Transgenic Expression of Stromal Cell-Derived Factor-1/CXC Chemokine Ligand 12 Enhances Myeloid Progenitor Cell Survival/Antiapoptosis In Vitro in Response to Growth Factor Withdrawal and Enhances Myelopoiesis In Vivo

Broxmeyer, Hal E.; Cooper, Scott; Kohli, Lisa L.; Hangoc, Giao; Lee, Younghee; Mantel, Charlie; Clapp, D. Wade; Kim, Chang H.

doi:10.4049/jimmunol.170.1.421

Cited by 153 publications

(155 citation statements)

References 35 publications

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“…Under these diff erent conditions, although the Cxcr4 Ϫ / Ϫ HSC compartment was preserved in mice treated with tamoxifen, it was " lost " in mice that received poly I/poly C. At present, the precise reason for this discrepancy cannot be ascertained, but might be related to a distinct role of CXCR4 in HSC survival in homeostatic state or under hematologic stress caused by poly I/poly C treatment. CXCL12 has been reported to enhance survival of primitive hematopoietic cells ( 23,24 ), and of myeloid progenitor cells after cytokine withdrawal ( 25 ). Although we did not observe any changes in apoptosis of freshly isolated Cxcr4 Ϫ / Ϫ HSCs as compared with the WT HSCs, it is possible that the survival of Cxcr4 Ϫ / Ϫ HSCs is impaired under stress conditions, thereby compromising hematologic recovery from chemoablation such as poly I/poly C treatment.…”

Section: Discussioncontrasting

confidence: 52%

CXCR4 is required for the quiescence of primitive hematopoietic cells

Nie¹,

Han²,

Zou³

2008

J Cell Biol

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Hematopoietic stem cells (HSCs) have robust proliferative potential, as they can undergo extensive expansion to quickly restore hematopoiesis after transplantation or histological injury. However, under steady state, HSCs proliferate at a very low rate and most HSCs are kept in the G 0 phase of the cell cycle ( 1 ). Disruption of HSC quiescence leads to premature exhaustion of the stem cell pool and causes hematological failure under stress conditions ( 2, 3 ). Thus, HSC self-renewal and quiescence have to be fi nely balanced to maintain a stable HSC pool that is capable of producing blood cells for the lifetime of the organism. Although numerous transcription factors and cell cycle molecules have been identifi ed to regulate HSC self-renewal, it is not understood how nuclear regulatory factors adjust the HSC self-renewal rate to accommodate hematopoiesis under homeostatic and cytopenic conditions. It has been reported that HSCs are relocated from the osteoblastic niche to vascular zones in the BM after myeloablation ( 4 ). The translocation of HSCs is accompanied with an increase in HSC proliferation, suggesting that signals emanating from the BM niche where HSCs reside determine the balance between quiescence and selfrenewal of HSCs.The chemokine CXCL12 is the major chemoattractant for HSCs ( 5 ). It is expressed at a high level by osteoblasts, endothelial cells, and by a subset of reticular cells scattered throughout the BM ( 6, 7 ). Inactivation of CXCL12 or its receptor CXCR4 impairs the translocation of HSCs from the fetal liver to the BM during embryogenesis ( 8 -11 ), and direct ablation of CXCR4 signaling or indirect modulation of CXCL12 level by proteases results in mobilization of primitive hematopoietic cells and compromises their engrafting activity ( 4, 12 -14 ). This suggests an important role for CXCR4/ CXCL12 in BM retention of primitive hematopoietic cells. Additional eff ects of CXCR4 on HSCs are still not fully understood, and studies evaluating its regulatory role in the cell cycle yielded contradictory results ( 7, 15 ). To better understand the function of CXCR4 in HSCs, we deleted the Cxcr4 gene during adult hematopoiesis. We found that the compartment of primitive hematopoietic cells (Flt3 Ϫ Lin Ϫ Sca-1 + c-Kit + cells) was stably maintained in the BM in the absence of CXCR4 and sustained longterm hematopoiesis. These CXCR4-defi cient primitive hematopoietic cells proliferated vigorously and outcompeted the coexisting WT counterpart in the same host. CXCL12 directly inhibited the cell cycle of WT, but not Cxcr4 Ϫ / Ϫ , primitive hematopoietic cells. Thus, our results demonstrate a critical role of CXCR4 in restraining HSCs in the quiescent state. The quiescence of hematopoietic stem cells (HSCs) is critical for preserving a lifelong steady pool of HSCs to sustain the highly regenerative hematopoietic system. It is thought that specialized niches in which HSCs reside control the balance between HSC quiescence and self-renewal, yet little is known about the extrinsic signals provided by t...

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Section: Discussioncontrasting

confidence: 52%

CXCR4 is required for the quiescence of primitive hematopoietic cells

Nie¹,

Han²,

Zou³

2008

J Cell Biol

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“…7 CXCL12 also enhances the survival/antiapoptosis of hematopoietic progenitor cells in vitro and in vivo. 8 Experiments using knockout mice have revealed that depleting CXCL12-abundant reticular cells leads to reduced hematopoietic stem cell numbers. 5 Morphologically, CXCL12-abundant reticular cells have long processes and are scattered throughout the murine bone marrow as a network.…”

mentioning

confidence: 99%

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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“…54 SDF-1 alone and in synergy with other cytokines enhances survival of primitive hematopoietic cells. 37,38,51,61 Therefore, the possibility existed that enhancement in survival of hematopoietic progenitor cells by SDF-1 could contribute to the enhanced transduction efficiency noted. However, given that the transduction procedure was carried out in the presence of serum and other cytokines, and that we did not observe significant changes in total numbers of CFU-GM and CFU-GEMM colonies, this possibility seems unlikely.…”

Section: Discussionmentioning

confidence: 99%

“…This is consistent with recent reports. 38,62 Recent studies have shown that prolonged stimulation of cell division in vitro can lead to uncontrolled proliferation and inhibition of differentiation in hematopoietic cells. Since SDF-1 does not stimulate proliferation and alter differentiation of primitive hematopoietic cells, SDF-1-enhanced transduction seems to avoid this potential risk.…”

Section: Discussionmentioning

confidence: 99%

“…[30][31][32][33][34][35] In addition, SDF-1 acts synergistically with other cytokines to enhance survival of hematopoietic progenitor cells. [36][37][38] However, the effect of SDF-1 on efficiency of retroviral-mediated gene transfer has not been explored. In this study, we show that SDF-1 significantly enhances the efficiency of retroviralmediated gene transfer into immature subsets of high proliferative murine BM and human umbilical cord blood (CB) progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

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SDF-1α/CXCL12 enhances retroviral-mediated gene transfer into immature subsets of human and murine hematopoietic progenitor cells

et al. 2003

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Genetic modification of hematopoietic stem and progenitor cells has the potential to treat diseases affecting blood cells. Oncoretroviral vectors have been used for gene therapy; however, clinical success has been limited in part by low gene transfer efficiencies. We found that the presence of stromal-derived factor 1 (SDF-1a)/CXCL12 during retroviral transduction significantly enhanced, in a dose-dependent fashion, gene transfer into immature subsets of high proliferative human and murine hematopoietic progenitor cells. Murine mononuclear bone marrow cells and purified c-Kit þ Lin À bone marrow cells were prestimulated and transduced with the bicistronic retroviral vector MIEG3 on Retronectin-coated surfaces in the presence and absence of SDF-1. SDF-1 enhanced gene transduction of murine bone marrow and c-Kit þ Lin À cells by 35 and 29%, respectively. Moreover, SDF-1 enhanced transduction of progenitors in these populations by 121 and 107%, respectively. SDF-1 also enhanced transduction of human immature subsets of high proliferative progenitors present in either nonadherent mononuclear or CD34 þ umbilical cord blood cells. Transduction of hematopoietic progenitors was further increased by preloading Retronectin-coated plates with retrovirus using low-speed centrifugation followed by increasing cell-virus interactions through brief centrifugation during the transduction procedure. These results may be of clinical relevance.

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Transgenic Expression of Stromal Cell-Derived Factor-1/CXC Chemokine Ligand 12 Enhances Myeloid Progenitor Cell Survival/Antiapoptosis In Vitro in Response to Growth Factor Withdrawal and Enhances Myelopoiesis In Vivo

Cited by 153 publications

References 35 publications

CXCR4 is required for the quiescence of primitive hematopoietic cells

CXCR4 is required for the quiescence of primitive hematopoietic cells

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

SDF-1α/CXCL12 enhances retroviral-mediated gene transfer into immature subsets of human and murine hematopoietic progenitor cells

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