Early hepatocyte DNA synthetic response posthepatectomy is modulated by IL-6 trans-signaling and PI3K/AKT activation

Nechemia-Arbely, Yael; Shriki, Anat; Denz, Ulrich; Drucker, Claudia; Scheller, Jürgen; Raub, J.; Pappo, Orit; Rose-John, Stefan; Galun, Eithan; Axelrod, Jonathan H.

doi:10.1016/j.jhep.2010.08.017

Cited by 34 publications

(39 citation statements)

References 41 publications

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“…Hyper-IL-6 reportedly activates various signaling cascades, including the JAK/STAT3, PI3K/AKT and MAPK/ERK pathways, in non-neuronal cells via direct binding to gp130. [36][37][38] Consistent with these previous results, hIL-6 promptly induced phosphorylation of STAT3 and AKT in cultured RGCs. Signal intensity as well as the number of positive RGCs were significantly higher compared to stimulation with CNTF.…”

Section: Discussionsupporting

confidence: 89%

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

et al. 2016

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Retinal ganglion cells (RGCs) do not normally regenerate injured axons, but die upon axotomy. Although IL-6-like cytokines are reportedly neuroprotective and promote optic nerve regeneration, their overall regenerative effects remain rather moderate. Here, we hypothesized that direct activation of the gp130 receptor by the designer cytokine hyper-IL-6 (hIL-6) might induce stronger RGC regeneration than natural cytokines. Indeed, hIL-6 stimulated neurite growth of adult cultured RGCs with significantly higher efficacy than CNTF or IL-6. This neurite growth promoting effect could be attributed to stronger activation of the JAK/STAT3 and PI3K/AKT/mTOR signaling pathways and was also observed in peripheral dorsal root ganglion neurons. Moreover, hIL-6 abrogated axon growth inhibition by central nervous system (CNS) myelin. Remarkably, continuous hIL-6 expression upon RGC-specific AAV transduction after optic nerve crush exerted stronger axon regeneration than other known regeneration promoting treatments such as lens injury and PTEN knockout, with some axons growing through the optic chiasm 6 weeks after optic nerve injury. Combination of hIL-6 with RGC-specific PTEN knockout further enhanced optic nerve regeneration. Therefore, direct activation of gp130 signaling might be a novel, clinically applicable approach for robust CNS repair.

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Section: Discussionsupporting

confidence: 89%

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

et al. 2016

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“…Previous studies have demonstrated that p21 inhibits DNA synthesis and results in a delay in the G1–S transition in the regenerating liver 28, 29. Meanwhile, Pten represses the AKT/PI3K signalling cascade, functioning as a regeneration suppressor 30, 31, 32. Indeed, we found that the loss of miR‐17~92 noticeably reduced AKT phosphorylation in the female mice, particularly at 24 and 36 hrs post‐operation (Fig.…”

Section: Resultsmentioning

confidence: 64%

MiR‐17~92 ablation impairs liver regeneration in an estrogen‐dependent manner

Zhou

Zhang

et al. 2016

J Cellular Molecular Medi

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As one of the most important post‐transcriptional regulators, microRNAs (miRNAs) participate in diverse biological processes, including the regulation of cell proliferation. MiR‐17~92 has been found to act as an oncogene, and it is closely associated with cell proliferation. However, its role in liver regeneration is still unclear. We generated a hepatocyte‐specific miR‐17~92‐deficient mouse and used a mouse model with 70% partial hepatectomy (PH) or intraperitoneal injection of carbon tetrachloride to demonstrate the role of MiR‐17~92 in liver regeneration. In quiescent livers, the expression of the miR‐17~92 cluster showed a gender disparity, with much higher expression in female mice. The expression of four members of this cluster was found to be markedly reduced after 70% PH. The ablation of miR‐17~92 led to obvious regeneration impairment during the early‐stage regeneration in the female mice. Ovariectomy greatly reduced miR‐17~92 expression but significantly promoted liver regeneration in wild‐type mice. In addition, early regeneration impairment in miR‐17~92‐deficient livers could be largely restored following ovariectomy. The proliferation suppressors p21 and Pten were found to be the target effectors of miR‐17~92. MiR‐17~92 disruption resulted in elevated protein levels of p21 and Pten in regenerating livers. MiR‐17~92 functions as a proliferation stimulator and acts in an oestrogen‐dependent manner. The loss of this miRNA results in increases in p21 and Pten expression and therefore impairs liver regeneration in female mice.

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“…As to the mechanism of tissue healing, IL-6 and IL-11 gene expression was upregulated in lung tissue after L-MSC or BM-MSC transplantation; IL-6 is a critical cytokine in liver regeneration [59,60], and there is a cooperative effect between IL-6 and HGF to stimulate hepatocyte DNA synthesis after partial hepatectomy [61], which is thought to involve IL-6 activation of nonparenchymal cells [62]. Recent studies also report that Hgf is an important mediator of the effects of MSCs to ameliorate elastase injury [7,63].…”

mentioning

confidence: 99%

Lung-Derived Mesenchymal Stromal Cell Post-Transplantation Survival, Persistence, Paracrine Expression, and Repair of Elastase-Injured Lung

Hoffman

Paxson

Mazan

et al. 2011

Stem Cells and Development

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While multipotent mesenchymal stromal cells have been recently isolated from adult lung (L-MSCs), there is very limited data on their biological properties and therapeutic potential in vivo. How L-MSCs compare with bone marrow-derived MSCs (BM-MSCs) is also unclear. In this study, we characterized L-MSC phenotype, clonogenicity, and differentiation potential, and compared L-MSCs to BM-MSCs in vivo survival, retention, paracrine gene expression, and repair or elastase injury after transplantation. L-MSCs were highly clonogenic, frequently expressed aldehyde dehydrogenase activity, and differentiated into osteocytes, chondrocytes, adipocytes, myofibroblasts, and smooth muscle cells. After intravenous injection (2 h), L-MSCs showed greater survival than BMMSCs; similarly, L-MSCs were significantly more resistant than BM-MSCs to anchorage independent culture (4 h) in vitro. Long after transplantation (4 or 32 days), a significantly higher number of CD45 neg L-MSCs were retained than BM-MSCs. By flow cytometry, L-MSCs expressed more intercellular adhesion molecule-1 (ICAM-1), platelet derived growth factor receptor alpha (PDGFRa), and integrin a2 than BM-MSCs; these proteins were found to modulate endothelial adherence, directional migration, and migration across Matrigel in L-MSCs. Further, L-MSCs with low ICAM-1 showed poorer lung retention and higher phagocytosis in vivo. Compared with BM-MSCs, L-MSCs expressed higher levels of several transcripts (e.g., Ccl2, Cxcl2, Cxcl10, IL-6, IL-11, Hgf, and Igf2) in vitro, although gene expression in vivo was increased by L-MSCs and BM-MSCs equivalently. Accordingly, both L-MSCs and BM-MSCs reduced elastase injury to the same extent. This study demonstrates that tissuespecific L-MSCs possess mechanisms that enhance their lung retention after intravenous transplantation, and produce substantial healing of elastase injury comparable to BM-MSCs.

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Early hepatocyte DNA synthetic response posthepatectomy is modulated by IL-6 trans-signaling and PI3K/AKT activation

Cited by 34 publications

References 41 publications

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

MiR‐17~92 ablation impairs liver regeneration in an estrogen‐dependent manner

Lung-Derived Mesenchymal Stromal Cell Post-Transplantation Survival, Persistence, Paracrine Expression, and Repair of Elastase-Injured Lung

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