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Essential roles of insulin and IGF-1 receptors during embryonic lineage development.

Citation
Okawa, E. R., et al. “Essential Roles Of Insulin And Igf-1 Receptors During Embryonic Lineage Development.”. Molecular Metabolism, p. 101164.
Center Joslin Diabetes Center
Author Erin R Okawa, Manoj K Gupta, Sevim Kahraman, Praneeth Goli, Masaji Sakaguchi, Jiang Hu, Kaiti Duan, Brittany Slipp, Jochen K Lennerz, Rohit N Kulkarni
Keywords Apoptosis, Insulin/IGF-1 receptors, Lineage development, Pluripotency, signaling
Abstract

The insulin and insulin-like growth factor-1 (IGF-1) receptors are important for the growth and development of embryonic tissues. To directly define their roles in the maintenance of pluripotency and differentiation of stem cells, we knocked out both receptors in induced pluripotent stem cells (iPSCs). iPSCs lacking both insulin and IGF-1 receptors (double knockout, DKO) exhibited preserved pluripotency potential despite decreased expression of transcription factors Lin28a and Tbx3 compared to control iPSCs. While embryoid body and teratoma assays revealed an intact ability of DKO iPSCs to form all three germ layers, the latter were composed of primitive neuroectodermal tumor-like cells in the DKO group. RNA-seq analyses of control vs DKO iPSCs revealed differential regulation of pluripotency, developmental, E2F1, and apoptosis pathways. Signaling analyses pointed to downregulation of the AKT/mTOR pathway and upregulation of the STAT3 pathway in DKO iPSCs in the basal state and following stimulation with insulin/IGF-1. Directed differentiation toward the three lineages was dysregulated in DKO iPSCs, with significant downregulation of key markers (Cebpα, Fas, Pparγ, and Fsp27) in adipocytes and transcription factors (Ngn3, Isl1, Pax6, and Neurod1) in pancreatic endocrine progenitors. Furthermore, differentiated pancreatic endocrine progenitor cells from DKO iPSCs showed increased apoptosis. We conclude that insulin and insulin-like growth factor-1 receptors are indispensable for normal lineage development and perturbations in the function and signaling of these receptors leads to upregulation of alternative compensatory pathways to maintain pluripotency.

Year of Publication
2021
Journal
Molecular metabolism
Volume
47
Number of Pages
101164
Date Published
01/2021
ISSN Number
2212-8778
DOI
10.1016/j.molmet.2021.101164
Alternate Journal
Mol Metab
PMID
33453419
PMCID
PMC7890209
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