Development of stabilin2+ endothelial cells from mouse embryonic stem cells by inhibition of TGFbeta/activin signaling.
ABSTRACT To understand the endothelial cell (EC) development, arterial, venous, and lymphatic EC (LEC) have been successfully induced from embryonic stem cells (ESC). However, tissue-specific EC, such as hepatic sinusoidal EC (HSEC), have never been generated from ESC. Based on the findings that TGFbeta/activin signaling negatively regulates differentiation of both LEC and HSEC, and that HSEC and LEC are distinguishable by the expression of marker genes, we assessed the role of TGFbeta/activin signaling in EC development from ESC. Here we show that the inhibition of TGFbeta/activin signaling by a TGFbeta receptor I (TGFbetaRI) kinase inhibitor increased the expression of Lyve1 and stabilin2 but not podoplanin in CD31+CD34+ EC derived from ESC. EC generated by the inhibition of TGFbetaRI signaling also exhibited stronger endocytic activity than control EC, indicating that their phenotype is similar to fetal HSEC. Our results reveal that TGFbeta/activin signaling negatively regulates the early events of HSEC differentiation.
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ABSTRACT: Tissue engineering is the process by which biological structures are recreated using a combination of molecular signals, cellular components and scaffolds. Although the perceived potential of this approach to reconstruct damaged or missing tissues is seemingly limitless, application of these ideas in vivo has been more difficult than expected. However, despite these obstacles, important advancements have been reported for a number of organ systems, including recent reports on the lymphatic system. These advancements are important since the lymphatic system plays a central role in immune responses, regulation of inflammation, lipid absorption and interstitial fluid homeostasis. Insights obtained over the past two decades have advanced our understanding of the molecular and cellular mechanisms that govern lymphatic development and function. Utilizing this knowledge has led to important advancements in lymphatic tissue engineering, which is the topic of this review.Future Oncology 09/2013; 9(9):1365-74. · 2.61 Impact Factor
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ABSTRACT: Sotatercept (ACE-011), a recombinant human fusion protein containing the extracellular domain of the human Activin receptor IIA, binds to and inhibits activin and other members of the transforming growth factor -β (TGF-β) superfamily. Administration of sotatercept led to a rapid and sustained increase in red blood cell (RBC) count and haemoglobin (Hb) in healthy volunteers (phase I clinical trials), but the mechanism is not fully understood. Mice treated with RAP-011 (murine ortholog of ACE-011) respond with a rapid (within 24 h) increase in haematocrit, Hb, and RBC count. These effects are accompanied by an equally rapid stimulation of late-stage erythroid precursors in the bone marrow (BM). RAP-011 also induces a significant increase in erythroid burst-forming units and erythropoietin, which could contribute to additional, sustained effects on RBC production. Further in vitro co-culture studies demonstrate that BM accessory cells are required for RAP-011 effects. To better understand which TGF-β family ligand(s) mediate RAP-011 effects, we evaluated the impact of several of these ligands on erythroid differentiation. Our data suggest that RAP-011 may act to rescue growth differentiation factor 11/Activin A-induced inhibition of late-stage erythropoiesis. These data define the mechanism of action of a novel agent that regulates RBC differentiation and provide the rationale to develop sotatercept for the treatment of anaemia and ineffective erythropoiesis.British Journal of Haematology 03/2014; · 4.94 Impact Factor
Article: Stem cells and liver engineering.[Show abstract] [Hide abstract]
ABSTRACT: Human hepatocytes, suitable for treatment of patients with liver failure, for the creation of bioartificial (BAL) devices, or for studies for toxicity and metabolisation studies in the pharmceutical industry, are in short supply due to the lack of donor organs. Therefore, methods that allow ex vivo expansion of hepatocytes with mature function are being pursued. One cell source, believed to be a possible inexhaustible source of hepatocytes, are pluripotent stem cells (PSCs). However, directed differentiation of PSCs to cells with features of adult hepatocytes is not yet possible. Differentiated progeny remains mixed and PSC progeny do not have a number of the functional features of mature hepatocytes. In this review article, we will address tools being developed that allow for identification of mature hepatocytes, in a non-invasive manner; to perform lineage tracing of PSC progeny; and novel culture systems being created for the in vitro differentiation of PSCs to hepatocyte like cells, and for the maintenance of primary liver derived hepatocytes or PSC-derived hepatic progeny in culture. As conventional two-dimensional (2D) static culture conditions poorly recapitulate the in vivo cellular environment, we will discuss bioreactor systems for liver tissue engineering, both macro-scale and micro-scale culture systems.Biotechnology advances 07/2013; · 8.91 Impact Factor