Significance and Therapeutic Potential of Endothelial Progenitor Cell Transplantation in a Cirrhotic Liver Rat Model

Nakamura, Tõru; Torimura, Takuji; Sakamoto, Masaharu; Hashimoto, Osamu; Taniguchi, Eitaro; Inoue, Kinya; Sakata, Ryuichiro; Kumashiro, Ryukichi; Murohara, Toyoaki; Ueno, Takato; Sata, Michio

doi:10.1053/j.gastro.2007.03.110

Cited by 141 publications

(162 citation statements)

References 56 publications

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“…In our study, LYVE-1-positive endothelial cells in EBs treated with AM and SB431542 expressed stabilin-2, and some exhibited fenestrae-like structures. In addition, transcription of the LSEC markers F8, Consistent with that idea, it was recently shown that transplanted sinusoidal endothelial cells can repopulate the liver endothelium and correct the phenotype of hemophilia A mice [7,15], and several reports have shown that endothelial progenitor cell transplantation ameliorates acute liver injury and liver cirrhosis in rats [18,23,31,32] . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 23 Our second major finding is that AM-RAMP2 system is the potentital target for the induction of LSECs.…”

Section: Discussionmentioning

confidence: 56%

Induction of LYVE-1/stabilin-2-positive liver sinusoidal endothelial-like cells from embryoid bodies by modulation of adrenomedullin-RAMP2 signaling

et al. 2011

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Embryonic stem cells (ESCs) are a useful source for various cell lineages. So far, however, progress toward reconstitution of mature liver morphology and function has been limited. We have shown that knockout mice deficient in adrenomedullin (AM), a multifunctional endogenous peptide, or its receptor-activity modifying protein (RAMP2) die in utero due to poor vascular development and hemorrhage within the liver. In this study, using embryoid bodies (EBs)-culture system, we successfully induced liver sinusoidal endothelial-like cells by modulation of AM-RAMP2. In an EB differentiation system, we found that co-administration of AM and SB431542, an inhibitor of transforming growth factor (TGF ) receptor type 1, markedly enhanced differentiation of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1)/stabilin-2-positive endothelial cells. These cells showed robust endocytosis of acetylated low-density lipoprotein (Ac-LDL) and upregulated expression of liver sinusoidal endothelial cells (LSECs)-specific markers, including factor 8 (F8), Fc-γ receptor 2b (Fcgr2b), and mannose receptor C type 1 (Mrc1), and also possess fenestrae-like structure, a key morphological feature of LSECs. In RAMP2-null liver, by contrast, LYVE-1 was downregulated in LSECs, and the sinusoidal structure was disrupted. Our findings highlight the importance of AM-RAMP2 signaling for

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Section: Discussionmentioning

confidence: 56%

Induction of LYVE-1/stabilin-2-positive liver sinusoidal endothelial-like cells from embryoid bodies by modulation of adrenomedullin-RAMP2 signaling

et al. 2011

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“…55 In contrast, progressive recruitment of bone-marrow-derived cells may occur over time, such that these cells can represent a substantial fraction of the total fibrogenic population in more chronic injury. Bone marrow recruitment of mesenchymal cells remains a somewhat confusing event because of contradictory findings that on the one hand, bone marrow may provide fibrogenic cells, yet on the other hand autologous bone marrow 56,57 and marrow-derived endothelial progenitor cells 58 can be antifibrotic. It remains unclear which cells within marrow contribute to fibrogenesis and which might be antifibrotic, and/or what mediators regulate these apparently divergent activities of bone-marrow-derived cells.…”

Section: Cellular Sources Of Ecm In Hepatic Fibrosis: An Evolving Parmentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, posttranscriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.The field of hepatic fibrosis is flourishing thanks to continued experimental advances complemented by exciting progress in the treatment of chronic liver disease. 1 Control of chronic hepatitis B and C by antiviral therapies has established that advanced fibrosis can regress in association with improved clinical outcomes, 2-4 thereby intensifying enthusiasm to uncover the mechanistic basis for hepatic fibrogenesis and its attenuation. At the same time, simple paradigms defining the cellular sources of extracellular matrix (ECM), and the roles of cytokines and paracrine interactions among resident liver cells and inflammatory cells have yielded a more nuanced understanding of how the liver responds to injury. These advances have had a collateral benefit towards understanding fibrosis in other organs, particularly the pancreas. 5 Thus, a review of the mechanisms underlying hepatic fibrosis is not only timely, but is more clinically relevant than ever. This article focuses on recent advances in the field, building on established principles from earlier reviews 6,7 while weaving in their clinical relevance, but also emphasizing the molecular subtleties that have emerged through continued progress in the field. General PrinciplesFibrosis, or scarring of the liver, is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. Although even acute injury will activate mechanisms of fibrogenesis, the sustained signals associated with chronic liver disease caused by infection, Cirrhosis, the most advanced stage ...

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“…47 The same group reported in 2007 that EPC (characterized by the expression of CD133, VEGFR2, Tie-2 and CD31) given intravenously were able to reduce significantly liver damage and fibrogenesis in a model of liver cirrhosis induced by chronic administration of carbon tetrachloride. 48 In our group, 49 we observed that intrasplenic injection of EPC resulted in marked improvement and long-term survival of mice injected with an adenovirus encoding CD40L, a model of fulminant hepatitis with 100% mortality. 50 Neovascularization plays a critical role in the growth and metastatic spread of tumors and involves recruitment of circulating EPC from BM as well as sprouting of preexisting endothelial cells.…”

Section: Bone Marrow-derived Endothelial Progenitor Cells As Carriersmentioning

confidence: 89%

Cells as vehicles for therapeutic genes to treat liver diseases

et al. 2008

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Significance and Therapeutic Potential of Endothelial Progenitor Cell Transplantation in a Cirrhotic Liver Rat Model

Cited by 141 publications

References 56 publications

Induction of LYVE-1/stabilin-2-positive liver sinusoidal endothelial-like cells from embryoid bodies by modulation of adrenomedullin-RAMP2 signaling

Induction of LYVE-1/stabilin-2-positive liver sinusoidal endothelial-like cells from embryoid bodies by modulation of adrenomedullin-RAMP2 signaling

Mechanisms of Hepatic Fibrogenesis

Cells as vehicles for therapeutic genes to treat liver diseases

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