Mechanosignalling via integrins directs fate decisions of pancreatic progenitors

Mamidi, Anant; Prawiro, Christy; Seymour, Philip A.; Lichtenberg, Kristian Honnens de; Jackson, Abigail; Serup, Palle; Semb, Henrik

doi:10.1038/s41586-018-0762-2

Cited by 193 publications

(194 citation statements)

References 45 publications

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“…Figure 5d Overall, these results suggested that encapsulation acts during iPSC differentiation through integrins, which probably translate the pressure elicited by the confinement of cells in the alginate matrix into signalling cascades. Of note, these pathways patterns of regulation are consistent with previously published reports 37 , in which their involvement in promoting β cell differentiation in a different system (micropatterned slides) was proposed, suggesting a general role of the pressure-integrin axis in promoting cell differentiation in confined structures. In this study, our goal was to characterize the specific effects of the encapsulation on the differentiation potential by studying its impact on the differentiating cells proteome fingerprint during either early or late differentiation.…”

Section: Pathway Analysis Is Suggestive Of Encapsulation Regulating Tsupporting

confidence: 91%

Encapsulation boosts islet-cell signature in differentiating human induced pluripotent stem cells via integrin signalling

Vethe

Legøy

Abadpour

et al. 2019

Preprint

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Cell replacement therapies hold great therapeutic potential. Nevertheless, our knowledge of the mechanisms governing the developmental processes is limited, impeding the quality of differentiation protocols. Generating insulin-expressing cells in vitro is no exception, with the guided series of differentiation events producing heterogeneous cell populations that display mixed pancreatic islet phenotypes and immaturity. The achievement of terminal differentiation ultimately requires the in vivo transplantation of, usually, encapsulated cells. Here we show the impact of cell confinement on the pancreatic islet signature during the guided differentiation of alginate encapsulated human induced pluripotent stem cells (hiPSCs). Our results show that encapsulation improves differentiation by significantly reshaping the proteome landscape of the cells towards an islet-like signature. Pathway analysis is suggestive of integrins transducing the encapsulation effect into intracellular signalling cascades promoting differentiation. These analyses provide a molecular framework for understanding the confinement effects on hiPSCs differentiation while confirming its importance for this process. References:1 9

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Section: Pathway Analysis Is Suggestive Of Encapsulation Regulating Tsupporting

confidence: 91%

Encapsulation boosts islet-cell signature in differentiating human induced pluripotent stem cells via integrin signalling

Vethe

Legøy

Abadpour

et al. 2019

Preprint

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“…10 The Notch signaling pathway plays an important role in the maintenance of CSCs 565,566 and can induce CSC differentiation. Abnormal activity of the Notch signaling pathway has been observed in many cancers, such as leukemia, 567 glioblastoma, 568,569 breast cancer, 570 lung cancer, 571 ovarian cancer, 572 pancreatic cancer, 573 and colon cancer. 574 At present, there are three major clinical methods used to inhibit Notch signaling, secretase inhibition (γ-secretase inhibitor (GSI)), Notch receptor or ligand antibodies, and combination therapy with other pathways.…”

Section: Agents Targeting Csc-associated Signaling Pathways In Clinicmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,318

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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“…Both these genes are strongly expressed in progenitor and differentiating spermatogonia, and have been suggested to drive spermatogonial differentiation (Ballow, Meistrich, Matzuk, & Rajkovic, 2006;Hara et al, 2014;Kaucher, Oatley, & Oatley, 2012;Nakagawa, Sharma, Nabeshima, Braun, & Yoshida, 2010;Phillips, Gassei, & Orwig, 2010;Suzuki et al, 2012;Zheng, Wu, Kaestner, & Wang, 2009). Interestingly, it has been shown that the expression of YAP and NGN3 is mutually exclusive in the mammalian pancreas (Cebola et al, 2015;George, Day, Boerner, Johnson, & Sarvetnick, 2012), and that YAP forms a complex with TEA domain family member 4 (TEAD4) and hes family bHLH transcription factor 1 (HES1) on the promoter of Ngn3 to inhibits its expression (Mamidi et al, 2018). YAP might therefore use a similar mechanism to decrease Ngn3 expression in undifferentiated spermatogonia, including SSCs.…”

Section: Resultsmentioning

confidence: 99%

“…In this assay, Thy1-positive testis cells enriched for SSCs are cultured with GDNF (glial cell line-derived neurotrophic factor) and FGF2 (fibroblast growth factor 2) for 1 week, during which aggregates or "clusters" of undifferentiated spermatogonia form. Interestingly, it has been shown that the expression of YAP and NGN3 is mutually exclusive in the mammalian pancreas(Cebola et al, 2015;George, Day, Boerner, Johnson, & Sarvetnick, 2012), and that YAP forms a complex with TEA domain family member 4 (TEAD4) and hes family bHLH transcription factor 1 (HES1) on the promoter of Ngn3 to inhibits its expression(Mamidi et al, 2018). Jonathan R. Yeh et al, 2007).…”

mentioning

confidence: 99%

Yes‐associated protein expression in germ cells is dispensable for spermatogenesis in mice

Nader

Levasseur

Zhang

et al. 2019

Genesis

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Yes-associated protein (YAP), a key effector of the Hippo signaling pathway, is expressed in the nucleus of spermatogonia in mice, suggesting a potential role in spermatogenesis. Here, we report the generation of a conditional knockout mouse model (Yap flox/flox ; Ddx4 cre/+ ) that specifically inactivates Yap in the germ cells. The inactivation of Yap in spermatogonia was found to be highly efficient in this model.The loss of Yap in the germ cells had no observable effect on spermatogenesis in vivo. Histological examination of the testes showed no structural differences between mutant animals and age-matched Yap flox/flox controls, nor was any differences detected in gonadosomatic index, expression of germ cell markers or sperm counts. Cluster-forming assay using undifferentiated spermatogonia, including spermatogonial stem cells (SSCs), also showed that YAP is dispensable for SSC cluster formation in vitro. However, an increase in the expression of spermatogenesis and oogenesis basic helix-loop-helix 1 (Sohlh1) and neurogenin 3 (Ngn3) was observed in clusters derived from Yap flox/flox ; Ddx4 cre/+ animals. Taken together, these results suggest that YAP fine-tunes the expression of genes associated with spermatogonial fate commitment, but that its loss is not sufficient to alter spermatogenesis in vivo. K E Y W O R D Sspermatogenesis, spermatogonia, transgenic mouse model, Yap

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Mechanosignalling via integrins directs fate decisions of pancreatic progenitors

Cited by 193 publications

References 45 publications

Encapsulation boosts islet-cell signature in differentiating human induced pluripotent stem cells via integrin signalling

Encapsulation boosts islet-cell signature in differentiating human induced pluripotent stem cells via integrin signalling

Targeting cancer stem cell pathways for cancer therapy

Yes‐associated protein expression in germ cells is dispensable for spermatogenesis in mice

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