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.
"While initial publications described that Activin A promoted maturation of BFU-E (Nakao et al, 1991), CFU-E (Shiozaki et al, 1989) and more mature erythroid precursors (Okabe- Kado et al, 1991), more recent publications evaluating haematopoietic differentiation of embryonic stem cells or induced pluripotent stem cell point to a pivotal role for Activin A signalling in the maintenance of self-renewal and pluripotency (Vallier et al, 2005; Xiao et al, 2006) as well as in maintaining commitment to the mesodermal lineage (Nostro et al, 2008; Pearson et al, 2008). However, Activin A was shown not to be necessary, and was perhaps even inhibitory with regard to definitive erythroid differentiation (Nonaka et al, 2008; Kennedy et al, 2012). Moreover, in transgenic mice over-expressing a soluble form of its receptor an increase on RBC parameters was also described (Yamawaki et al, 2013). "
[Show abstract][Hide abstract] 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; 165(6). DOI:10.1111/bjh.12838 · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have determined the occurrence of responses at different levels (morphological, physiological and biochemical) in the omnivorous rodent Akodon azarae upon cold acclimation (15 degrees C). A short-term enhancement in food consumption appeared to account for the maintenance of both mass and body composition. At the morphological level, the main response was an increase in the dimensions of small intestine, which constitutes the section of the gut where absorption and secretion take place. An increase in sucrase specific activity was only found in small intestine. Sucrose independent maltase activity was very low since 99.8% of total maltase activity was due to sucrase-isomaltase (SI) complex. Protease specific activities were not affected. The fact that resting metabolic rates determined at 15 and 23 degrees C were similar in cold acclimated animals suggests a change in lower critical temperature. In conclusion, our results show that A. azarae exhibits different strategies to support cold environment that could lead to an enhancement in digestion and absorption efficiency. Furthermore, this work suggests that low temperature is an independent cue of other environmental factors to trigger the strategies allowing the maintenance of body condition in A. azarae.
Comparative Biochemistry and Physiology - Part A Molecular & Integrative Physiology 01/2005; 139(4):503-12. DOI:10.1016/j.cbpb.2004.10.013 · 1.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transforming growth factor (TGF)-betas and their family members, including bone morphogenetic proteins (BMPs), Nodal and activins, have been implicated in the development and maintenance of various organs, in which stem cells play important roles. Stem cells are characterized by their ability to self-renew and to generate differentiated cells of a particular tissue, and are classified into embryonic and somatic stem cells. Embryonic stem (ES) cells self-renew indefinitely and contribute to derivatives of all three primary germ layers. In contrast, somatic stem cells, which can be identified in various adult organs, exhibit limited abilities for self-renewal and differentiation in most cases. The multi-lineage differentiation capacity of ES cells and somatic stem cells has opened possibilities for cell replacement therapies for genetic, malignant and degenerative diseases. In order to utilize stem cells for therapeutic applications, it is essential to understand the extrinsic and intrinsic factors regulating self-renewal and differentiation of stem cells. More recently, induced pluripotent stem (iPS) cells have been generated from mouse and human fibroblasts that resemble ES cells via ectopic expression of four transcription factors. iPS cells may have an advantage in regenerative medicine, since they overcome the immunogenicity and ethical controversy of ES cells. Moreover, recent studies have highlighted the involvement of cancer stem cells during the formation and progression of various types of cancers, including leukemia, glioma, and breast cancer. Here, we illustrate the roles of TGF-beta family members in the maintenance and differentiation of ES cells, somatic stem cells, and cancer stem cells.
Cell Research 01/2009; 19(1):103-15. DOI:10.1038/cr.2008.323 · 12.41 Impact Factor
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