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1.
Sci Rep ; 14(1): 13608, 2024 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-38871849

RESUMEN

Transplantation of stem cell-derived ß-cells is a promising therapeutic advancement in the treatment of type 1 diabetes mellitus. A current limitation of this approach is the long differentiation timeline that generates a heterogeneous population of pancreatic endocrine cells. To address this limitation, an inducible lentiviral overexpression system of mature ß-cell markers was introduced into human induced-pluripotent stem cells (hiPSCs). Following the selection of the successfully transduced hiPSCs, the cells were treated with doxycycline in the pancreatic progenitor induction medium to support their transition toward the pancreatic lineage. Cells cultured with doxycycline presented the markers of interest, NGN3, PDX1, and MAFA, after five days of culture, and glucose-stimulated insulin secretion assays demonstrated that the cells were glucose-responsive in a monolayer culture. When cultured as a spheroid, the markers of interest and insulin secretion in a static glucose-stimulated insulin secretion assay were maintained; however, insulin secretion upon consecutive glucose challenges was limited. Comparison to human fetal and adult donor tissues identified that although the hiPSC-derived spheroids present similar markers to adult insulin-producing cells, they are functionally representative of fetal development. Together, these results suggest that with optimization of the temporal expression of these markers, forward programming of hiPSCs towards insulin-producing cells could be a possible alternative for islet transplantation.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Diferenciación Celular , Proteínas de Homeodominio , Células Madre Pluripotentes Inducidas , Células Secretoras de Insulina , Factores de Transcripción Maf de Gran Tamaño , Proteínas del Tejido Nervioso , Transactivadores , Humanos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/citología , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Transactivadores/metabolismo , Transactivadores/genética , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/citología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Factores de Transcripción Maf de Gran Tamaño/metabolismo , Factores de Transcripción Maf de Gran Tamaño/genética , Insulina/metabolismo , Glucosa/metabolismo , Glucosa/farmacología , Secreción de Insulina/efectos de los fármacos , Células Cultivadas , Doxiciclina/farmacología
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