Murine Embryonic Stem Cells Secrete Cytokines/Growth Modulators That Enhance Cell Survival/Anti-Apoptosis and Stimulate Colony Formation of Murine Hematopoietic Progenitor Cells

Guo, Ying; Graham‐Evans, Barbara; Broxmeyer, Hal E.

doi:10.1634/stemcells.2005-0457

Cited by 58 publications

(53 citation statements)

References 10 publications

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“…The theoretical predictions regarding removal of secreted factors were experimentally verified by collecting VEGF, which is known to be secreted by mESCs (27). We were indeed able to measure secreted VEGF (Fig.…”

Section: Resultssupporting

confidence: 52%

“…Because the exit from the ESC state seen under perfusion is related to the presence of the intact ECM, it is possible that a removal of MMPs under perfusion is responsible. Indeed, MMPs are known to be secreted by mESCs (27), and we are able to recover MMP2 from perfused cells (Fig. 3H), illustrating that it is being removed by flow.…”

Section: Down-regulation Of Cell-secreted Signals Drives Escs Toward Anmentioning

confidence: 75%

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Attenuation of extrinsic signaling reveals the importance of matrix remodeling on maintenance of embryonic stem cell self-renewal

Przybyla¹,

Voldman

2012

Proc. Natl. Acad. Sci. U.S.A.

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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 selfrenewing 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 cellsecreted 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. I t has long been known that cell-secreted signals are required for cellular processes such as growth, survival, differentiation, metastasis, and apoptosis (1-5). However, the precise contributions of autocrine and/or paracrine signals to a particular process are often difficult to determine. When the cell-secreted factors and/or receptors are known, one can use chemical or genetic inhibition of target molecules, derivation of knockout cell lines, or overexpression of candidate molecules and receptors to study autocrine/paracrine processes. However, when the cell-secreted factors are unknown, one is typically limited to varying cell density and looking for density-dependent phenotypes. Because autocrine loops can be self-sufficient even at clonal density (6), these methods are incomplete.Pluripotent stem cells isolated from the developing blastocyst are well-suited for the study of cell-secreted signaling, because extrinsic signals generated by the embryo are essential for proper development (7,8), and autocrine and paracrine signals are likewise important in stem cell self-renewal (9), growth (3), and differentiation (1, 10). Mouse embryonic stem cells (mESCs) are pluripotent cells derived from the inner cell mass of preimplanta...

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Section: Resultssupporting

confidence: 52%

Section: Down-regulation Of Cell-secreted Signals Drives Escs Toward Anmentioning

confidence: 75%

Attenuation of extrinsic signaling reveals the importance of matrix remodeling on maintenance of embryonic stem cell self-renewal

Przybyla¹,

Voldman

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, compound mutant AT2 cells showed increased expression of SDF1a. This molecule is a regulator of progenitor cell recruitment, vascular cell differentiation, and angiogenesis (76)(77)(78), and has previously been shown to be suppressed by FGF signaling (79,80).…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor Receptors Control Epithelial–Mesenchymal Interactions Necessary for Alveolar Elastogenesis

Srisuma¹,

Bhattacharya²,

Simon³

et al. 2010

Am J Respir Crit Care Med

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Rationale: The mechanisms contributing to alveolar formation are poorly understood. A better understanding of these processes will improve efforts to ameliorate lung disease of the newborn and promote alveolar repair in the adult. Previous studies have identified impaired alveogenesis in mice bearing compound mutations of fibroblast growth factor (FGF) receptors (FGFRs) 3 and 4, indicating that these receptors cooperatively promote postnatal alveolar formation. Objectives: To determine the molecular and cellular mechanisms of FGF-mediated alveolar formation. Methods: Compound FGFR3/FGFR4-deficient mice were assessed for temporal changes in lung growth, airspace morphometry, and genome-wide expression. Observed gene expression changes were validated using quantitative real-time RT-PCR, tissue biochemistry, histochemistry, and ELISA. Autocrine and paracrine regulatory mechanisms were investigated using isolated lung mesenchymal cells and type II pneumocytes. Measurements and Main Results: Quantitative analysis of airspace ontogeny confirmed a failure of secondary crest elongation in compound mutant mice. Genome-wide expression profiling identified molecular alterations in these mice involving aberrant expression of numerous extracellular matrix molecules. Biochemical and histochemical analysis confirmed changes in elastic fiber gene expression resulted in temporal increases in elastin deposition with the loss of typical spatial restriction. No abnormalities in elastic fiber gene expression were observed in isolated mesenchymal cells, indicating that abnormal elastogenesis in compound mutant mice is not cell autonomous. Increased expression of paracrine factors, including insulin-like growth factor21, in freshly-isolated type II pneumocytes indicated that these cells contribute to the observed pathology. Conclusions: Epithelial/mesenchymal signaling mechanisms appear to contribute to FGFR-dependent alveolar elastogenesis and proper airspace formation.

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“…The 25% ESC-CM group showed a decrease in apoptotic cells and p21 protein expression. Furthermore, it was also reported that the cells cultured in 25% ESC-CM had enhanced HCEC proliferation and promoted HCECs into the cell cycle [26][27][28][29][30]. To summarize, in these studies, primary cultures of HCECs were cultured using 25% mouse embryonic stem cell-conditioned medium.…”

Section: Mouse Embryonic Stem Cell-conditioned Mediummentioning

confidence: 99%

Concise Review: An Update on the Culture of Human Corneal Endothelial Cells for Transplantation

Parekh

Ferrari

Sheridan

et al. 2015

Stem Cells Translational Medicine

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The cornea forms the front window of the eye, enabling the transmission of light to the retina through a crystalline lens. Many disorders of the cornea lead to partial or total blindness, and therefore corneal transplantation becomes mandatory. Recently, selective corneal layer (as opposed to full thickness) transplantation has become popular because this leads to earlier rehabilitation and visual outcomes. Corneal endothelial disorders are a common cause of corneal disease and transplantation. Corneal endothelial transplantation is successful but limited worldwide because of lower donor corneal supply. Alternatives to corneal tissue for endothelial transplantation therefore require immediate attention. The field of human corneal endothelial culture for transplantation is rapidly emerging as a possible viable option. This manuscript provides an update regarding these developments. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:258-264 SIGNIFICANCEThe cornea is the front clear window of the eye. It needs to be kept transparent for normal vision. It is formed of various layers of which the posterior layer (the endothelium) is responsible for the transparency of the cornea because it allows the transport of ions and solutes to and from the other layers of the cornea. Corneal blindness that results from the corneal endothelial dysfunction can be treated using healthy donor tissues. There is a huge demand for human donor corneas but limited supply, and therefore there is a need to identify alternatives that would reduce this demand. Research is underway to understand the isolation techniques for corneal endothelial cells, culturing these cells in the laboratory, and finding possible options to transplant these cells in the patients. This review article is an update on the recent developments in this field.

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Murine Embryonic Stem Cells Secrete Cytokines/Growth Modulators That Enhance Cell Survival/Anti-Apoptosis and Stimulate Colony Formation of Murine Hematopoietic Progenitor Cells

Abstract: STEM CELLS 2006;24: 850 -856

Cited by 58 publications

References 10 publications

Attenuation of extrinsic signaling reveals the importance of matrix remodeling on maintenance of embryonic stem cell self-renewal

Attenuation of extrinsic signaling reveals the importance of matrix remodeling on maintenance of embryonic stem cell self-renewal

Fibroblast Growth Factor Receptors Control Epithelial–Mesenchymal Interactions Necessary for Alveolar Elastogenesis

Concise Review: An Update on the Culture of Human Corneal Endothelial Cells for Transplantation

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