Leukemia Inhibitory Factor and Fibroblast Growth Factor 2 Critically and Mutually Sustain Pluripotency of Rabbit Embryonic Stem Cells

Abstract

Effects of leukemia inhibitory factor (LIF) and fibroblast growth factor 2 (FGF2) on establishment and maintenance of rabbit embryonic stem cell (rESC) lines were assessed. When grown on MEF feeders, rESC lines derived from fertilized embryos were established and maintained in medium containing paracrine factors LIF (via STAT3) and/or FGF2 (via MEK-ERK1/2 and PI3K-AKT). However, high levels of ERK1/2 and AKT activities in rESCs were crucial for maintaining their undifferentiated proliferation. Although rESCs under the influence of either LIF (500, 1,000, and 2,000 U/ml) or FGF2 (5, 10, and 20 ng/ml) alone had enhanced expression of pluripotency markers, peak expression occurred when both LIF (1,000 U/ml) and FGF2 (10 ng/ml) were applied. Induced dephosphorylation of STAT3, ERK1/2, and AKT by specific inhibitors limited growth of rESCs and caused remarkable losses of self-renewal capacity; therefore, we inferred that STAT3, ERK, and AKT had essential roles in maintaining rESC proliferation and self-renewal. We concluded that LIF and FGF2 jointly maintained the undifferentiated state and self-renewal of rESCs through an integrative signaling module.

Protective effect of LIF-huMSCs on the retina of diabetic model rats

“…This study aimed to evaluate the changes in the levels of immunologic inflammation and neurotrophic biomarkers in STZ-diabetic rats after intravitreal injection of LIF-hUCMSCs, as well as the effects of the injection on the retinal structure and function in DR rats. LIF has important effects on the differentiation, apoptosis, and proliferation of hUCMSCs and can maintain the proliferative capacity of embryonic stem cells and other types of stem cells by inhibiting their differentiation [5,19] . In addition, LIF inhibits cell apoptosis, which induces the proliferation of hUCMSCs [20] .…”

Pluripotent Stem Cells for Transgenesis in the Rabbit: A Utopia?

“…The self-renewal of rbESCs depends on the activin A/TGFβ/SMAD2-3 and FGF2 pathways [46,47]. FGF2 appears indispensable by inducing the PI3K/AKT and MAPK pathways [48,49], while the WNT/β-catenin pathway may also be indirectly activated by FGF2 [50]. It is possible to derive cells without any growth factor in the medium if they are cultured on feeder cells, showing that LIF is not necessary for the maintenance of rbESCs [51].…”

“…It is possible to derive cells without any growth factor in the medium if they are cultured on feeder cells, showing that LIF is not necessary for the maintenance of rbESCs [51]. However, the addition of LIF to the culture medium of rbESCs has often been used [48,49,52], and several studies have described the effect of LIF on the derivation of rbESCs and the induction of LIF-receptor expression [52,53]. Unlike the derivation of rodent ESCs stabilized in the naive state [54], MEK and GSK3β inhibitors do not enhance epiblast cell differentiation in vivo [55] or rbESC derivation in vitro [51].…”

Impact of IFN‐β and LIF overexpression on human adipose‐derived stem cells properties

“…Another interesting cytokine in the treatment of MS is leukemia inhibitory factor (LIF) as a pleiotropic cytokine that belongs to interleukin (IL)‐6 cytokine family (Janssens et al, 2015; Nicola & Babon, 2015). LIF has different effects on stem cells such as increasing proliferation and inhibiting the differentiation (He, Li, Zhen, Feng, & Ding, 2006; Hu, Wu, Yin, Shi, & Yin, 2016; Lo et al, 2015). In addition, LIF has a regulatory role in self‐tolerance and recently is recognized as a promoting factor for myelin production (Janssens et al, 2015).…”