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
Highlights
The developing mammalian pancreas has a highly organized structure, in which subpopulations of progenitor cells and lineage-committed cells can be identified based on their molecular profile and location within the pancreatic epithelium, following the initiation of branching morphogenesis
We propose that the SOX9+/PTF1A+ cells in the human pancreas are uncommitted multipotent progenitor cells (MPCs)-like cells that reside at the tips of the expanding pancreatic epithelium, directing self-renewal and inducing pancreatic organogenesis
We investigated the utility of the Smartflare technology to isolate and profile SOX9+/PTF1A+ cells in the human fetal pancreas during the second trimester
Summary
The developing mammalian pancreas has a highly organized structure, in which subpopulations of progenitor cells and lineage-committed cells can be identified based on their molecular profile and location within the pancreatic epithelium, following the initiation of branching morphogenesis. Pancreatic multipotent progenitor cells (MPCs) in the early mouse embryo are known to express several key transcription factors such as Pdx, Sox, and Ptf1a, which are indispensable for MPC establishment, maintenance, and proliferation [1,2,3,4]. Characterization of Human Pancreatic Progenitors e12.5 in the mouse [6], MPCs express Ptf1a and other transcription factors and are localized at the tips of the branching epithelium. These cells remain multipotent with the potentials to give rise to the three major pancreatic lineages, that is, endocrine, acinar, and ductal cells, until they become restricted to the acinar lineage [7]. Less is known about whether hMPCs persist in the second trimester, well after the first appearance of endocrine cells at 8WGA [24, 25]
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