Abstract
BackgroundSmall hepatocyte-like progenitor cells (SHPCs) appear to form transient clusters in rat livers treated with retrorsine (Ret) and 70% partial hepatectomy (PH). We previously reported that the expansion of SHPCs was amplified in Ret/PH-treated rat livers transplanted with Thy1+ cells derived from d-galactosamine-treated injured livers. Extracellular vesicles (EVs) produced by hepatic Thy1+ donor cells activated SHPCs via interleukin (IL)-17 receptor B signaling. As bone marrow-derived mesenchymal cells (BM-MCs) also express Thy1, we aimed to determine whether BM-MCs could also promote the growth of SHPCs.MethodsBM-MCs were isolated from dipeptidyl-peptidase IV (DPPIV)-positive rats. BM-MCs or BM-MC-derived EVs were administered to DPPIV-negative Ret/PH rat livers, and the growth and the characteristics of SHPC clusters were evaluated 14 days post-treatment. miRNA microarrays and cytokine arrays examined soluble factors within EVs. Small hepatocytes (SHs) isolated from an adult rat liver were used to identify factors enhancing hepatocytic progenitor cells growth.ResultsThe recipient’s livers were enlarged at 2 weeks post-BM-MC transplantation. The number and the size of SHPCs increased remarkably in livers transplanted with BM-MCs. BM-MC-derived EVs also stimulated SHPC growth. Comprehensive analyses revealed that BM-MC-derived EVs contained miR-146a-5p, interleukin-6, and stem cell factor, which could enhance SHs’ proliferation. Administration of EVs derived from the miR-146a-5p-transfected BM-MCs to Ret/PH rat livers remarkably enhanced the expansion of SHPCs.ConclusionsmiR-146a-5p involved in EVs produced by BM-MCs may play a major role in accelerating liver regeneration by activating the intrinsic hepatocytic progenitor cells.
Highlights
Small hepatocyte-like progenitor cells (SHPCs) appear to form transient clusters in rat livers treated with retrorsine (Ret) and 70% partial hepatectomy (PH)
Expression of genes encoding growth factor receptors in small hepatocyte-like progenitor cells (SHPCs) induced by bone marrow-derived mesenchymal cells (BM-MCs) transplantation To confirm whether cytokines might be related to the enlargement of SHPC clusters in livers transplanted with BM-MCs, we investigated the expression of genes encoding specific receptors with that of growth factors in SHPCs and their surrounding mature hepatocytes (MHs)
We demonstrated that the administration of IL-6 and Stem cell factor (SCF) stimulated the growth of small hepatocytes (SHs) in vitro and that the expression of genes encoding the receptors was upregulated in both MHs and SHPCs from livers transplanted with BM-MCs
Summary
Small hepatocyte-like progenitor cells (SHPCs) appear to form transient clusters in rat livers treated with retrorsine (Ret) and 70% partial hepatectomy (PH). We previously reported that the expansion of SHPCs was amplified in Ret/PH-treated rat livers transplanted with Thy1+ cells derived from D-galactosamine-treated injured livers. Liver stem/progenitor cells (LSPCs) and mature hepatocytes (MHs) are considered cellular transplant sources for liver regeneration [3]. Small hepatocytes (SHs), and small hepatocyte-like progenitor cells (SHPCs) are well-recognized LSPCs. Oval cells, which are named for their ovoid nuclei, express Thy-1 (CD90), a specific marker of mesenchymal stem cells [4]. Previous reports demonstrated that Thy1+ cells emerge transiently in the periportal area soon after D-galactosamine (GalN)-injured liver, and some differentiate into MHs via CD44+ hepatocytes [5, 6]. The SHPCs’ origin and their precise location in the liver remain controversial [13,14,15,16]
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