Role Of Stem Cell Derived Microvesicles In Alcoholic Liver Injury Grant uri icon


  • Project Summary/Cell-derived extracellular microvesicles (MVs) have recently emerged as a well-preserved evolutionarymechanism of hepatic cell-to-cell communication. The main functions of MVs are to signal target cells throughspecific interactions and to transfer gene products. Human liver stem cells (HLSCs) and mesenchymal stemcells (MSCs) were extensively investigated for their reparative, regenerative and immunomodulatory properties.We have made the following key observations regarding the cellular mechanisms of ncRNA gene expression inmesenchymal and hepatic stem cell derived microvesicles: (a) The biological action of microvesicles requiredtheir miR-181 and let-7 miRNA-dependent incorporation into hepatic cells. (b) In vivo, microvesiclesaccelerated the morphologic and functional recovery of CCl4-induced acute liver injury (ALI) and alcoholic liverinjury (ALD) in SCID mice by inducing proliferation/anti-senescence effects of hepatic cells. (c) Stem cellderived MVs shuttle a specific subset of cellular ncRNA, such as miR-181, let-7, uc.189 and uc.338 that areassociated with the stemness phenotypes and anti-apoptosis/anti-senescence potentials. (d) In human ALDliver tissues, miR-181b and let-7a are silenced whereas uc.189 and uc.338 are up-regulated. Based on thecompelling data, we propose the central hypothesis that ncRNAs in stem cell derived MVs contribute tothe recovery of alcoholic liver injury through anti-apoptosis and anti-senescence effects in hepaticcells. To test this hypothesis, we have established techniques for ncRNA and gene manipulation, functionalinvestigation and interaction analysis, and generated animal models of acute and alcoholic liver injury (NIAAAmodel). Our long-term objective is to identify and isolate stem cell derived microvesicles and characterize theirfunctional properties in tissue repair during alcoholic liver injury. In this application, we propose the systematicinvestigation of stemness dependent ncRNAs as markers in stem cell derived MVs, which possess therapeuticpotential for alcoholic liver injury. We will address our central hypothesis by focusing on the following specificaims: 1) To identify functional, stemness regulated ncRNAs involved in tissue repair-related cellular functionsin hepatic cells during alcoholic liver injury. In this study, we will characterize the interactions between miR-181/let-7 and uc.338/uc.189 family members and define the role of stemness dependent ncRNA signaling inethanol treated hepatocytes with or without stem cell derived MVs and human ALD liver tissues through flowcytometry analysis, immunoblots and real-time PCR. 2) To determine the effects of stemness related ncRNAenriched microvesicles on accelerating the morphologic and functional recovery of acute and alcoholic liverinjury in SCID/C57 mice with or without immunosuppression in vivo. Therapeutic effects of microvesiclesderived from stem cells will be evaluated. New information on the mechanisms of ncRNA in stem cell derivedmicrovesicles in ALD will be obtained. Meanwhile, the fundamental new knowledge acquired about regulationof tissue repair by stem cell derived microvesicles is expected to advance the general field of stem cell biology.  

date/time interval

  • 2017 - 2019