Low-dose radiation augments vasculogenesis signaling through HIF-1–dependent and –independent SDF-1 induction

Lerman, Oren Z.; Greives, Timothy J.; Singh, Sunil P.; Thanik, Vishal; Chang, Christopher; Seiser, Natalie; Brown, Daniel; Knobel, Denis; Schneider, Robert J.; Formenti, Silvia C.; Saadeh, Pierre B.; Levine, Jamie P.

doi:10.1182/blood-2009-03-213629

Cited by 58 publications

(43 citation statements)

References 35 publications

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“…These data are in-line with the induction of SDF-1 expression after radiation injury in rodents and in humans, through HIF1a-dependent and HIF1a-independent pathways. 39,46,[84][85][86] More relevant for chemotactic function, we identified a transient elevation of SDF-1 transcripts near the endosteum at day 2 following injury that directs MKs away from the vascular niche ( Figures 3C and 5A). Evidence pointing to a cell population that may contribute to altered SDF-1 distribution comes from the work of Dominici et al, 39 Olson et al, 47 and Caselli et al 87 who described an expansion of osteoblasts arising from a subset of radioresistant mesenchymal cells at the endosteal surface concomitant with MK relocation following lethal TBI.…”

Section: Discussionmentioning

confidence: 96%

SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury

Niswander

Fegan²,

Kingsley³

et al. 2014

Blood

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• SDF-1 acutely affects megakaryocyte spatial distribution in the bone marrow at steady state and in the setting of radiation injury.• SDF-1-directed localization of megakaryocytes into the vascular niche increases platelet output.Megakaryocyte (MK) development in the bone marrow progresses spatially from the endosteal niche, which promotes MK progenitor proliferation, to the sinusoidal vascular niche, the site of terminal maturation and thrombopoiesis. The chemokine stromal cellderived factor-1 (SDF-1), signaling through CXCR4, is implicated in the maturational chemotaxis of MKs toward sinusoidal vessels. Here, we demonstrate that both IV administration of SDF-1 and stabilization of endogenous SDF-1 acutely increase MKvasculature association and thrombopoiesis with no change in MK number. In the setting of radiation injury, we find dynamic fluctuations in marrow SDF-1 distribution that spatially and temporally correlate with variations in MK niche occupancy. Stabilization of altered SDF-1 gradients directly affects MK location. Importantly, these SDF-1-mediated changes have functional consequences for platelet production, as the movement of MKs away from the vasculature decreases circulating platelets, while MK association with the vasculature increases circulating platelets. Finally, we demonstrate that manipulation of SDF-1 gradients can improve radiation-induced thrombocytopenia in a manner additive with earlier TPO treatment. Taken together, our data support the concept that SDF-1 regulates the spatial distribution of MKs in the marrow and consequently circulating platelet numbers. This knowledge of the microenvironmental regulation of the MK lineage could lead to improved therapeutic strategies for thrombocytopenia. (Blood. 2014;124(2):277-286) Introduction Platelet-producing megakaryocytes (MKs) are derived from megakaryocyte progenitors (MKPs), which are defined functionally by their capacity to form colonies in vitro. 1,2 MKPs are thought to reside near the bone surface in an "endosteal niche," where environmental cues encourage expansion, but suppress terminal maturation.3-6 Polyploid MKs mature cytoplasmically, extrude proplatelets in association with sinusoidal vasculature, and shed platelets into the peripheral blood. [7][8][9] This process results in past-maturity "exhausted" MKs comprised of a nucleus with a thin layer of cytoplasm surrounded by a cell membrane. 10,11 Megakaryopoiesis is primarily regulated by the cytokine thrombopoietin (TPO), which signals through its receptor Mpl to promote MKP proliferation and MK maturation. [12][13][14] Although the physical association of MKs with sinusoidal vasculature was first appreciated several decades ago, 15-17 the functional significance of the "vascular niche" for MK maturation and thrombopoiesis has only more recently begun to be elucidated. 4,[18][19][20][21] Several studies have implicated the chemokine stromal cellderived factor-1 ([SDF-1] or CXCL12) signaling through receptor CXCR4 in the maturational localization of MKs to the vascular nic...

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Section: Discussionmentioning

confidence: 96%

SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury

Niswander

Fegan²,

Kingsley³

et al. 2014

Blood

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“…Although Celastrol induced the transient accumulation of HIF-1α and VEGF, whether it can promote tumor angiogenesis and metastasis is a remaining question. Previous studies have shown that Celastrol could suppress tumor invasion and metastasis [14], [50]–[52]; however, when considering that radiation-induced HIF-1α activation plays a crucial role in triggering tumor radioresistance [53], [54], the effects of Celastrol on tumor angiogenesis and vasculogenesis may warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

Celastrol Stimulates Hypoxia-Inducible Factor-1 Activity in Tumor Cells by Initiating the ROS/Akt/p70S6K Signaling Pathway and Enhancing Hypoxia-Inducible Factor-1α Protein Synthesis

Han

Sun

Zhao³

et al. 2014

PLoS ONE

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Celastrol, a tripterine derived from the traditional Chinese medicine plant Tripterygium wilfordii Hook F. (“Thunder of God Vine”), has been reported to have multiple effects, such as anti-inflammation, suppression of tumor angiogenesis, inhibition of tumor growth, induction of apoptosis and protection of cells against human neurodegenerative diseases. However, the mechanisms that underlie these functions are not well defined. In this study, we reported for the first time that Celastrol could induce HIF-1α protein accumulation in multiple cancer cell lines in an oxygen-independent manner and that the enhanced HIF-1α protein entered the nucleus and promoted the transcription of the HIF-1 target genes VEGF and Glut-1. Celastrol did not influence HIF-1α transcription. Instead, Celastrol induced the accumulation of the HIF-1α protein by inducing ROS and activating Akt/p70S6K signaling to promote HIF-1α translation. In addition, we found that the activation of Akt by Celastrol was transient. With increased exposure time, inhibition of Hsp90 chaperone function by Celastrol led to the subsequent depletion of the Akt protein and thus to the suppression of Akt activity. Moreover, in HepG2 cells, the accumulation of HIF-1α increased the expression of BNIP3, which induced autophagy. However, HIF-1α and BNIP3 did not influence the cytotoxicity of Celastrol because the main mechanism by which Celastrol kills cancer cells is through stimulating ROS-mediated JNK activation and inducing apoptosis. Furthermore, our data showed that the dose required for Celastrol to induce HIF-1α protein accumulation and enhance HIF-1α transcriptional activation was below its cytotoxic threshold. A cytotoxic dose of Celastrol for cancer cells did not display cytotoxicity in LO2 normal human liver cells, which indicated that the novel functions of Celastrol in regulating HIF-1 signaling and inducing autophagy might be used in new applications, such as in anti-inflammation and protection of cells against human neurodegenerative diseases. Future studies regarding these applications are required.

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“…37;38;42 In addition to its HIF-dependent regulation under low oxygen conditions, SDF-1 has also been shown to be independent of HIF in some cases. 43 We were, therefore, prompted to examine whether VEGF and SDF-1 were regulated by an HIF-dependent mechanism in hypoxic MSC. We inhibited HIF by using adenoviral transduction of AdXHifαdn.…”

Section: Discussionmentioning

confidence: 99%

Oxygen tension plays a critical role in the hematopoietic microenvironment in vitro

Jing

Wobus²,

Poitz³

et al. 2011

Haematologica

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BackgroundIn the bone marrow mesenchymal stromal cells and osteoblasts form functional niches for hematopoietic stem and progenitor cells. This microenvironment can be partially mimicked using in vitro co-culture systems. In this study, we examined the oxygen tension in three distinct compartments in a co-culture system of purified CD34 + cells and mesenchymal stromal cells with regard to different spatial localizations. Design and MethodsHypoxic cells in the co-culture were visualized by pimonidazole staining. Hematopoietic cell distribution, and functional and phenotypic characteristics were analyzed by flow cytometry. The secretion of vascular endothelial growth factor and stromal-derived factor-1 by mesenchymal stromal cells in low oxygen co-cultures was determined by an enzyme-linked immunosorbent assay. The effect of co-culture medium on the hematopoietic cell migration potential was tested in a transwell assay. ResultsIn co-cultures under atmospheric oxygen tension, regions of low oxygen tension could be detected beneath the feeder layer in which a reservoir of phenotypically more primitive hematopoietic cells is located in vitro. In low oxygen co-culture, the adhesion of hematopoietic cells to the feeder layer was decreased, whereas hematopoietic cell transmigration beneath mesenchymal stromal cells was favored. Increased vascular endothelial growth factor-A secretion by mesenchymal stromal cells under low oxygen conditions, which increased the permeability of the monolayer, was responsible for this effect. Furthermore, vascular endothelial growth factor-A expression in low oxygen mesenchymal stromal cells was induced via hypoxia-inducible factor signaling. However, stromal cell-derived factor-1 secretion by mesenchymal stromal cells was down-regulated under low oxygen conditions in a hypoxia-inducible factorindependent manner. ConclusionsWe demonstrate for the first time that differences in oxygen tension cause selective modification of hematopoietic cell and mesenchymal stromal cell interactions in a co-culture system, thus confirming that oxygen tension plays a critical role in the interaction between hematopoietic cells and the niche environment.

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Low-dose radiation augments vasculogenesis signaling through HIF-1–dependent and –independent SDF-1 induction

Abstract: The inflammatory response to ionizing radiation (IR) includes a proangiogenic effect that could be counterproductive in cancer but can be exploited for treating impaired wound healing. We demonstrate for the first time that IR stimulates hypoxia-inducible factor-1␣ (

Cited by 58 publications

References 35 publications

SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury

SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury

Celastrol Stimulates Hypoxia-Inducible Factor-1 Activity in Tumor Cells by Initiating the ROS/Akt/p70S6K Signaling Pathway and Enhancing Hypoxia-Inducible Factor-1α Protein Synthesis

Oxygen tension plays a critical role in the hematopoietic microenvironment in vitro

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