Distinctive contact between CD34+ hematopoietic progenitors and CXCL12+ CD271+ mesenchymal stromal cells in benign and myelodysplastic bone marrow

Flores-Figueroa, Eugenia; Varma, Sushama; Montgomery, Kelli; Greenberg, Peter L.; Gratzinger, Dita

doi:10.1038/labinvest.2012.93

Cited by 76 publications

(71 citation statements)

References 52 publications

(61 reference statements)

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“…Moreover, CXCL12 þ cell density in MDS/AML-MRC bone marrow was greater than in control bone marrow. Our result agrees with recent data showing that CD271 þ /ALP þ mesenchymal stromal cells (MSCs) were immunoreactive for CXCL12 in human bone marrow and that CD271 þ MSC area and CXCL12 þ /ALP þ cell area were both increased in MDS, 21 and that CXCL12 cytokine levels were high in MDS bone marrow plasma. 22,23 With regard to the interaction between CXCL12 þ cells and hematopoietic cells, our analyses of in vitro cocultures and MDS samples indicated that contact or interaction with CXCL12 þ cells enhances BCL-2 expression and antiapoptosis in CD34 þ hematopoietic cells through CXCL12/CXCR4 signaling in MDS bone marrow.…”

Section: Discussionsupporting

confidence: 93%

CXCL12+ stromal cells as bone marrow niche for CD34+ hematopoietic cells and their association with disease progression in myelodysplastic syndromes

Abe‐Suzuki

Kurata

Abe

et al. 2014

Laboratory Investigation

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The bone marrow microenvironment, known as 'hematopoietic stem cell niche,' is essential for the survival and maintenance of hematopoietic stem cells. Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases, which eventually result in leukemic transformation (acute myelogenous leukemia with myelodysplasia-related changes, AML-MRC). However, the precise components and functions of the MDS niche remain unclear. Recently, CXCL12-abundant reticular cells were shown to act as a hematopoietic stem cell niche in the murine bone marrow. Using immunohistochemistry, we show here that CXCL12 þ cells were located in the cellular marrow or perivascular area, and were in contact with CD34 þ hematopoietic cells in control and MDS/AML-MRC bone marrow. MDS bone marrow exhibited higher CXCL12 þ cell density than control or AML, not otherwise specified (AML-NOS) bone marrow. Moreover, AML-MRC bone marrow also exhibited higher CXCL12 þ cell density than control bone marrow. CXCL12 þ cell density correlated positively with bone marrow blast ratio in MDS cases. CXCL12 mRNA level was also higher in MDS bone marrow than in control or AML-NOS bone marrow. In vitro coculture analysis revealed that overexpression of CXCL12 in stromal cells upregulated BCL-2 expression of leukemia cell lines. Triple immunostaining revealed that the CD34 þ hematopoietic cells of MDS bone marrow in contact with CXCL12 þ cells were BCL-2-positive and TUNEL-negative. In the bone marrow of MDS cases, CXCL12-high group showed significantly higher Bcl-2 þ /CD34 þ cell ratio and lower apoptotic cell ratio than CXCL12-low group. Moreover, CXCL12-high refractory cytopenia with multilineage dysplasia (RCMD) cases had a greater tendency to progress to refractory anemia with excess blasts (RAEBs) or AML-MRC than CXCL12-low RCMD cases. These results suggest that CXCL12 þ cells constitute the niche for CD34 þ hematopoietic cells, and may be associated with the survival/antiapoptosis of CD34 þ hematopoietic cells and disease progression in MDS. Thus, CXCL12 þ cells may represent a novel MDS therapeutic target.

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Section: Discussionsupporting

confidence: 93%

CXCL12+ stromal cells as bone marrow niche for CD34+ hematopoietic cells and their association with disease progression in myelodysplastic syndromes

Abe‐Suzuki

Kurata

Abe

et al. 2014

Laboratory Investigation

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“…Immunohistochemistry studies indicate that 86% of the primitive CD34 + human HSPCs localize closely to CD271 + alkaline phosphatase (ALP) positive perivascular MSCs that are positive for CXCL12 (Flores-Figueroa et al, 2012), and that CD45 + CD34 + CD38 − human HSCs are enriched in the trabecular areas of the bone (Guezguez et al, 2013). In vitro co-culture studies have provided further information about the identity of the human HSC-supportive BM niche cells and the environmental factors regulating human HSC function.…”

Section: Advances In Understanding the Human Hsc Nichementioning

confidence: 99%

Normal and Leukemic Stem Cell Niches: Insights and Therapeutic Opportunities

2015

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Hematopoietic stem cells (HSC) rely on instructive cues from the bone marrow (BM) niche to maintain their quiescence and adapt blood production to the organism’s needs. Alterations in the BM niche are commonly observed in blood malignancies and directly contribute to the aberrant function of disease-initiating leukemic stem cells (LSC). Here, we review recent insights into the cellular and molecular determinants of the normal HSC niche and describe how genetic changes in stromal cells and leukemia-induced BM niche remodeling contribute to blood malignancies. Moreover, we discuss how these findings can be applied to non cell-autonomous therapies targeting the LSC niche.

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“…In order for EMH to develop, a niche environment must be activated and expanded by multiple factors, including bone marrow failure, excessive hematopoietic stimulation and tissue inflammation, injury and repair, as well as abnormal cytokine production (7,26). It has been demonstrated that treatment with granulocyte-colony stimulating factor and granulocyte macrophage colony-stimulating factor induces an increase in spleen size associated with EMH (50,51).…”

Section: Microenvironment Of Emhmentioning

confidence: 99%

“…It was recently demonstrated that niche-constituting cells within human bone marrow include critical elements, for example mesenchymal stromal cells (MSCs), blood vessels, perivascular cells, macrophages and endosteal cells (7). Investigations into the various mechanisms underlying the interaction between these elements and HSCs have also been conducted.…”

Section: Introductionmentioning

confidence: 99%

Extramedullary hematopoiesis: Elucidating the function of the hematopoietic stem cell niche (Review)

Yamamoto

Miwa

Abe‐Suzuki

et al. 2015

Molecular Medicine Reports

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Distinctive contact between CD34+ hematopoietic progenitors and CXCL12+ CD271+ mesenchymal stromal cells in benign and myelodysplastic bone marrow

Cited by 76 publications

References 52 publications

CXCL12+ stromal cells as bone marrow niche for CD34+ hematopoietic cells and their association with disease progression in myelodysplastic syndromes

CXCL12+ stromal cells as bone marrow niche for CD34+ hematopoietic cells and their association with disease progression in myelodysplastic syndromes

Normal and Leukemic Stem Cell Niches: Insights and Therapeutic Opportunities

Extramedullary hematopoiesis: Elucidating the function of the hematopoietic stem cell niche (Review)

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