Abstract
Generation of pancreatic β cells from pluripotent stem cells is a key technology to develop cell therapy for insulin-dependent diabetes and considerable efforts have been made to produce β cells. However, due to multiple and lengthy differentiation steps, production of β cells is often unstable. It is also desirable to eliminate undifferentiated cells to avoid potential risks of tumorigenesis. To isolate β cell precursors from late stage pancreatic endocrine progenitor (EP) cells derived from iPS cells, we have identified CD82, a member of the tetraspanin family. CD82+ cells at the EP stage differentiated into endocrine cells more efficiently than CD82− EP stage cells. We also show that CD82+ cells in human islets secreted insulin more efficiently than CD82− cells. Furthermore, knockdown of CD82 expression by siRNA or inhibition of CD82 by monoclonal antibodies in NGN3+ cells suppressed the function of β cells with glucose-stimulated insulin secretion, suggesting that CD82 plays a role in maturation of EP cells to β cells.
Highlights
Generation of pancreatic β cells from pluripotent stem cells is a key technology to develop cell therapy for insulin-dependent diabetes and considerable efforts have been made to produce β cells
Pancreatic islets consist of α, β, δ, and Pancreatic polypeptide (PP) endocrine cells and β cells are responsible for the glucose stimulated insulin (INS) secretion (GSIS)
In order to isolate endocrine progenitor (EP) cells from human iPS cells, we utilized a double knock-in human iPS reporter cell line, in which mCherry and Venus genes are inserted at the NGN3 and INS locus, respectively[12]
Summary
Generation of pancreatic β cells from pluripotent stem cells is a key technology to develop cell therapy for insulin-dependent diabetes and considerable efforts have been made to produce β cells. We show that CD82+ cells in human islets secreted insulin more efficiently than CD82− cells. Pancreatic islets consist of α, β, δ, and Pancreatic polypeptide (PP) endocrine cells and β cells are responsible for the glucose stimulated insulin (INS) secretion (GSIS). Some patients with type 1 diabetes develop hypoglycemia unawareness, a life-threatening condition that is not treatable with insulin injection For such patients, transplantation of pancreas or pancreatic islets is an effective treatment option. Differentiation in vitro is induced through multiple steps, i.e. definitive endoderm (DE), primitive gut tube (PG), pancreatic progenitors (PP), endocrine progenitors (EP) and maturation to β cells. We isolated the cells highly expressing NGN3 from hiPS-EP cells efficiently differentiated into pancreatic islet cells, β cells. We provide evidence that CD82 plays an important role in β cell function
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