Hepatocyte homeostasis for chromosome ploidization and liver function is regulated by Ssu72 protein phosphatase.

UNLABELLED: Hepatocyte chromosome polyploidization is an important feature of liver development and seems to be required for response to liver stress and injury signals. However, the question of how polyploidization can be tightly regulated in liver growth remains to be answered. Using a conditional knockout mouse model, liver-specific depletion of Ssu72 protein phosphatase was found to result in impairment in regulation of polyploidization. Interestingly, the aberrant polyploidization in Ssu72-depleted mice was associated with impaired liver damage response and increased markers of liver injury and seemed to mimic the phenotypic features of liver diseases such as fibrosis, steatosis, and steatohepatitis. In addition, depletion of Ssu72 caused deregulation of cell cycle progression by overriding the restriction point of the cell cycle and aberrantly promoting DNA endoreplication through G2 /M arrest. CONCLUSION: Ssu72 plays a substantial role in the maintenance of hepatic chromosome homeostasis and would allow monitoring of liver function.

Metabolites can regulate stem cell behavior through the STAT3/AKT pathway in a similar trend to that under hypoxic conditions.

Stem cell therapy has long been considered a promising mode of treatment for many incurable diseases. Human mesenchymal stem cells (hMSCs) have provided the most promising results to date for regenerative medicine. Nevertheless, due to several obstacles such as difficulty in sourcing and characterizing hMSCs, they remain largely unavailable for clinical use. The signaling requirements for maintaining stem cell function have been studied widely, but little is known about how metabolism contributes to stem cell function. hMSCs have been shown to promote therapeutic efficacy in hypoxic conditions through metabolic conversion. According to published studies, certain metabolites are able to convert stem cell metabolism from oxidative phosphorylation to glycolysis. In this study, we selected several metabolites (fructose-1,6-bisphosphate (FBP), Phosphoenolpyruvic acid (PEP) and sodium oxalate (OXA)) to examine the relation between metabolites and stem cell functions. In addition, we investigated the ability of selected metabolites to induce rapid expansion of this cell population. Our results indicate that selected metabolites stimulate stem cell proliferation by induce glycolytic metabolism via AKT/STAT signaling.

Protein profiling and angiogenic effect of hypoxia-cultured human umbilical cord blood-derived mesenchymal stem cells in hindlimb ischemia.

The aim of the present study was to investigate protein profiles of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) cultured in normoxic (21% O2) and hypoxic (1% O2) conditions, and evaluate oxygenation effects on angiogenesis in an ischemic hindlimb mouse model using a modified ischemic scoring system. Hypoxic conditions did not change the expression of phenotypic markers and increased adipogenesis and chondrogenesis. Epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), TGF-ß RII, and vascular endothelial growth factor (VEGF) were upregulated in the conditioned medium of hypoxic hUCB-MSCs, which are commonly related to angiogenesis and proliferation of biological processes by Gene Ontology. In the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, significant enrichment of the phosphorylation of abelson murine leukemia viral oncogene homolog 1 (ABL1) (Phospho-Tyr204) and B-cell lymphoma-extra large (BCL-XL) (Phospho-Thr47) as anti-apoptotic pathways was observed in hypoxic hUCB-MSCs. Furthermore, hypoxic conditions induced proliferation and migration, and reduced apoptosis of hUCB-MSCs in vitro. Based on the results of protein antibody array, we evaluated the angiogenic effects of injecting normoxic or hypoxic hUCB-MSCs (1×106) into the ischemic hindlimb muscles of mice. Ischemic scores and capillary generation were significantly greater in the hypoxic hUCB-MSC injection group than in the normoxic hUCB-MSC group. Our findings demonstrate that culturing hUCB-MSCs in hypoxic conditions not only significantly enriches phosphorylation in the anti-apoptosis pathway and enhances the secretion of several angiogenic proteins from cells, but also alleviates ischemic injury of hindlimb of mice.