Abstract
Pancreatic beta cell transplantation is the ideal method for treatment of type 1 diabetes mellitus (T1DM), and the generation of beta cells from induced pluripotent stem cells (iPSCs) of patients is a promising strategy. In this study, we improved a previous strategy to produce beta cells using extracellular vesicles (EVs) derived from mature beta cells and differentiated beta cells from iPSCs (i-Beta cells), which secreted insulin under glucose stimulation in vitro and ameliorated hyperglycemia in vivo. Mechanistic analyses revealed that EV-carried microRNA (miR)-212/132 (EV-miR-212/132) directly bound to the 3′ UTR of FBW7 to prevent its translation and FBW7 combined with NGN3 to accelerate its proteasomal degradation. EV-miR-212/132 stabilized NGN3 expression to promote differentiation of endocrine cells from induced iPSCs. Moreover, NGN3 bound to PDX1 to enhance transcription of endogenous miR-212/132 and formed a positive regulatory circuit that maintained the functions of mature pancreatic beta cells.ConclusionThis study describes a novel approach for beta cell production and supports the use of iPSCs for cell replacement therapy of T1DM.
Highlights
Pancreatic beta cells control glucose homeostasis, which have well-tuned machinery to sense glucose and secrete insulin
This study describes a novel approach for beta cell production and supports the use of Induced pluripotent stem cells (iPSCs) for beta cell replacement therapy of type 1 diabetes mellitus
The characteristics of extracellular vesicles (EVs) were analyzed by detecting specific proteins (CD63, CD9, and Alix) that indicated the presence of EV components using western blotting, observing the morphology of particles to clarify the integrity of EVs using transmission electron microscopy (TEM), and calculating the distribution of the diameter of particles and their number to show the characteristics of EV populations
Summary
Pancreatic beta cells control glucose homeostasis, which have well-tuned machinery to sense glucose and secrete insulin. Type 1 diabetes mellitus (T1DM) results from autoimmune destruction of beta cells in pancreatic islets. Replacement of these pancreatic beta cells with healthy cells is the ideal therapy for T1DM. IPSCs have provided a new prospect for patient-specific cell therapy and the development of regenerative medicine. A scalable differentiation protocol to generate glucoseresponsive beta cells from iPSCs in vitro has been reported previously (Pagliuca et al, 2014), but this protocol is complicated to prepare the factors and small molecules used for differentiation of iPSCs
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