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Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients

Generation of functional β cells from pluripotent sources would accelerate diagnostic and therapeutic applications for diabetes research and therapy. However, it has been challenging to generate competent β cells with dynamic insulin-secretory capacity to glucose and incretin stimulations. We introd...

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Detalles Bibliográficos
Autores principales: Zhu, Yaxi, Tonne, Jason M., Liu, Qian, Schreiber, Claire A., Zhou, Zhiguang, Rakshit, Kuntol, Matveyenko, Aleksey V., Terzic, Andre, Wigle, Dennis, Kudva, Yogish C., Ikeda, Yasuhiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700523/
https://www.ncbi.nlm.nih.gov/pubmed/31378674
http://dx.doi.org/10.1016/j.stemcr.2019.07.006
Descripción
Sumario:Generation of functional β cells from pluripotent sources would accelerate diagnostic and therapeutic applications for diabetes research and therapy. However, it has been challenging to generate competent β cells with dynamic insulin-secretory capacity to glucose and incretin stimulations. We introduced transcription factors, critical for β-cell development and function, in differentiating human induced pluripotent stem cells (PSCs) and assessed the impact on the functionality of derived β-cell (psBC) progeny. A perifusion system revealed stepwise transduction of the PDX1, NEUROG3, and MAFA triad (PNM) enabled in vitro generation of psBCs with glucose and GLP-1 responsiveness within 3 weeks. PNM transduction upregulated genes associated with glucose sensing, insulin secretion, and β-cell maturation. In recipient diabetic mice, PNM-transduced psBCs showed glucose-responsive insulin secretion as early as 1 week post transplantation. Thus, enhanced pre-emptive β-cell specification of PSCs by PNM drives generation of glucose- and incretin-responsive psBCs in vitro, offering a competent tissue-primed biotherapy.