MSCs therapy sustained the active proliferative responses in the 30PLT+MSCs group.

<p>Immunochemical staining for PCNA and cyclin D1 at 72 h after reperfusion (magnification ×100). Compared with the 30PLT+PBS group, MSCs therapy markedly promoted the expressions of PCNA and CyD1 in graft. (Mean ± SD; *p<0.01.)</p

Rapamycin treatment improves the intrahepatic microstructure in BDL-Ra rats, evaluated by transmission electron microscopy (TEM).

<p>Representative liver TEM micrographs of (A) SHAM, (B) SHAM-Ra, (C) BDL, (D) BDL-Ra (magnification A, B: 5000×; C, D: 3000×, respectively). Arrow heads point to liver nuclei, triangles represent fibroblasts and asterisks denote neutrophils.</p

Rapamycin treatment attenuates intrahepatic inflammation in BDL-Ra rats.

<p>Representative western blot (A) and densitometric analyses (B) for precursor- and mature-IL-1β expressions in rat livers respectively (mean±SEM; *p<0.05; **p<0.01; ***p<0.005; ns - nonsignificant).</p

Rapamycin treatment downregulates liver fibrosis- and inflammatory-related genes in BDL-Ra rats.

<p>(A) mTOR, (B) P70S6K, (C) 4EBP1, (D) Procollagen (PC) α1(I), (E) α-SMA, (F) PDGF, (G) PDGFRβ, (H) TGF β1, (I) TIMP-1, (J) TNF-α, and (K) iNOS mRNA, measured by fluorescence quantitative PCR and normalized to GAPDH (mean±SEM; *p<0.05; **p<0.01; ***p<0.005; ns - nonsignificant).</p

Mesenchymal stem cell (MSC) culture and identification.

<p>(A) The morphology of MSCs cultured at 5th, 7th, and 11st day (magnification ×100); (B) Fluorescence-activated cell sorting analysis of rat MSCs. Numbers in the panels represent percentage of the cells expressing each marker.</p

PI3K/AKT/mTOR signaling pathway.

<p>Rapamycin bound to FKBP12 mainly blocked the activity of mTORC1.</p

Mesenchymal Stem Cells Promote Liver Regeneration and Prolong Survival in Small-For-Size Liver Grafts: Involvement of C-Jun N-Terminal Kinase, Cyclin D1, and NF-κB

<div><p>Background</p><p>The therapeutic potential of mesenchymal stem cells (MSCs) has been highlighted recently for treatment of acute or chronic liver injury, by possibly differentiating into hepatocyte-like cells, reducing inflammation, and enhancing tissue repair. Despite recent progress, exact mechanisms of action are not clearly elucidated. In this study, we attempted to explore whether and how MSCs protected hepatocytes and stimulated allograft regeneration in small-for-size liver transplantation (SFSLT).</p><p>Methods</p><p>SFSLT model was established with a 30% partial liver transplantation (30PLT) in rats. The differentiation potential and characteristics of bone marrow derived MSCs were explored in vitro. MSCs were infused transvenously immediately after graft implantation in therapy group. Expressions of apoptosis-, inflammatory-, anti-inflammatory-, and growth factor-related genes were measured by RT-PCR, activities of transcription factors AP-1 and NF-κB were analyzed by EMSA, and proliferative responses of the hepatic graft were evaluated by immunohistochemistry and western blot.</p><p>Results</p><p>MSCs were successfully induced into hepatocyte-like cells, osteoblasts and adipocytes in vitro. MSCs therapy could not only alleviate ischemia reperfusion injury and acute inflammation to promote liver regeneration, but also profoundly improve one week survival rate. It markedly up-regulated the mRNA expressions of HGF, Bcl-2, Bcl-XL, IL-6, IL-10, IP-10, and CXCR2, however, down-regulated TNF-α. Increased activities of AP-1 and NF-κB, as well as elevated expressions of p-c-Jun, cyclin D1, and proliferating cell nuclear antigen (PCNA), were also found in MSCs therapy group.</p><p>Conclusion</p><p>These data suggest that MSCs therapy promotes hepatocyte proliferation and prolongs survival in SFSLT by reducing ischemia reperfusion injury and acute inflammation, and sustaining early increased expressions of c-Jun N-terminal Kinase, Cyclin D1, and NF-κB.</p></div

Rapamycin treatment ameliorates liver size and splenomegaly in BDL-Ra rats.

<p>Representative photographs of liver and spleen from (A) SHAM, (B) SHAM-Ra, (C) BDL, (D) BDL-Ra rats.</p

Oligonucleotide sequence of transcription factor detected by EMSA.

<p>Oligonucleotide sequence of transcription factor detected by EMSA.</p

Animal characteristic and hemodynamic parameters.

<p>Animal characteristic and hemodynamic parameters.</p