Claudia Cavelti-Weder1, Weida Li2,3, Adrian Zumsteg3, Marianne Stemann-Andersen1, Yuemei Zhang3, Takatsugu Yamada1, Max Wang3, Jiaqi Lu3, Agnes Jermendy1, Yong Mong Bee1, Susan Bonner-Weir1, Gordon C Weir1, Qiao Zhou4. 1. Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard University, Boston, MA, USA. 2. Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Life Sciences and Technology, Shanghai, The People's Republic of China. 3. Department of Stem Cell and Regenerative Biology, Harvard University, Sherman Fairchild 258C, 7 Divinity Ave, Cambridge, MA, 02138, USA. 4. Department of Stem Cell and Regenerative Biology, Harvard University, Sherman Fairchild 258C, 7 Divinity Ave, Cambridge, MA, 02138, USA. qiao_zhou@harvard.edu.
Abstract
AIMS/HYPOTHESIS: Reprogramming of pancreatic exocrine to insulin-producing cells by viral delivery of the genes encoding transcription factors neurogenin-3 (Ngn3), pancreas/duodenum homeobox protein 1 (Pdx1) and MafA is an efficient method for reversing diabetes in murine models. The variables that modulate reprogramming success are currently ill-defined. METHODS: Here, we assess the impact of glycaemia on in vivo reprogramming in a mouse model of streptozotocin-induced beta cell ablation, using subsequent islet transplantation or insulin pellet implantation for creation of groups with differing levels of glycaemia before viral delivery of transcription factors. RESULTS: We observed that hyperglycaemia significantly impaired reprogramming of exocrine to insulin-producing cells in their quantity, differentiation status and function. With hyperglycaemia, the reprogramming of acinar towards beta cells was less complete. Moreover, inflammatory tissue changes within the exocrine pancreas including macrophage accumulation were found, which may represent the tissue's response to clear the pancreas from insufficiently reprogrammed cells. CONCLUSIONS/ INTERPRETATION: Our findings shed light on normoglycaemia as a prerequisite for optimal reprogramming success in a diabetes model, which might be important in other tissue engineering approaches and disease models, potentially facilitating their translational applications.
AIMS/HYPOTHESIS: Reprogramming of pancreatic exocrine to insulin-producing cells by viral delivery of the genes encoding transcription factors neurogenin-3 (Ngn3), pancreas/duodenum homeobox protein 1 (Pdx1) and MafA is an efficient method for reversing diabetes in murine models. The variables that modulate reprogramming success are currently ill-defined. METHODS: Here, we assess the impact of glycaemia on in vivo reprogramming in a mouse model of streptozotocin-induced beta cell ablation, using subsequent islet transplantation or insulin pellet implantation for creation of groups with differing levels of glycaemia before viral delivery of transcription factors. RESULTS: We observed that hyperglycaemia significantly impaired reprogramming of exocrine to insulin-producing cells in their quantity, differentiation status and function. With hyperglycaemia, the reprogramming of acinar towards beta cells was less complete. Moreover, inflammatory tissue changes within the exocrine pancreas including macrophage accumulation were found, which may represent the tissue's response to clear the pancreas from insufficiently reprogrammed cells. CONCLUSIONS/ INTERPRETATION: Our findings shed light on normoglycaemia as a prerequisite for optimal reprogramming success in a diabetes model, which might be important in other tissue engineering approaches and disease models, potentially facilitating their translational applications.
Entities:
Keywords:
Diabetes; Exocrine to beta cell reprogramming; Hyperglycaemia
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