ArticleProceedings of the National Academy of Sciences of the United States of America2012
Attenuation of extrinsic signaling reveals the importance of matrix remodeling on maintenance of embryonic stem cell self-renewal.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed.
- Toward robust and reproducible pluripotent stem cell expansion in bioprinted GelMA constructs.International journal of bioprinting · 2025Article
- NJGCG: A node-based joint Gaussian copula graphical model for gene networks inference across multiple states.Computational and structural biotechnology journal · 2024Article
- Macroscopic quorum sensing sustains differentiating embryonic stem cells.Nature chemical biology · 2023Article
- Kernelized multiview signed graph learning for single-cell RNA sequencing data.BMC bioinformatics · 2023Article
- Multiplexed microfluidic chip for cell co-culture.The Analyst · 2022Article
- Hydrogels Containing Gradients in Vascular Density Reveal Dose-Dependent Role of Angiocrine Cues on Stem Cell Behavior.Advanced functional materials · 2021Article
- Highly parallelized human embryonic stem cell differentiation to cardiac mesoderm in nanoliter chambers on a microfluidic chip.Biomedical microdevices · 2021Article
- Molecular networks in Network Medicine: Development and applications.Wiley interdisciplinary reviews. Systems biology and medicine · 2020Review
- Microfluidic perfusion modulates growth and motor neuron differentiation of stem cell aggregates.The Analyst · 2020Article
- Cell patterning by surface tension pinning in microfluidic channels.Biomicrofluidics · 2020Article
- Joint learning of multiple gene networks from single-cell gene expression data.Computational and structural biotechnology journal · 2020Article
- An automated microfluidic device for time-lapse imaging of mouse embryonic stem cells.Biomicrofluidics · 2019Article
- Caring for cells in microsystems: principles and practices of cell-safe device design and operation.Lab on a chip · 2018Review
- Hydrodynamics in Cell Studies.Chemical reviews · 2018Review
- A microfluidic trap array for longitudinal monitoring and multi-modal phenotypic analysis of individual stem cell aggregates.Lab on a chip · 2017Article
- Conceptual and Experimental Tools to Understand Spatial Effects and Transport Phenomena in Nonlinear Biochemical Networks Illustrated with Patchy Switching.Annual review of biochemistry · 2017Review
- Harnessing endogenous signals from hepatocytes using a low volume multi-well plate.Integrative biology : quantitative biosciences from nano to macro · 2017Article
- Stem Cell Spheroids and Ex Vivo Niche Modeling: Rationalization and Scaling-Up.Journal of cardiovascular translational research · 2017Review
- Detecting cell-secreted growth factors in microfluidic devices using bead-based biosensors.Microsystems & nanoengineering · 2017Article
- Aneuploid embryonic stem cells exhibit impaired differentiation and increased neoplastic potential.The EMBO journal · 2016Article
Corrections and comments
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Authors and funding
2 authors.
Funding
Abstract
The role of extrinsic factors in maintaining self-renewal of embryonic stem cells (ESCs) has been extensively studied since the cells' isolation, but the necessity for cell-secreted factors in self-renewal has remained undefined to date. Although it is generally accepted that addition of leukemia inhibitory factor (LIF) together with either serum or bone morphogenetic protein 4 (BMP4) is sufficient to maintain mouse ESCs (mESCs) in a self-renewing state, this does not preclude the possibility that autocrine factors are also required. Here we make use of a microfluidic perfusion device that is able to globally diminish diffusible autocrine signaling by applying continuous media flow to deplete cell-secreted factors. We demonstrate mESC culture for several days under continuous microfluidic perfusion and show that cell-secreted factors are removed and can be recovered downstream. We find that perturbing cell-secreted signaling causes mESCs to exit their stable self-renewing state in defined conditions that normally support self-renewal and to exhibit properties characteristic of epiblast cells. This state change is not due to the presence of the known autocrine differentiation inducer fibroblast growth factor 4, but, remarkably, it can be prevented by global remodeling of the extracellular matrix (ECM). We also find that cell-secreted matrix remodeling proteins are removed under perfusion and that inhibition of extracellular matrix remodeling causes mESCs to differentiate. Taken together, our data indicate that LIF and BMP4 are not sufficient to maintain self-renewal and that cell-secreted factors are necessary to continuously remodel the ECM and thereby prevent differentiation, revealing a previously undescribed level of mESC regulation through the use of microfluidic perfusion technology.
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