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Primary myelofibrosis and the "bad seeds in bad soil" concept.

Le Bousse-Kerdil├Ęs MC - Fibrogenesis Tissue Repair (2012)

Bottom Line: We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells.These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions.A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation.

View Article: PubMed Central - HTML - PubMed

Affiliation: The French INSERM and the European EUMNET networks on Myelofibrosis, The French Intergroup of Myeloproliferative disorders (FIM), INSERM U972, Paris XI University, Laboratory of Hematology, Paul Brousse Hospital, 14, av. Paul-Vaillant Couturier ; 948007, Villejuif Cedex, France.

ABSTRACT
Primary Myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by a clonal myeloproliferation and a myelofibrosis. The concomitant presence of neoangiogenesis and osteosclerosis suggests a deregulation of medullar stem cell niches in which hematopoietic stem cells are engaged in a constant crosstalk with their stromal environment. Despite the recently discovered mutations including the JAK2(Val617F) mutation, the primitive molecular event responsible for the clonal hematopoietic proliferation is still unknown. We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells. These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions. Therefore, PMF is a remarkable "model" in which deregulation of the stem cell niche is of utmost importance for the disease development. A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the medullar niches. In healthy adults, hematopoiesis occurs in the bone marrow where hematopoietic stem cells (HSCs) are engaged in a constant crosstalk within specific niches. Very schematically, these haematopoietic stem cell niches are conceptually divided into two niches: The endosteal niche in which osteoblasts, derived from Mesenchymal Stromal Cell (MSC) differentiation and contributing to bone formation and osteoclats, derived from HSCs, and participating in bone resorption played a crucial role. The vascular niche in which endothelial cells, resulting from the proliferation and differentiation of Endothelial Stem Cells (ESC), are in close contact with HSC within the perivascular spaces. Beyond cell-cell contacts through receptor-ligand and adhesion molecule interactions, extracellular matrix component (EMC), cytokines and chemokines, proteases, calcium and oxygen concentrations are essential environmental components of these niches.
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Figure 2: Schematic representation of the medullar niches. In healthy adults, hematopoiesis occurs in the bone marrow where hematopoietic stem cells (HSCs) are engaged in a constant crosstalk within specific niches. Very schematically, these haematopoietic stem cell niches are conceptually divided into two niches: The endosteal niche in which osteoblasts, derived from Mesenchymal Stromal Cell (MSC) differentiation and contributing to bone formation and osteoclats, derived from HSCs, and participating in bone resorption played a crucial role. The vascular niche in which endothelial cells, resulting from the proliferation and differentiation of Endothelial Stem Cells (ESC), are in close contact with HSC within the perivascular spaces. Beyond cell-cell contacts through receptor-ligand and adhesion molecule interactions, extracellular matrix component (EMC), cytokines and chemokines, proteases, calcium and oxygen concentrations are essential environmental components of these niches.

Mentions: Whether the concept of hematopoietic niches is dating from Schofield in 1978 [12], their exact location in the bone marrow is still under debate. In healthy adult mice, it is commonly accepted that most HSCs are located close to the endosteal lining cells in the trabecular area. Staining of sections of adult hematopoietic tissues also revealed the presence of HSCs around bone marrow sinusoids (perivascular niches) (Figure 2). However, it is uncertain whether both locations represent niches and, if so, whether they are spatially distinct niches or whether endosteal cells and perivascular cells collaborate to form a common niche in which mesenchymal stem cells would be an essential link [13-15]. Furthermore, it remains to be determined whether these locations actively promote the maintenance of HSCs, or whether HSCs simply pass through some of them during their migration.


Primary myelofibrosis and the "bad seeds in bad soil" concept.

Le Bousse-Kerdil├Ęs MC - Fibrogenesis Tissue Repair (2012)

Schematic representation of the medullar niches. In healthy adults, hematopoiesis occurs in the bone marrow where hematopoietic stem cells (HSCs) are engaged in a constant crosstalk within specific niches. Very schematically, these haematopoietic stem cell niches are conceptually divided into two niches: The endosteal niche in which osteoblasts, derived from Mesenchymal Stromal Cell (MSC) differentiation and contributing to bone formation and osteoclats, derived from HSCs, and participating in bone resorption played a crucial role. The vascular niche in which endothelial cells, resulting from the proliferation and differentiation of Endothelial Stem Cells (ESC), are in close contact with HSC within the perivascular spaces. Beyond cell-cell contacts through receptor-ligand and adhesion molecule interactions, extracellular matrix component (EMC), cytokines and chemokines, proteases, calcium and oxygen concentrations are essential environmental components of these niches.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368798&req=5

Figure 2: Schematic representation of the medullar niches. In healthy adults, hematopoiesis occurs in the bone marrow where hematopoietic stem cells (HSCs) are engaged in a constant crosstalk within specific niches. Very schematically, these haematopoietic stem cell niches are conceptually divided into two niches: The endosteal niche in which osteoblasts, derived from Mesenchymal Stromal Cell (MSC) differentiation and contributing to bone formation and osteoclats, derived from HSCs, and participating in bone resorption played a crucial role. The vascular niche in which endothelial cells, resulting from the proliferation and differentiation of Endothelial Stem Cells (ESC), are in close contact with HSC within the perivascular spaces. Beyond cell-cell contacts through receptor-ligand and adhesion molecule interactions, extracellular matrix component (EMC), cytokines and chemokines, proteases, calcium and oxygen concentrations are essential environmental components of these niches.
Mentions: Whether the concept of hematopoietic niches is dating from Schofield in 1978 [12], their exact location in the bone marrow is still under debate. In healthy adult mice, it is commonly accepted that most HSCs are located close to the endosteal lining cells in the trabecular area. Staining of sections of adult hematopoietic tissues also revealed the presence of HSCs around bone marrow sinusoids (perivascular niches) (Figure 2). However, it is uncertain whether both locations represent niches and, if so, whether they are spatially distinct niches or whether endosteal cells and perivascular cells collaborate to form a common niche in which mesenchymal stem cells would be an essential link [13-15]. Furthermore, it remains to be determined whether these locations actively promote the maintenance of HSCs, or whether HSCs simply pass through some of them during their migration.

Bottom Line: We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells.These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions.A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation.

View Article: PubMed Central - HTML - PubMed

Affiliation: The French INSERM and the European EUMNET networks on Myelofibrosis, The French Intergroup of Myeloproliferative disorders (FIM), INSERM U972, Paris XI University, Laboratory of Hematology, Paul Brousse Hospital, 14, av. Paul-Vaillant Couturier ; 948007, Villejuif Cedex, France.

ABSTRACT
Primary Myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by a clonal myeloproliferation and a myelofibrosis. The concomitant presence of neoangiogenesis and osteosclerosis suggests a deregulation of medullar stem cell niches in which hematopoietic stem cells are engaged in a constant crosstalk with their stromal environment. Despite the recently discovered mutations including the JAK2(Val617F) mutation, the primitive molecular event responsible for the clonal hematopoietic proliferation is still unknown. We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells. These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions. Therefore, PMF is a remarkable "model" in which deregulation of the stem cell niche is of utmost importance for the disease development. A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation.

No MeSH data available.


Related in: MedlinePlus