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1. Activin Receptors
Yaron Shav-Tal, Smadar Lapter, Reshmi Parameswaran, and Dov Zipori Cytokine Reference 2001, www.academicpress.com/cytokinereference/
Activin receptors are structurally related membrane proteins that belong to the transforming growth factor (TGF)beta receptor superfamily. Two main types, I and II activin receptors have been identified which consist of an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain containing a serine/threonine kinase region. A dimer of each of these receptors participates in forming a receptor complex on the cell surface with the dimeric ligand. This activated complex signals intracellularly through the kinase domain of type I receptor to recruit and activate the intracellular mediators of activin signaling, receptor regulated (R)-Smad proteins. The latter form a hetero-oligomeric complex with a common (Co)-Smad protein shared by all TGFbeta induced signaling pathways. This complex then translocates to the nucleus and forms a transcription complex that binds to promoters and regulates several genes. One of these genes encodes an inhibitory (I)-Smad protein which negatively regulates further signaling. Activin receptors are widely expressed in various organs and cells types. Activin binding to its receptors leads to a plethora of biological functions which are antagonized by inhibin that competes with activin for binding to the receptor. However, activin receptors bind additional ligands and thus mediate functions which are not necessarily related to activin. Studies on mutant activin receptors in different species including mammalians, revealed dramatic phenotypes that demonstrate the crucial role of these receptors in early mesoderm induction. Accordingly, activin receptors control the expression of several mesoderm differentiation genes. Furthermore, activin receptors control embryonic axis symmetry determination and organ development and are also involved in the control of specific adult organ function.
2. Role of activin A in negative regulation of normal and tumor B lymphocytes.
Zipori D, Barda-Saad M.
J Leukoc Biol. 2001, 69:867-73
Activin A, a member of the transforming growth factor beta superfamily, has a wide spread expression pattern and pleiotropic functions. In this overview we summarize data that points to a role of activin A in negative regulation of B lineage lymphocytes. Experiments performed by us and by other groups revealed the capacity of activin A to cause apoptotic death of tumor myeloma cells, through mechanisms of cell cycle inhibition and antagonism with the survival signal of interleukin-6. In vitro studies on B lymphocyte generation from bone marrow stem cells and use of human nasal polyps as a model of inflamed tissue further demonstrate an inhibitory role of activin A in B cell spread and accumulation. These data are analyzed with respect to our model of tissue organization that we term the "restrictin model of cell growth regulation." This model assumes a morphogen-like role of activin A in the hematopoietic system. Thus, the relative concentration of biologically functional activin A, in different parts of the tissue, may determine the local B cell content and functional state of these cells within a specific microenvironment.
3. The role of activin a in regulation of hemopoiesis.
Shav-Tal Y, Zipori D.Stem Cells 2002;20(6):493-500
Activin A, a cytokine member of the transforming growth factor-beta superfamily, is expressed locally by the mesenchymal component of the hemopoietic microenvironment. Its expression is regulated on the mRNA level by different cytokines, and the biological activity of the protein is tightly controlled by several inhibitory molecules. Activin A affects hemopoietic cells of various lineages, as evidenced by in vitro studies of leukemia and lymphoma cell lines, which were used to elucidate the mechanism of its action. In the B-cell lineage, activin A is a cell cycle inhibitor, a mediator of apoptosis, and a cytokine antagonist. Limited information is available on the effects of activin A on normal hemopoietic cells. Recent studies suggest that it might be a negative regulator of normal B lymphopoiesis. Whereas the functions of activin A in vitro are well established, further research tools are needed to elucidate its role within specific hemopoietic microenvironments in vivo.
4. PSF and p54(nrb)/NonO--multi-functional nuclear proteins.
Shav-Tal Y, Zipori D. FEBS Lett 2002 Nov 6;531(2):109-14
Proteins are often referred to in accordance with the activity with which they were first associated or the organelle in which they were initially identified. However, a variety of nuclear factors act in multiple molecular reactions occurring simultaneously within the nucleus. This review describes the functions of the nuclear factors PSF (polypyrimidine tract-binding protein-associated splicing factor) and p54(nrb)/NonO. PSF was initially termed a splicing factor due to its association with the second step of pre-mRNA splicing while p54(nrb)/NonO was thought to participate in transcriptional regulation. Recent evidence shows that the simplistic categorization of PSF and its homolog p54(nrb)/NonO to any single nuclear activity is not possible and in fact these proteins exhibit multi-functional characteristics in a variety of nuclear processes.
Prindull G, Zipori D
Blood. 2004, 103:2892-9
Epithelial mesenchymal transitions are a remarkable example of cellular plasticity. These transitions are the hallmark of embryo development, are pivotal in cancer progression, and seem to occur infrequently in adult organisms. The reduced incidence of transitions in the adult could result from restrictive functions of the microenvironment that stabilizes adult cell phenotypes and prevents plastic behavior. Multipotential progenitor cells exhibiting a mesenchymal phenotype have been derived from various adult tissues. The ability of these cells to differentiate into all germ layer cell types, raises the question as to whether mesenchymal epithelial transitions occur in the adult organism more frequently than presently appreciated. A series of cytokines are known to promote the transitions between epithelium and mesenchyme. Moreover, several transcription factors and other intracellular regulator molecules have been conclusively shown to mediate these transitions. However, the exact molecular basis of these transitions is yet to be resolved. The identification of the restrictive mechanisms that prevent cellular transitions in adult organisms, which seem to be unleashed in cancerous tissues, may lead to the development of tools for therapeutic tissue repair and effective tumor suppression.
6. The nature of stem cells: state rather than entity.Stem cells are endowed with self-renewal and multipotential differentiation capacities. Contrary to the expectation that stem cells would selectively express specific genes, these cells have a highly promiscuous gene-expression pattern. Here, I suggest that the transient stem cell state, termed the 'stem state', may be assumed by any cell and that the search for specific genes expressed by all stem cells, which would characterize the stem cell as a cell type, might be futile.
Zipori D.
Nat Rev Genet. 2004, 5:873-8 7. Mesenchymal stem cells: harnessing cell plasticity to tissue and organ repair.
Zipori D.
Blood Cells Mol Dis. 2004, 33:211-5
Plastic behavior of cells is a hallmark of embryonic development. The emergence of primary mesenchyme from within the inner cell mass entails the first epithelial-mesenchymal transition step that is then followed by sequential transitions; the formation of new tissues and organs requires transitions from mesenchyme into epithelium and vice versa. Although it is currently believed that in the adult such transitions do not persist, the frequent occurrence of mesenchymal stem cells (MSCs) in various tissues of the adult organisms, and the reported plasticity of such adult mesenchymal cells, raises the question as to whether the frequency of mesenchymal epithelial transitions in the adult have been underestimated. Indeed, adult mesenchymal stem cells have been reported to differentiate in culture into a multitude of mature cell types including epithelial cells. This opens the way to the use of these stem cells for the construction of new tissues and organs for therapeutic purposes, but the question is still open as to whether mesenchymal stem cells transdifferentiate also in vivo. The molecular mechanism that underlies the plasticity of mesenchymal stem cells and their capacity to transdifferentiate is unresolved. We found that these cells have a promiscuous gene expression pattern; mesenchymal cells, whether primary or cloned cell lines, express T cell receptor (TCR) beta and alpha genes, along with other components of the TCR complex. These cells may therefore be in a standby state, in which many gene families are expressed at a low level thereby making the cell readily capable of shifting fates.
8. The stem state: plasticity is essential, whereas self-renewal and hierarchy are optional.
Zipori D.
Stem Cells. 2005, 23:719-26
The prevailing stem cell concept is derived from the large body of evidence available on the structure of the blood-generating system. Hemopoiesis is organized such that a multipotent stem cell, endowed with self-renewal capacity, is viewed as being positioned at the origin of a hierarchical tree of branching specificities, increasing maturity and decreasing self-renewal ability. Data accumulated in recent years on various stem cell systems often contradict this traditional view of stem cells and are reviewed herein. It is suggested that other options should be considered and put to experimental scrutiny; it is argued that the organization of the hemopoietic system may not represent a general structure of stem cell systems. The basic trait of the stem state is proposed to be plasticity. Self-renewal is not a specific stem cell trait; rather, it is exhibited by some mature cell types, whereas other particular stem cells are endowed with relatively poor renewal ability. Hierarchical structuring is also proposed to be an optional stem cell trait and may exist only in specific tissues where it serves the need for rapid expansion. The stem state is therefore defined by the highest degree of plasticity of a cell, within the repertoire of cell types present in the organism.
9. The stem state: Mesenchymal plasticity as a paradigm.
Zipori D.
Current Stem Cell Research and Therapy. 2006, 1:95-102
The mesenchyme is a remarkably plastic tissue in the embryo. Recent studies have led to the discovery of mesenchymal cells in the adult organism that can differentiate in vitro into unexpected directions, beyond the well-known ability of the mesenchyme to give rise to mesodermal derivatives. These studies highlighted the plastic nature of the mesenchyme, also beyond the embryonic developmental stage. This review discusses the possible functions of the mesenchyme in the adult and the reason for the maintenance of plasticity throughout mammalian life. The properties of the mesenchymal cells clearly exemplify the stem state concept; cells, whether early or late in the differentiation cascade may assume a stem state that entails high plasticity.
Zipori D.
Cancer and Metha Rev. 2006, 25: 459-67
Tissues and organs harbor a component of supportive mesenchymal stroma. The organ stroma is vital for normal functioning since it expresses factors instructing growth and differentiation along with molecules that restrain these processes. Similarly, the growth of tumors is strictly dependent on the tumor stroma. This review first discusses the possibility of developing tools to block the propagation of the tumor-associated stroma, that may halt tumor progression. It further describes how the tropism of mesenchymal stroma to tumor sites may be utilized to cause regression of the cancerous tissue. Mesenchyme can be genetically modified to overexpress specific regulatory molecules with known effects on specific tumors, such as interferon?? studied in the context of melanoma and glyoma and activin A, a transforming growth factor? cytokine, examined in multiple myeloma. These studies point to the possibility that genetically modified mesenchymal cells may be used as a therapeutic modality for incurable human diseases. It is proposed that further development of methods of tumor stroma targeting, or alternatively the use of stromal mesenchyme as a cell or cell/gene therapy modalities, may yield novel clinical tools for the treatment of human cancers.
11. Environmental Signals Regulating Mesenchymal Progenitor Cell Growth and Differentiation.
Meirav Pevsner-Fischer and Dov Zipori
V.K. Rajasekhar, M.C. Vemuri (eds.), Regulatory Networks in Stem Cells, Stem Cell Biology and Regenerative Medicine, 175 DOI 10.1007/978-1-60327-227-8 16, © Humana Press, a part of Springer Science+Business Media, LLC 2009.
Mesenchymal progenitor cells are widespread in the organism and are implicated in a variety of physiological and pathological processes. As such, these cells should be able to respond to microenvironmental signals. Here we review some of the conditions that modulate the biological functions of mesenchymal progenitors, particularly during inflammation and stress.
Dov Zipori.
Cancer Microenvironment. 2010 Feb 5;3(1):15-28.
Multiple myeloma cells are reminiscent of hemopoietic stem cells in their strict dependence upon the bone marrow microenvironment. However, from all other points of view, multiple myeloma cells differ markedly from stem cells. The cells possess a mature phenotype and secrete antibodies, and have thus made the whole journey to maturity, while maintaining a tumor phenotype. Not much credence was given to the possibility that the bulk of plasma-like multiple myeloma tumor cells is generated from tumor-initiating cells. Although interleukin-6 is a major contributor to the formation of the tumor's microenvironment in multiple myeloma, it is not a major factor within hemopoietic stem cell niches. The bone marrow niche for myeloma cells includes the activity of inflammatory cytokines released through osteoclastogenesis. These permit maintenance of myeloma cells within the bone marrow. In contrast, osteoclastogenesis constitutes a signal that drives hemopoietic stem cells away from their bone marrow niches. The properties of the bone marrow microenvironment, which supports myeloma cell maintenance and proliferation, is therefore markedly different from the characteristics of the hemopoietic stem cell niche. Thus, multiple myeloma presents an example of a hemopoietic tumor microenvironment that does not resemble the corresponding stem cell renewal niche.
13. Transition of endothelium to cartilage and bone.
Shoshani O, Zipori D.
Cell Stem Cell. Jan 7; 8(1):10-1.
Mesenchymal stromal cells (MSCs) are capable of differentiating into bone-forming osteoblasts. A recent Nature Medicine study (Medici et al., 2010) shows that the mislocalized bone in the human disease fibrodisplasia ossificans progressiva (FOP) originates from vascular endothelium that gives rise to MSCs.
14. Mammalian cell dedifferentiation as a possible outcome of stress.
Shoshani O, Zipori D.
Stem Cell Rev. 2011 Jan 29.
Differentiation cascades are arranged hierarchically; stem cells positioned at the top of the hierarchy generate committed progenitors that, in turn, proliferate and further differentiate stepwise into mature progeny. This rigid, irreversible structure ensures the phenotypic stability of adult tissues. However, such rigidity may be problematic under conditions of tissue damage when reconstitution is required. Although it may seem unlikely that the restrictions on changes in cell phenotypes would be lifted to enable tissue reconstitution, it is nevertheless possible that mammalian tissues are endowed with sufficient flexibility to enable their adaptation to extreme conditions.
15. The role of mesenchymal cells in cancer: contribution to tumor stroma and tumorigenic capacity.
Ofer Shoshani, Dov Zipori
The Tumor Microenvironment 2010, Volume 3, Part 2, 75-96,
DOI: 10.1007/978-90-481-9531-2_5Mesenchymal stromal cells were first isolated from the bone marrow, where they serve as a component of the tissue microenvironment. These cells provide a physical support for the other cells of the tissue; i.e., the hemopoietic cell lineage, and further participate in the formation of bone structures. Most importantly, stromal cells regulate the growth and differentiation of hemopoietic stem cells. The mesenchyme is not specific to the bone marrow: such cells are found body-wide, and serve similar regulatory functions. By the same token, the mesenchymal stroma contributes to tumor formation by providing regulatory signals. In addition, the stromal cells themselves may undergo transformation, and subsequently form tumors. This chapter discusses these two major aspects of stromal cell involvement in the tumorigenic process.
16. The origins of mesenchymal stromal cell heterogeneity.
Meirav Pevsner-Fischer, Sarit Levin and Dov Zipori
Stem Cell Reviews and Reports DOI: 10.1007/s12015-011-9229-7
Cultured mesenchymal stromal cell (MSC) populations are best characterized by the capacity of some cells within this population to differentiate into mesodermal derivatives such as osteoblasts, chondrocytes and adipocytes. However, this progenitor property is not shared by all cells within the MSC population. Furthermore, MSCs exhibit variability in their phenotypes, including proliferation capacity, expression of cell surface markers and ability to secrete cytokines. These facts raise three major questions: (1) Does the in vitro observed variability reflect the existence of MSC subsets in vivo? (2) What is the molecular basis of the in vitro observed heterogeneity? and (3) What is the biological significance of this variability? This review considers the possibility that the variable nature of MSC populations contributes to the capacity of adult mammalian tissues to adapt to varying microenvironmental demands.
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