The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mesenchymal stromal cells into osteoblasts

The proto-oncogene Src is an important non-receptor protein tyrosine kinase involved in signaling pathways that control cell adhesion, growth, migration and differentiation. It negatively regulates osteoblast activity, and, as such, its inhibition is a potential means to prevent bone loss. Dasatinib is a new dual Src/Bcr-Abl tyrosine kinase inhibitor initially developed for the treatment of chronic myeloid leukemia. It has also shown promising results in preclinical studies in various solid tumors. However, its effects on the differentiation of human osteoblasts have never been examined.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Early diverging lineages within Cryptomycota and Chytridiomycota dominate the fungal communities in ice-covered lakes of the McMurdo Dry Valleys, Antarctica

Antarctic ice-covered lakes are exceptional sites for studying the ecology of aquatic fungi under conditions of minimal human disturbance. In this study, we explored the diversity and community composition of fungi in five permanently covered lake basins located in the Taylor and Miers Valleys of Antarctica. Based on analysis of the 18S rRNA sequences, we showed that fungal taxa represented between 0.93% and 60.32% of the eukaryotic sequences. Cryptomycota and Chytridiomycota dominated the fungal communities in all lakes; however, members of Ascomycota, Basidiomycota, Zygomycota, and Blastocladiomycota were also present. Of the 1313 fungal OTUs identified, the two most abundant, belonging to LKM11 and Chytridiaceae, comprised 74% of the sequences. Significant differences in the community structure were determined among lakes, water depths, habitat features (i.e., brackish vs. freshwaters), and nucleic acids (DNA vs. RNA), suggesting niche differentiation. Network analysis suggested the existence of strong relationships among specific fungal phylotypes as well as between fungi and other eukaryotes. This study sheds light on the biology and ecology of basal fungi in aquatic systems. To our knowledge, this is the first report showing the predominance of early diverging lineages of fungi in pristine limnetic ecosystems, particularly of the enigmatic phylum Cryptomycota.National Science Foundation/[PLR1439774]/NSF/Estados UnidosNational Science Foundation/[PLR1115245]/NSF/Estados UnidosNational Science Foundation/[PLR 1543537]/NSF/Estados UnidosNational Aeronautics and Space Administration/[NNH14ZDA001N-PSTAR]/NASA/Estados UnidosUCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Biologí

Cord Blood-Derived Macrophage-Lineage Cells Rapidly Stimulate Osteoblastic Maturation in Mesenchymal Stem Cells in a Glycoprotein-130 Dependent Manner

In bone, depletion of osteoclasts reduces bone formation in vivo, as does osteal macrophage depletion. How osteoclasts and macrophages promote the action of bone forming osteoblasts is, however, unclear. Since recruitment and differentiation of multi-potential stromal cells/mesenchymal stem cells (MSC) generates new active osteoblasts, we investigated whether human osteoclasts and macrophages (generated from cord blood-derived hematopoietic progenitors) induce osteoblastic maturation in adipose tissue-derived MSC. When treated with an osteogenic stimulus (ascorbate, dexamethasone and β-glycerophosphate) these MSC form matrix-mineralising, alkaline phosphatase-expressing osteoblastic cells. Cord blood-derived progenitors were treated with macrophage colony stimulating factor (M-CSF) to form immature proliferating macrophages, or with M-CSF plus receptor activator of NFκB ligand (RANKL) to form osteoclasts; culture medium was conditioned for 3 days by these cells to study their production of osteoblastic factors. Both osteoclast- and macrophage-conditioned medium (CM) greatly enhanced MSC osteoblastic differentiation in both the presence and absence of osteogenic medium, evident by increased alkaline phosphatase levels within 4 days and increased mineralisation within 14 days. These CM effects were completely ablated by antibodies blocking gp130 or oncostatin M (OSM), and OSM was detectable in both CM. Recombinant OSM very potently stimulated osteoblastic maturation of these MSC and enhanced bone morphogenetic protein-2 (BMP-2) actions on MSC. To determine the influence of macrophage activation on this OSM-dependent activity, CM was collected from macrophage populations treated with M-CSF plus IL-4 (to induce alternative activation) or with GM-CSF, IFNγ and LPS to cause classical activation. CM from IL-4 treated macrophages stimulated osteoblastic maturation in MSC, while CM from classically-activated macrophages did not. Thus, macrophage-lineage cells, including osteoclasts but not classically activated macrophages, can strongly drive MSC-osteoblastic commitment in OSM-dependent manner. This supports the notion that eliciting gp130-dependent signals in human MSC would be a useful approach to increase bone formation