Small molecule Me6TREN mobilizes hematopoietic stem/progenitor cells by activating MMP-9 expression and disrupting SDF-1/CXCR4 axis

Zhang, Jing; Ren, Xiangliang; Shi, Wei; Wang, Sihan; Chen, Haixu; Zhang, Bowen; Wang, Zhidong; Zhou, Yong; Chen, Lin; Zhang, Rui; Lv, Yang; Zhou, Junnian; Nan, Xue; He, Liyun; Yue, Wen; Li, Yanhua; Pei, Xuetao

doi:10.1182/blood-2013-04-498535

Cited by 29 publications

(37 citation statements)

References 39 publications

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“…This result indicated the relevance of SDF-1 in the migration of endogenous NSCs after brain injury. Similar results have been observed in the migration of human bone marrow stromal cells in the brain tissue of immunodeficient mice in vivo [32,33]. Our results strongly suggested the important role of SDF-1/CXCR4 axis in the migration of Nestin-positive cell after brain injury in vivo and may be useful in the researches about the homing of both endogenous and grafted NSCs in stem cell therapy.…”

Section: Discussionsupporting

confidence: 88%

The Effect of Stromal Cell-Derived Factor 1 in the Migration of Neural Stem Cells

Xue¹,

Wang

et al. 2014

Cell Biochem Biophys

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Neural stem cells (NSCs) have widely been used in the treatment of human neurological disorders as cell therapy via intracerebral or intraventricular infusion. However, the migration mechanism required for NSCs homing and recruitment remains to be elucidated. Recently, SDF-1/CXCR4 axis was shown to be responsible for in cell migration and differentiation during the neural development stage and involved in the pathophysiological process of neurological disorders. In this study, we investigated the effect of SDF-1 in migration of NSCs in vitro and in vivo. The expression of CXCR4 receptor was examined by immunocytochemistry and RT-PCR. The migratory ability of NSCs induced by SDF-1 was assessed by transwell chemotaxis assay. The traumatic brain injury rat model was well established, and the recruitment of NSCs and expression of SDF-1 were investigated in vivo. Our findings demonstrated that SDF-1, in vitro, significantly induced the migratory of NSCs in a dose-dependent manner. An overexpression of neural stem cell marker Nestin in the hippocampus was observed after TBI, and the expressions of SDF-1 surrounding the lesion areas were significantly increased. Our results suggested that the migration of NSCs was activated by chemotactic effect of SDF-1. It was also proved the relevance of SDF-1 in the migration of endogenous NSCs after brain injury. Taken together, these results demonstrated that SDF-1/CXCR4 axis may play crucial role in the migration of Nestin-positive cell after brain injury.

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Section: Discussionsupporting

confidence: 88%

The Effect of Stromal Cell-Derived Factor 1 in the Migration of Neural Stem Cells

Xue¹,

Wang

et al. 2014

Cell Biochem Biophys

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“…However, G-CSF-based mobilization requires multiple doses over a number of days, is known to alter the function of the HSC niche as well as bone formation 3 , can cause bone pain and spleen enlargement and on rare occasions G-CSF results in splenic rupture, myocardial infarction or cerebral ischaemia (reviewed in refs 4,5). These inherent disadvantages of G-CSF have driven efforts to identify alternate mobilization strategies based on the use of single doses of small molecules 6,7 . For example, the Food and Drug Administration (FDA)-approved chemokine (C-X-C motif) receptor 4 (CXCR4) antagonist AMD3100 (Plerixafor; Mozobil TM ) has been shown to rapidly mobilize HSC with limited toxicity issues 8,9 .…”

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confidence: 99%

Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist

Cao

Zhang

Grassinger

et al. 2016

Experimental Hematology

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The inherent disadvantages of using granulocyte colony-stimulating factor (G-CSF) for hematopoietic stem cell (HSC) mobilization have driven efforts to identify alternate strategies based on single doses of small molecules. Here, we show targeting a 9 b 1 /a 4 b 1 integrins with a single dose of a small molecule antagonist (BOP (N-(benzenesulfonyl)-L-prolyl-L-O-(1-pyrrolidinylcarbonyl)tyrosine)) rapidly mobilizes long-term multi-lineage reconstituting HSC. Synergistic engraftment augmentation is observed when BOP is co-administered with AMD3100. Impressively, HSC in equal volumes of peripheral blood (PB) mobilized with this combination effectively out-competes PB mobilized with G-CSF. The enhanced mobilization observed using BOP and AMD3100 is recapitulated in a humanized NODSCIDIL2Rg À / À model, demonstrated by a significant increase in PB CD34 þ cells. Using a related fluorescent analogue of BOP (R-BC154), we show that this class of antagonists preferentially bind human and mouse HSC and progenitors via endogenously primed/activated a 9 b 1 /a 4 b 1 within the endosteal niche. These results support using dual a 9 b 1 /a 4 b 1 inhibitors as effective, rapid and transient mobilization agents with promising clinical applications.

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“…Further analysis showed Me 6 TREN mobilizes more HSPC than AMD3100 or G-CSF, synergizes with G-CSF and sustains HSPC levels in PB for up to 3 days after a single dose [105]. Although the direct target of Me 6 TREN was not elucidated, it is speculated the mechanism is distinct to AMD3100 based on their differing mobilization kinetics [105]. Nevertheless, Me 6 TRENinduced mobilization was shown to occur through activation of MMP-9 and disruption of the CXCF4/SDF-1 axis, which are downstream effects that have also been attributed to AMD3100 [106].…”

Section: Novel Mobilization Agents From Random Screeningmentioning

confidence: 99%

“…Nevertheless, the novel small molecule mobilization agent Me 6 TREN (Fig. 2) was identified in a compound screen through phenotypic analysis of murine HSPC in PB of treated mice [105]. Further analysis showed Me 6 TREN mobilizes more HSPC than AMD3100 or G-CSF, synergizes with G-CSF and sustains HSPC levels in PB for up to 3 days after a single dose [105].…”

Section: Novel Mobilization Agents From Random Screeningmentioning

confidence: 99%

“…2) was identified in a compound screen through phenotypic analysis of murine HSPC in PB of treated mice [105]. Further analysis showed Me 6 TREN mobilizes more HSPC than AMD3100 or G-CSF, synergizes with G-CSF and sustains HSPC levels in PB for up to 3 days after a single dose [105]. Although the direct target of Me 6 TREN was not elucidated, it is speculated the mechanism is distinct to AMD3100 based on their differing mobilization kinetics [105].…”

Section: Novel Mobilization Agents From Random Screeningmentioning

confidence: 99%

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New agents in HSC mobilization

2016

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Small molecule Me6TREN mobilizes hematopoietic stem/progenitor cells by activating MMP-9 expression and disrupting SDF-1/CXCR4 axis

Abstract: Key Points The small molecule Me6TREN is a new potent and efficacious mobilizing agent of HSPCs and works more effectively than G-CSF or AMD3100. Me6 mobilizes murine HSPCs and functions by upregulating MMP-9 expression and disrupting the SDF-1α/CXCR4 axis.

Cited by 29 publications

References 39 publications

The Effect of Stromal Cell-Derived Factor 1 in the Migration of Neural Stem Cells

The Effect of Stromal Cell-Derived Factor 1 in the Migration of Neural Stem Cells

Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist

New agents in HSC mobilization

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