Discovery of chemerin as the new chemoattractant of human mesenchymal stem cells

Background The homing capacity of human mesenchymal stem cells (hMSCs) to the injured sites enables systemic administration of hMSCs in clinical practice. In reality, only a small proportion of MSCs are detected in the target tissue, which is a major bottleneck for MSC-based therapies. We still dont know the mechanism how MSCs are chemo-attracted to certain target organ and engrafted through trans-endothelial migration. In this study, we aimed to determine the mechanism how the circulating hMSCs home to the injured liver. Methods and results When we compare the cytokine array between normal and injured mouse liver at 1-day thioacetamide (TAA)-treatment, we found that chemerin, CXCL2, and CXCL10 were higher in the injured liver than normal one. Among three, only chemerin was the chemoattractant of hMSCs in 2D- and 3D-migration assay. Analysis of the signal transduction pathways in hMSCs showed that chemerin activated the phosphorylation of JNK1/2, ERK1/2 and p38, and finally upregulated CD44, ITGA4, and MMP-2 that are involved in the transendothelial migration and extravasation of MSCs. Upstream transcription regulators of CD44, ITGA4, and MMP-2 after chemerin treatment were MZF1, GATA3, STAT3, and STAT5A. To develop chemerin as a chemoattractant tool, we cloned gene encoding the active chemerin under the CMV promoter (CMV-aChemerin). We analyzed the migration of hMSCs in the 3D model for space of the Disse, which mimics transmigration of hMSCs in the liver. CMV-aChemerin-transfected hepatocytes were more effective to attract hMSC than control hepatocytes, leading to the enhanced transendothelial migration and homing of hMSCs to liver. The homing efficiency of the intravascularly-delivered hMSCs to liver was evaluated after systemic introduction of the CMV-aChemerin plasmid packed in liposome-vitamin A conjugates which target liver. CMV-aChemerin plasmid targeting liver significantly enhanced homing efficiency of hMSCs to liver compared with control plasmid vector. Conclusions Chemerin is the newly found chemoattractant of hMSCs and may be a useful tool to manipulate the homing of the intravascularly-administered hMSC to the specific target organ.This work was supported by the Korea Health Technology R&D Project Strategic Center of Cell and Bio Therapy [Grant number HI17C2085] and Korea Research-Driven Hospital [Grant number HI14C1277] through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (MHW), Republic of Korea. The funders had no role in the study design, data collection and analysis, deci‑sion to publish, or preparation of the manuscript

Retinol from hepatic stellate cells via STRA6 induces lipogenesis on hepatocytes during fibrosis

BackgroundHepatic stellate cells (HSCs) are activated in response to liver injury with TIF1 gamma -suppression, leading to liver fibrosis. Here, we examined the mechanism how reduction of TIF1 gamma in HSCs induces damage on hepatocytes and liver fibrosis.MethodLrat:Cas9-ERT2:sgTif1 gamma mice were treated Tamoxifen (TMX) or wild-type mice were treated Thioacetamide (TAA). HSCs were isolated from mice liver and analyzed role of Tif1 gamma. HepG2 were treated retinol with/without siRNA for Stimulated by retinoic acid 6 (STRA6) or Retinoic acid receptor(RAR)-antagonist, and LX2 were treated siTIF1 gamma and/or siSTRA6. TAA treated mice were used for evaluation of siSTRA6 effect in liver fibrosis.ResultsWhen we blocked the Tif1 gamma in HSCs using Lrat:Cas9-ERT2:sgTif1 gamma mice, retinol is distributed into hepatocytes. Retinol influx was confirmed using HepG2, and the increased intracellular retinol led to the upregulation of lipogenesis-related-genes and triglyceride. This effect was inhibited by a RAR-antagonist or knock-down of STRA6. In the LX2, TIF1 gamma -suppression resulted in upregulation of STRA6 and retinol release, which was inhibited by STRA6 knock-down. The role of STRA6-mediated retinol transfer from HSCs to hepatocytes in liver fibrosis was demonstrated by in vivo experiments where blocking of STRA6 reduced fibrosis.ConclusionsRetinol from HSCs via STRA6 in response to injury with TIF1 gamma -reduction is taken up by hepatocytes via STRA6, leading to fat-deposition and damage, and liver fibrosis.Y

Biological Nicotinamide Cofactor as a Redox-Active Motif for Reversible Electrochemical Energy Storage

Nicotinamide adenine dinucleotide (NAD(+)) is one of the most well-known redox cofactors carrying electrons. Now, it is reported that the intrinsically charged NAD(+) motif can serve as an active electrode in electrochemical lithium cells. By anchoring the NAD(+) motif by the anion incorporation, redox activity of the NAD(+) is successfully implemented in conventional batteries, exhibiting the average voltage of 2.3 V. The operating voltage and capacity are tunable by altering the anchoring anion species without modifying the redox center itself. This work not only demonstrates the redox capability of NAD(+), but also suggests that anchoring the charged molecules with anion incorporation is a viable new approach to exploit various charged biological cofactors in rechargeable battery systems.