Abstract
Ductal epithelium is primarily detected in porcine neonatal pancreatic cell clusters (NPCCs) bearing grafts, suggesting that transplants might exhibit progenitor-like phenotypes. Here we found that soon after NPCC isolation, PDX1+/insulin− and SOX9+ pancreatic progenitor-like cells dramatically increased while dual-hormonal progenitor-like cells were routinely observed in NPCC culture. After transplantation (Tx), insulin+ cells increased and PDX1+ and SOX9+ cells gradually decreased in both non-diabetic (NDM) and streptozotocin-induced diabetic (DM) grafts over 2 months. Strikingly, a significantly higher percentage of insulin+ cells were detected in 9-day and 16-day, but not in 23-day, 30-day and 60-day grafts implying that hyperglycemia could only facilitate NPCC-derived β cells early post-Tx. A higher percentage of NPCC-derived β cells in early DM grafts was determined via an enhanced neogenic differentiation based on the detection of insulin+ cells budding out from PDX1+/SOX9+ epithelium. Interestingly, a drop in SOX9+ progenitor-like cells was detected 16 days post-Tx in DM grafts whilst PDX1+ cells do not show a significant difference until 60 days post-Tx between DM and NDM grafts, demonstrating that distinct progenitor-like populations fuel new β cells post-Tx. In conclusion, PDX1+/SOX9+ cells could be quickly activated after NPCC isolation, maintain their multipotency in culture and differentiate into new β cell post-Tx.
Highlights
Series of studies have tested the role of potential islet differentiation triggers such as glucagon-like peptide 1 (GLP-1)[10], cholecystokinin (CCK)[11] and insulin-like growth factor-1 (IGF-1)[12] in promoting maturation of fetal islet-bearing grafts either in vitro[13,14] or in vivo[11,15] aiming to shorten the latent period between Tx and reversal of hyperglycemia
It is noteworthy that, regardless of ages of neonatal pigs, endocrine cell fate seems to dedifferentiate in response to neonatal pancreatic cell clusters (NPCCs) isolation procedure as insulin+, glucagon+ and PP+ cells are decreased after isolation compared to neonatal pig pancreas (Fig. 1D,F and Supplemental Fig. 2C) reflecting that NPCCs possess great plasticity for cellular dedifferentiation/redifferentiation
We demonstrated that when accompanied by enriched endocrine cells, the Pancreatic and duodenal homeobox 1 (PDX1)+/Sex-determining region Y-box containing gene 9 (SOX9)+ pancreatic progenitor-like cells could be activated during NPCC isolations and NPCC-derived precursor-like cells could maintain their multipotency in cultivation
Summary
Series of studies have tested the role of potential islet differentiation triggers such as glucagon-like peptide 1 (GLP-1)[10], cholecystokinin (CCK)[11] and insulin-like growth factor-1 (IGF-1)[12] in promoting maturation of fetal islet-bearing grafts either in vitro[13,14] or in vivo[11,15] aiming to shorten the latent period between Tx and reversal of hyperglycemia. Based on recent advances in understanding the molecular hierarchy in pancreatic organogenesis[16] and previous studies showing that 57% of in vitro cultivated NPCCs exhibited primarily epithelial progenitor-like phenotypes[4], we determined the expression of progenitor markers Pancreatic and duodenal homeobox 1 (PDX1) and Sex-determining region Y-box containing gene 9 (SOX9) in cultured NPCCs and NPCC grafts from both nondiabetic (NDM) and streptozotocin-induced diabetic (DM) receipt mice to better delineate a potential progenitor mediated β cell differentiation as well as a hyperglycemia mediated effect for porcine islet precursor-like cells
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