Dual stem cell therapy after myocardial infarction acts specifically by enhanced homing via the SDF-1/CXCR4 axis

Theiß, Hans; Vallaster, Markus; Rischpler, Christoph; Krieg, Lisa; Zaruba, Marc-Michael; Brunner, Stefan; Vanchev, Yordan; Fischer, R; Gröbner, Michael; Hüber, Bruno; Wollenweber, Timm; Assmann, G.; Mueller-Hoecker, Josef; Hacker, Markus; Franz, Wolfgang-M.

doi:10.1016/j.scr.2011.05.003

Cited by 105 publications

(79 citation statements)

References 32 publications

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“…66,75 This strategy has been used to stabilize SDF-1 in several contexts, including the homing and engraftment of hematopoietic stem cells and the recruitment of marrow-derived progenitors to sites of cardiac ischemia for myocardial regeneration. 68,[76][77][78] DPP4 was recently shown to truncate several cytokines, including IL-6, and is predicted to truncate TPO. 79 While we cannot exclude effects of stabilization of these cytokines by Diprotin A, the short timeframe of our experiments coupled with the lack of change in the number or ploidy distribution of MKs ( Figure 1A; supplemental Figure 3 CXCR4 can be internalized after SDF-1 stimulation, and either recycled to the membrane or degraded.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

Niswander

Fegan²,

Kingsley³

et al. 2014

Blood

View full text Add to dashboard Cite

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“…99,100 Furthermore, plasma levels of CXCL12 and circulating levels of progenitor cells are increased in human diabetic subjects treated with DPP-4 inhibitor, sitagliptin. 101 Given the extensive preclinical data linking CXCL12 activity to DPP-4 inhibitor-mediated cardioprotection, 91,93,97,98,102,103 CXCL12 is widely viewed as a putative mediator of DPP-4 action in the heart.…”

Section: Cardioprotective Actions Of Dpp-4 Inhibitors In Preclinical mentioning

confidence: 99%

Cardiovascular Actions of Incretin-Based Therapies

Ussher

Drucker

2014

Circulation Research

302

244

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“…The dose of AMD3100 was 1 mg/kg/ day, which is sufficient for blocking CXCR4 without causing stem cell mobilization. 20,21 The same amount of normal saline was used in the control group.…”

Section: Administration Of Amd3100mentioning

confidence: 99%

CXCR4 Antagonist AMD3100 Protects Blood–Brain Barrier Integrity and Reduces Inflammatory Response After Focal Ischemia in Mice

Huang

Tang

et al. 2013

Stroke

178

180

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Background and Purpose-Inflammatory response plays a critical role in propagating tissue damage after focal cerebral ischemia. CXCL12 is a key chemokine for leukocyte recruitment. However, the role of CXCL12 and its receptor CXCR4 in ischemia-induced inflammatory response is unclear. Here we use the pharmacological antagonist of CXCR4, AMD3100, to investigate the function of CXCL12/CXCR4 in regulating inflammatory response during acute ischemia. Methods-Adult male CD-1 mice (n=184) underwent permanent suture middle cerebral artery occlusion (MCAO). AMD3100 was injected for 3 days (1 mg/kg/day) after MCAO. Brain water content, infarct volume, neurological score, and myeloperoxidase (MPO) expression and activity were examined at 24, 48, and 72 hours after MCAO. Proinflammatory cytokine RNA and protein levels in brain tissue were measured by RT-PCR and enzyme linked immunosorbent assay. Results-Neurological score was greatly improved in AMD3100-treated mice compared with the control mice 3 days after MCAO (P<0.05). Brain edema-induced change of water content, IgG protein leakage, Evans blue extravasation, occludin, and ZO-1 expression in ipsilateral hemisphere were alleviated by acute treatment of AMD3100. MPO expression and activity revealed that AMD3100 profoundly reduced the number of MPO-positive cells in the ischemic region (P<0.05). It also attenuated proinflammatory cytokines including interleukin 6, tumor necrosis factor α, and interferon γ; their mRNA and protein levels changed accordingly compared with the controls (P<0.05). Conclusions-CXCR4 antagonist AMD3100 significantly suppressed inflammatory response and reduced blood-brain barrier disruption after MCAO. AMD3100 attenuated ischemia-induced acute inflammation by suppressing leukocyte migration and infiltration, in addition to reducing proinflammatory cytokine expression in the ischemic region.

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Dual stem cell therapy after myocardial infarction acts specifically by enhanced homing via the SDF-1/CXCR4 axis

Abstract: Our data give final proof that homing through the SDF-1/CXCR-4 axis is essential for the success of dual stem cell therapy.

Cited by 105 publications

References 32 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

Cardiovascular Actions of Incretin-Based Therapies

CXCR4 Antagonist AMD3100 Protects Blood–Brain Barrier Integrity and Reduces Inflammatory Response After Focal Ischemia in Mice

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