miR-18a counteracts AKT and ERK activation to inhibit the proliferation of pancreatic progenitor cells

Li, Xuyan; Zhang, Zhenwu; Li, Yunchao; Zhao, Yicheng; Zhai, Wenjun; Yang, Lin; Kong, Delin; Wu, Chunyan; Chen, Zhenbao; Teng, Chun‐Bo

doi:10.1038/srep45002

Cited by 17 publications

(18 citation statements)

References 46 publications

(51 reference statements)

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“…An increased fraction of dissociated cells entering S phase facilitated the generation of ~90% NKX6.1 + /Ki67 + proliferative progenitors at the end of stage 4 in our optimized protocol. Moreover, few studies have reported the essential role of cell proliferation regulators in enhancing pancreatic differentiation [ 45 , 46 ]. Therefore, an increased co-expression of PDX1 and NKX6.1 (P2-D) may be due to increased proliferation of the progenitor cells during differentiation.…”

Section: Discussionmentioning

confidence: 99%

Enhanced differentiation of human pluripotent stem cells into pancreatic progenitors co-expressing PDX1 and NKX6.1

et al. 2018

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BackgroundPancreatic progenitors (PPs) co-expressing the two transcription factors (TFs) PDX1 and NKX6.1 are recognized as the indispensable precursors of functional pancreatic β cells. Here, we aimed to establish an efficient protocol for maximizing generation of PDX1+/NKX6.1+ PPs from human pluripotent stem cells (hPSCs).MethodsIn order to enhance the PDX1+/NKX6.1+ population, we manipulated in vitro culture conditions during differentiation by dissociating densely formed endodermal cells and re-plating them at different densities. These dissociated cells were subjected to an augmented duration of retinoid and fibroblast growth factor (FGF)10 signaling to induce higher PDX1 and NKX6.1 expression.ResultsOur optimized protocol dramatically increased the expression of NKX6.1, leading to an increase in the proportion of PDX1+/NKX6.1+ progenitors (~90%) in monolayer, higher than the previously published protocols, as well as upregulated key TFs controlling pancreatic development. The improved efficiency of pancreatic differentiation was complemented by an inhibited hepatic specification and an increased proliferation of NKX6.1+ cells. Interestingly, we were able to enrich a novel PDX1–/NKX6.1+ population by manipulating the re-plating density; these oriented themselves in three-dimensional clusters. Further differentiation validated the ability of our PDX1+/NKX6.1+ progenitors to generate NGN3+ endocrine progenitors.ConclusionsWe provide a novel technique that facilitates appropriate cellular rearrangement in monolayer culture to yield a high proportion of PDX1+/NKX6.1+ PPs with an elevated self-replicating capacity, thereby aiding scalable production of functional β cells from hPSCs in vitro. Our innovative method also enriches a novel NKX6.1+/PDX1– population, with characteristics of proposed endocrine precursors, allowing further studies on deciphering routes to β-cell development.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0759-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Enhanced differentiation of human pluripotent stem cells into pancreatic progenitors co-expressing PDX1 and NKX6.1

et al. 2018

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“…Generally, some of the tumor-associated miRs might contribute to the higher proliferation index of BON and QGP compared to panNETs or authentic NET cell lines like miR-18a. This miR counteracts EGFR and AKT to inhibit the proliferation of pancreatic progenitors [50] and might explain the poor sensitivity of these cells to the mTOR inhibitor RAD001 (everolimus) [51]. This is of note given that everolimus is being used for the treatment of patients with panNETs [51,52].…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1

Luley

Biedermann

Künstner

et al. 2020

Cancers

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Experimental models of neuroendocrine tumor disease are scarce, with only a few existing neuroendocrine tumor cell lines of pancreatic origin (panNET). Their molecular characterization has so far focused on the neuroendocrine phenotype and cancer-related mutations, while a transcription-based assessment of their developmental origin and malignant potential is lacking. In this study, we performed immunoblotting and qPCR analysis of neuroendocrine, epithelial, developmental endocrine-related genes as well as next-generation sequencing (NGS) analysis of microRNAs (miRs) on three panNET cell lines, BON-1, QGP-1, and NT-3. All three lines displayed a neuroendocrine and epithelial phenotype; however, while insulinoma-derived NT-3 cells preferentially expressed markers of mature functional pancreatic β-cells (i.e., INS, MAFA), both BON-1 and QGP-1 displayed high expression of genes associated with immature or non-functional β/δ-cells genes (i.e., NEUROG3), or pancreatic endocrine progenitors (i.e., FOXA2). NGS-based identification of miRs in BON-1 and QGP-1 cells revealed the presence of all six members of the miR-17-92 cluster, which have been implicated in β-cell function and differentiation, but also have roles in cancer being both oncogenic or tumor suppressive. Notably, both BON-1 and QGP-1 cells expressed several miRs known to be negatively associated with epithelial-mesenchymal transition, invasion or metastasis. Moreover, both cell lines failed to exhibit migratory activity in vitro.Cancers 2020, 12, 691 2 of 18 Taken together, NT-3 cells resemble mature functional β-cells, while both BON-1 and QGP-1 are more similar to immature/non-functional pancreatic β/δ-cells or pancreatic endocrine progenitors. Based on the recent identification of three transcriptional subtypes in panNETs, NT-3 cells resemble the "islet/insulinoma tumors" (IT) subtype, while BON-1 and QGP-1 cells were tentatively classified as "metastasis-like/primary" (MLP). Our results provide a comprehensive characterization of three panNET cell lines and demonstrate their relevance as neuroendocrine tumor models.

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“…Based on the studies of cancer cells or stem cells out of the central nervous system (CNS), miR-19 facilitates proliferation via targeting HIPK1 [54], Plzf [55], and Cyld [56]. Besides, miR-18 regulates tumorigenesis by suppressing SOCS5 [57], CTGF, Nedd9, IGF1, and CDK19 [58]. However, whether or not these genes are also expressed in NSCs and regulated by miR-18/19 sub-families need to be further clarified.…”

Section: The Regulatory Network Of Mir-17~92 Familymentioning

confidence: 99%

The microRNA-17 ~ 92 Family as a Key Regulator of Neurogenesis and Potential Regenerative Therapeutics of Neurological Disorders

Xia

Wang

Zheng

2020

Stem Cell Rev and Rep

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miR-17 ~ 92, an miRNA family containing three paralogous polycistronic clusters, was initially considered as an oncogene and was later demonstrated to trigger various physiological and pathological processes. Emerging evidence has implicated miR-17 ~ 92 family as a master regulator of neurogenesis. Through targeting numerous genes that affect cell cycle arrest, stemness deprivation, and lineage commitment, miR-17 ~ 92 family controls the proliferation and neuronal differentiation of neural stem/progenitor cells in both developmental and adult brains. Due to the essential roles of miR-17 ~ 92 family, its misexpression is widely associated with acute and chronic neurological disorders by attenuating neurogenesis and facilitating neuronal apoptosis. The promising neurogenic potential of miR-17 ~ 92 family also makes it a promising “medicine” to activate the endogenous and exogenous regenerative machinery, thus enhance tissue repair and function recovery after brain injury. In this review, we focus on the recent progress made toward understanding the involvement of miR-17 ~ 92 family in regulating both developmental and adult neurogenesis, and discuss the regenerative potential of miR-17 ~ 92 family in treating neurological disorders.

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miR-18a counteracts AKT and ERK activation to inhibit the proliferation of pancreatic progenitor cells

Cited by 17 publications

References 46 publications

Enhanced differentiation of human pluripotent stem cells into pancreatic progenitors co-expressing PDX1 and NKX6.1

Enhanced differentiation of human pluripotent stem cells into pancreatic progenitors co-expressing PDX1 and NKX6.1

A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1

The microRNA-17 ~ 92 Family as a Key Regulator of Neurogenesis and Potential Regenerative Therapeutics of Neurological Disorders

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