain in the branched epithelium of human fetal pancreas between 13.5 and 17.5 gestational weeks by immunohistological staining. We also used a novel RNA‐based technology to isolate live cells followed by gene expression analyses. We identified cells co‐expressing SOX9 and PTF1A, two transcription factors known to be important for pancreatic MPCs, within the tips of the epithelium and observed a decrease in their proportions over time. Pancreatic SOX9+/PTF1A+ cells were enriched for MPC markers, including MYC and GATA6. These cells were proliferative and appeared active in branching morphogenesis and matrix remodeling, as evidenced by gene set enrichment analysis. We identified a hub of genes pertaining to the expanding tip progenitor niche, such as FOXF1, GLI3, TBX3, FGFR1, TGFBR2, ITGAV, ITGA2, and ITGB3. YAP1 of the Hippo pathway emerged as a highly enriched component within the SOX9+/PTF1A+ cells. Single‐cell RNA‐sequencing further corroborated the findings by identifying a cluster of SOX9+/PTF1A+ cells with multipotent characteristics. Based on these results, we propose that the SOX9+/PTF1A+ cells in the human pancreas are uncommitted MPC‐like cells that reside at the tips of the expanding pancreatic epithelium, directing self‐renewal and inducing pancreatic organogenesis. Stem Cells Translational Medicine 2019;8:1249&1264

Details

Language :
English
ISSN :
21576580 and 21576564
Volume :
8
Issue :
12
Database :
Directory of Open Access Journals
Journal :
Stem Cells Translational Medicine
Publication Type :
Academic Journal
Accession number :
edsdoj.86c086f4a8b140cd9a10a3ec0262e53e
Document Type :
article
Full Text :
https://doi.org/10.1002/sctm.19-0231