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Concept: Leukemia inhibitory factor

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Aim: To develop a clinically applicable MRI technique for tracking stem cells in matrix-associated stem-cell implants, using the US FDA-approved iron supplement ferumoxytol. Materials & methods: Ferumoxytol-labeling of adipose-derived stem cells (ADSCs) was optimized in vitro. A total of 11 rats with osteochondral defects of both femurs were implanted with ferumoxytol- or ferumoxides-labeled or unlabeled ADSCs, and underwent MRI up to 4 weeks post matrix-associated stem-cell implant. The signal-to-noise ratio of different matrix-associated stem-cell implant was compared with t-tests and correlated with histopathology. Results: An incubation concentration of 500 µg iron/ml ferumoxytol and 10 µg/ml protamine sulfate led to significant cellular iron uptake, T2 signal effects and unimpaired ADSC viability. In vivo, ferumoxytol- and ferumoxides-labeled ADSCs demonstrated significantly lower signal-to-noise ratio values compared with unlabeled controls (p < 0.01). Histopathology confirmed engraftment of labeled ADSCs, with slow dilution of the iron label over time. Conclusion: Ferumoxytol can be used for in vivo tracking of stem cells with MRI. Original submitted 28 February 2012; Revised submitted 8 November 2012.

Concepts: Iron, Cell division, Stem cell, In vivo, In vitro, Inner cell mass, Signal-to-noise ratio, Leukemia inhibitory factor

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Embryonic stem cells (ESCs) cultured in leukemia inhibitory factor (LIF) plus fetal bovine serum (FBS) exhibit heterogeneity in the expression of naive and primed transcription factors. This heterogeneity reflects the dynamic condition of ESCs and their versatility to promptly respond to signaling effectors promoting naive or primed pluripotency. Here, we report that ESCs lacking Nanog or overexpressing Otx2 exhibit an early primed identity in LIF + FBS and fail to convert into 2i-induced naive state. Conversely, Otx2-null ESCs possess naive identity features in LIF + FBS similar to Nanog-overexpressing ESCs and convert poorly into FGF-induced early primed state. When both Nanog and Otx2 are inactivated, ESCs cultured in LIF + FBS exhibit primed identity and weakened ability to convert into naive state. These data suggest that, through mutual antagonism, NANOG and OTX2 specify the heterogeneous identity of ESCs cultured in LIF + FBS and individually predispose them for optimal response to naive or primed inducing factors.

Concepts: DNA, Cell nucleus, Gene expression, Transcription, Developmental biology, Stem cell, Embryonic stem cell, Leukemia inhibitory factor

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Leukemia inhibitory factor (LIF) has been reported to possess various pharmacological effects, including displaying vascular and neuroprotective properties, during retinal disease. The aim of this study was to investigate the vascular and structural changes in the retina of diabetic mice and to explore whether LIF prevents experimental diabetes-induced retinal injury in the early stages.

Concepts: Pharmacology, Cancer, The Canon of Medicine, Retina, Leukemia inhibitory factor

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We defined how blood-derived vitronectin (VTN) rapidly and potently activates leukemia inhibitory factor (LIF) and pro-inflammatory interleukin 6 (IL-6) in vitro and after vascular injury in the brain. VTN (not fibrinogen, fibronectin, laminin-111, collagen-I) robustly increased LIF and IL-6 within 4 hr in C6-astroglioma cells, while VTN-/- mouse plasma was less effective than wildtype. LIF and IL-6 were induced by intracerebral injection of rhVTN in mice, but less by intracerebral hemorrhage in VTN-/- than wildtype littermates. In vitro, VTN effects were inhibited by RGD,αvβ3 and avb5 integrin blocking peptides, and antibodies. VTN activated focal adhesion kinase (FAK), whereas pharmacological or siRNA inhibition of FAK, but not PYK2, reduced LIF and IL-6 in C6 and endothelial cells, and after traumatic cell injury. Dominant negative FAK (Y397F) reduced injury-induced LIF and IL-6. Pharmacological inhibition or knockdown of uPAR, which binds VTN, also reduced cytokine expression, possibly through a common target of uPAR and integrins. We propose that VTN leakage into tissues promotes inflammation. Integrin-FAK signaling is a novel IL-6 and LIF regulation mechanism relevant to the inflammation and stem cell fields.

Concepts: Inflammation, Gene, Gene expression, Enzyme, Interleukin, Integrin, Vitronectin, Leukemia inhibitory factor

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Self-renewal is one of the most important features of embryonic stem (ES) cells. SC1 is a small molecule modulator that effectively maintains the self-renewal of mouse ES cells in the absence of leukemia inhibitory factor (LIF), serum and feeder cells. However, the mechanism by which SC1 maintains the undifferentiated state of mouse ES cells remains unclear.

Concepts: Stem cell, Cellular differentiation, Embryonic stem cell, Leukemia inhibitory factor

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Please note that Carolina Blüguermann’s surname was misspelled (as Blugüermann) in this article as originally published.

Concepts: Stem cell, Leukemia inhibitory factor

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The aim of this study was to compare the endometrial expression of milk fat globule-EGF factor 8 (MFG-E8), its receptor integrin αvβ3, and leukemia inhibitory factor (LIF) in patients with endometriosis and infertility and in healthy fertile patients during the window of implantation.

Concepts: Pregnancy, Nutrition, Infertility, Fertility, Endometrium, Implantation, Endometriosis, Leukemia inhibitory factor

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A receptive endometrium is essential for maternal-embryonic molecular communication during implantation. However, the specific molecular regulatory mechanisms of the endometrial capacity remain poorly understood. Here, we examined activating transcription factor 3 (ATF3) expression in human endometria and the functional effect of ATF3 on embryo attachment in vitro.

Concepts: DNA, Pregnancy, Transcription, Embryo, P53, Endometrium, Implantation, Leukemia inhibitory factor

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The cytokine Leukemia inhibitory factor (LIF) is essential for rendering the uterus receptive for blastocyst implantation. In mice LIF receptor expression (LIFR) is largely restricted to the uterine luminal epithelium (LE). LIF, secreted from the endometrial glands (GE) binds to the LIFR, activating the Jak-Stat3 signaling pathway in the LE. JAK-STAT activation converts the LE to a receptive state so that juxtaposed blastocysts begin to implant. To specifically delete the LIFR in the LE we derived a line of mice in which Cre recombinase was inserted into the endogenous Lactoferrin gene (Ltf-Cre). Lactoferrin expression in the LE is induced by E2 and we demonstrate that Cre recombinase activity is restricted to the LE and GE. To determine the requirement of the LIFR in implantation, we derived an additional mouse line carrying a conditional (floxed) Lifrflx/flx gene. Crossing Ltf-Cre mice with Lifrflx/flx mice, generated Lifrflx/Δ:LtfCre/+ females that were overtly normal, but infertile. Many of these females, despite repeated matings, did not become pregnant. Unimplanted blastocysts were recovered from the Lifrflx/Δ:LtfCre/+ uteri and when transferred to WT recipients, implanted normally, indicating that uterine receptivity rather than the embryo’s competency is compromised. The loss of Lifr results in both the failure for STAT3 to translocate to the LE nuclei and a reduction in the expression of the LIF regulated gene Msx1 that regulates uterine receptivity. These results reveal that uterine expression of the LIFR is essential for embryo implantation, and further define the components of the LIF signaling pathway necessary for effective implantation.

Concepts: Pregnancy, Embryo, Uterus, Endometrium, Cervix, Implantation, Blastocyst, Leukemia inhibitory factor

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The embryo implantation is crucial step for successful pregnancy. Diverse factors including adhesion molecules, growth factors, and cytokines are important to the embryo implantation through improving endometrial receptivity. Benzoic acid (BA), a component of various plants, has been shown to have anti-fungal and anti-oxidant effects. However, the effect of BA on the embryo implantation remains unknown. Here, we showed the contribution of BA for the enhancement of endometrial receptivity through the leukemia inhibitory factor (LIF)-dependent increase of integrin αV, β3, and β5 expression. Furthermore, in vivo study using mifepristone-induced implantation failure model showed that BA definitely improves the numbers of implantation embryos. Taken together, we suggest that BA has a novel function for embryo implantation through the up-regulation of LIF-mediated integrins, and may be a candidate for therapeutic medicine to increase the pregnancy rate.

Concepts: Pregnancy, Embryo, Uterus, In vivo, Endometrium, Implantation, Integrin, Leukemia inhibitory factor