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1. Toll-like receptors and their ligands control mesenchymal stem cell functions.
Pevsner-Fischer M, Morad V, Cohen-Sfady M, Rousso-Noori L, Zanin-Zhorov A, Cohen S, Cohen IR, Zipori D. Blood. 2007 Feb 15;109(4):1422-32 Mesenchymal stem cells (MSC) are widespread in adult organisms and may be involved in tissue maintenance and repair, as well as in the regulation of hemopoiesis and immunological responses. Thus, it is important to discover the factors controlling MSC renewal and differentiation. Here we report that adult MSC express functional Toll-like receptors (TLR), confirmed by the responses of MSC to TLR ligands. Pam3Cys, a prototypic TLR-2 ligand, augmented interleukin-6 secretion by MSC, induced nuclear factor kappa B (NF-kappaB) translocation, reduced MSC basal motility and increased MSC proliferation. The hallmark of MSC function is their capacity to differentiate into several mesodermal lineages. We show herein that Pam3Cys inhibited MSC differentiation into osteogenic, adipogenic and chondrogenic cells while sparing their immunosuppressive effect. Our study therefore shows that a TLR ligand can antagonize MSC differentiation triggered by exogenous mediators and consequently maintains the cells in an undifferentiated and proliferating state in vitro. Moreover, MSC derived from myeloid factor 88 (MyD88) deficient mice lacked the capacity to differentiate effectively into osteogenic and chondrogenic cells. It appears that TLR and their ligands can serve as regulators of MSC proliferation and differentiation and might affect the maintenance of MSC multipotency.
Morad V, Pevsner-Fischer M, Barnees S, Samokovlisky A, Rousso-Noori L, Rosenfeld R, Zipori D.
Stem Cells. 2008 Sep;26(9):2275-2286.
Cultured bone marrow stromal cells create an in vitro milieu supportive of long-term hemopoiesis and serve as a source for multipotent mesenchymal progenitor cells defined by their ability to differentiate into a variety of mesodermal derivatives. This study aims to examine whether the capacity to support myelopoiesis is coupled with the multipotency. Our results show that the myelopoietic supportive ability of stromal cells, whether from the bone marrow or from embryo origin, is not linked with multipotency; cell populations that possess multipotent capacity may or may not support myelopoiesis, whereas others, lacking multipotency, may possess full myelopoietic supportive ability. However, upon differentiation, the ability of multipotent mesenchymal progenitors to support myelopoiesis is varied. Osteogenic differentiation did not affect myelopoietic supportive capacity, whereas adipogenesis resulted in reduced ability to support the maintenance of myeloid progenitor cells. These differences were accompanied by a divergence in glycosylation patterns, as measured by binding to lectin microarrays; osteogenic differentiation was associated with an increased level of antennarity of N-linked glycans, whereas adipogenic differentiation caused a decrease in antennarity. Inhibition of glycosylation prior to seeding the stroma with bone marrow cells resulted in reduced capacity of the stromal cells to support the formation of cobblestone areas. Our data show that myelopoietic support is unrelated to the multipotent phenotype of cultured mesenchymal progenitors but is dependent on the choice of differentiation pathway and upon correct glycosylation of the stromal cells.
