CHAPTER SIX
From Pancreas Morphogenesis to b-Cell Regeneration Fabio Avolio*,†,{, Anja Pfeifer*,†,{, Monica Courtney*,†,{, Elisabet Gjernes*,†,{, Nouha Ben-Othman*,†,{, Andhira Vieira*,†,{, Noémie Druelle*,†,{, Biljana Faurite*,†,{, Patrick Collombat*,†,{,1 *Univ. Nice Sophia Antipolis, iBV, UMR 7277, Nice, France † Inserm, iBV, U1091, Nice, France { CNRS, iBV, UMR 7277, Nice, France 1 Corresponding author: e-mail address: [email protected]
Contents 1. Anatomy of the Pancreas 2. Diabetes 3. Pancreatic Morphogenesis 4. The Endocrine Differentiation Program 5. Regenerative Medicine Acknowledgments References
218 218 220 223 228 232 232
Abstract Type 1 diabetes is a metabolic disease resulting in the selective loss of pancreatic insulinproducing b-cells and affecting millions of people worldwide. The side effects of diabetes are varied and include cardiovascular, neuropathologic, and kidney diseases. Despite the most recent advances in diabetes care, patients suffering from type 1 diabetes still display a shortened life expectancy compared to their healthy counterparts. In an effort to improve b-cell-replacement therapies, numerous approaches are currently being pursued, most of these aiming at finding ways to differentiate stem/progenitor cells into b-like cells by mimicking embryonic development. Unfortunately, these efforts have hitherto not allowed the generation of fully functional b-cells. This chapter summarizes recent findings, allowing a better insight into the molecular mechanisms underlying the genesis of b-cells during the course of pancreatic morphogenesis. Furthermore, a focus is made on new research avenues concerning the conversion of pre-existing pancreatic cells into b-like cells, such approaches holding great promise for the development of type 1 diabetes therapies.
Current Topics in Developmental Biology, Volume 106 ISSN 0070-2153 http://dx.doi.org/10.1016/B978-0-12-416021-7.00006-7
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2013 Elsevier Inc. All rights reserved.
217
218
Fabio Avolio et al.
1. ANATOMY OF THE PANCREAS The mature pancreas is an abdominal gland connected to the duodenum, which consists of two functionally and morphologically distinct compartments deriving from the endoderm. The exocrine compartment (98% of the total organ mass) mostly contains enzyme-secreting acinar cells organized into clusters surrounding a network system of ducts. Mature duct cells actively secrete bicarbonate and mucins. The duct network also collects digestive enzymes from acinar cells that are emptied into the duodenum where they contribute to food processing (Slack, 1995). The endocrine compartment (
From Pancreas Morphogenesis to b-Cell Regeneration Fabio Avolio*,†,{, Anja Pfeifer*,†,{, Monica Courtney*,†,{, Elisabet Gjernes*,†,{, Nouha Ben-Othman*,†,{, Andhira Vieira*,†,{, Noémie Druelle*,†,{, Biljana Faurite*,†,{, Patrick Collombat*,†,{,1 *Univ. Nice Sophia Antipolis, iBV, UMR 7277, Nice, France † Inserm, iBV, U1091, Nice, France { CNRS, iBV, UMR 7277, Nice, France 1 Corresponding author: e-mail address: [email protected]
Contents 1. Anatomy of the Pancreas 2. Diabetes 3. Pancreatic Morphogenesis 4. The Endocrine Differentiation Program 5. Regenerative Medicine Acknowledgments References
218 218 220 223 228 232 232
Abstract Type 1 diabetes is a metabolic disease resulting in the selective loss of pancreatic insulinproducing b-cells and affecting millions of people worldwide. The side effects of diabetes are varied and include cardiovascular, neuropathologic, and kidney diseases. Despite the most recent advances in diabetes care, patients suffering from type 1 diabetes still display a shortened life expectancy compared to their healthy counterparts. In an effort to improve b-cell-replacement therapies, numerous approaches are currently being pursued, most of these aiming at finding ways to differentiate stem/progenitor cells into b-like cells by mimicking embryonic development. Unfortunately, these efforts have hitherto not allowed the generation of fully functional b-cells. This chapter summarizes recent findings, allowing a better insight into the molecular mechanisms underlying the genesis of b-cells during the course of pancreatic morphogenesis. Furthermore, a focus is made on new research avenues concerning the conversion of pre-existing pancreatic cells into b-like cells, such approaches holding great promise for the development of type 1 diabetes therapies.
Current Topics in Developmental Biology, Volume 106 ISSN 0070-2153 http://dx.doi.org/10.1016/B978-0-12-416021-7.00006-7
#
2013 Elsevier Inc. All rights reserved.
217
218
Fabio Avolio et al.
1. ANATOMY OF THE PANCREAS The mature pancreas is an abdominal gland connected to the duodenum, which consists of two functionally and morphologically distinct compartments deriving from the endoderm. The exocrine compartment (98% of the total organ mass) mostly contains enzyme-secreting acinar cells organized into clusters surrounding a network system of ducts. Mature duct cells actively secrete bicarbonate and mucins. The duct network also collects digestive enzymes from acinar cells that are emptied into the duodenum where they contribute to food processing (Slack, 1995). The endocrine compartment (
