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Abstract
Surrogate β-cells derived from stem cells are needed to cure type 1 diabetes, and neonatal liver cells may be an attractive alternative to stem cells for the generation of β-cells. In this study, we attempted to generate insulin-producing cells from neonatal porcine liver-derived cells using adenoviruses carrying three genes: pancreatic and duodenal homeobox factor1 (PDX1)/VP16, BETA2/NeuroD and v-maf musculo aponeurotic fibrosarcoma oncogene homolog A (MafA), which are all known to play critical roles in pancreatic development. Isolated neonatal porcine liver-derived cells were sequentially transduced with triple adenoviruses and grown in induction medium containing a high concentration of glucose, epidermal growth factors, nicotinamide and a low concentration of serum following the induction of aggregation for further maturation. We noted that the cells displayed a number of molecular characteristics of pancreatic β-cells, including expressing several transcription factors necessary for β-cell development and function. In addition, these cells synthesized and physiologically secreted insulin. Transplanting these differentiated cells into streptozotocin-induced immunodeficient diabetic mice led to the reversal of hyperglycemia, and more than 18% of the cells in the grafts expressed insulin at 6 weeks after transplantation. These data suggested that neonatal porcine liver-derived cells can be differentiated into functional insulin-producing cells under the culture conditions presented in this report and indicated that neonatal porcine liver-derived cells (NPLCs) might be useful as a potential source of cells for β-cell replacement therapy in efforts to cure type I diabetes.
Highlights
Pancreatic islet cell transplantation has proven effective in achieving insulin-independent persistent normoglycemia in patients with diabetes since the Edmonton protocol was reported by Shapiro [1]
The CCK-8 assay was performed 3 days after isolation, and the results indicated that neonatal porcine liverderived cells (NPLCs) included a greater number of viable cells than adult hepatocytes under normal growth conditions (Figure 1D)
This study clearly demonstrated that neonatal porcine liverderived cells (NPLCs) could be transdifferentiated into functional insulin-producing cells under the described culture conditions
Summary
Pancreatic islet cell transplantation has proven effective in achieving insulin-independent persistent normoglycemia in patients with diabetes since the Edmonton protocol was reported by Shapiro [1]. This significant progress in diabetes treatment is limited by the shortage of donor organs and the need to follow a lifelong immunosuppressive regimen [2]. Pancreatic endocrine differentiation is induced by the sequential expression of specific transcription factors (TFs) during development [9,10]. Many researchers have reported a critical role of other transcription factors, including BETA2/NeuroD [13,14,15] and MafA [16,17], in b-cell differentiation. The combination of these three TFs is considered a useful tool for the transdifferentiation of non-b-cells [18]
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