Bone marrow mononuclear cells exert long-term neuroprotection in a rat model of ischemic stroke by promoting arteriogenesis and angiogenesis

Wang, Jianping; Yu, Lie; Jiang, Chao; Chen, Ming; Ou, Chunying; Wang, Jian

doi:10.1016/j.bbi.2013.07.010

Cited by 55 publications

(43 citation statements)

References 43 publications

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“…Bone marrow and peripheral blood mononuclear cells were collected as previously described (Wang et al, 2013). The mice were sacrificed after a sublethal intraperitoneal injection of 4% chloral hydrate.…”

Section: Methodsmentioning

confidence: 99%

Cerebral ischemia increases bone marrow CD4+CD25+FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system

Wang

Jiang

et al. 2015

Brain, Behavior, and Immunity

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Recent evidence has shown that an increase in CD4+CD25+FoxP3+ regulatory T (Treg) cells may contribute to stroke-induced immunosuppression. However, the molecular mechanisms that underlie this increase in Treg cells remain unclear. Here, we used a transient middle cerebral artery occlusion model in mice and specific pathway inhibitors to demonstrate that stroke activates the sympathetic nervous system, which was abolished by 6-OHDA. The consequent activation of β2-adrenergic receptor (AR) signaling increased prostaglandin E2 (PGE2) level in bone marrow. β2-AR antagonist prevented the upregulation of PGE2. PGE2, which acts on prostaglandin E receptor subtype 4 (EP4), upregulated the expression of receptor activator for NF-κB ligand (RANKL) in CD4+ T cells and mediated the increase in Treg cells in bone marrow Treatment of MCAO mice with RANKL antagonist OPG inhibited the increase in percent of bone marrow Treg cells. PGE2 also elevated the expression of indoleamine 2,3 dioxygenase in CD11C+ dendritic cells and promoted the development of functional Treg cells. The effect was neutralized by treatment with indomethacin. Concurrently, stroke reduced production of stromal cell-derived factor-1 (SDF-1) via β3-AR signals in bone marrow but increased the expression of C-X-C chemokine receptor (CXCR) 4 in Treg and other bone marrow cells. Treatment of MCAO mice with β3-AR antagonist SR-59230A reduced the percent of Treg cells in peripheral blood after stroke. The disruption of the CXCR4–SDF-1 axis may facilitate mobilization of Treg cells and other CXCR4+ cells into peripheral blood. This mechanism could account for the increase in Treg cells, hematopoietic stem cells, and progenitor cells in peripheral blood after stroke. We conclude that cerebral ischemia can increase bone marrow CD4+CD25+FoxP3+ regulatory T cells via signals from the sympathetic nervous system.

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Section: Methodsmentioning

confidence: 99%

Cerebral ischemia increases bone marrow CD4+CD25+FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system

Wang

Jiang

et al. 2015

Brain, Behavior, and Immunity

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“…However, the underlying mechanism of action for intravenous transplantation of BMMNCs in ischemic diseases is unclear. Some investigators have shown that transplanted cells, such as MSCs [39], neural stem cells [40], endothelial progenitor cells [41], and BMMNCs [7, 19, 28], are able to migrate to the ischemic lesion, remain viable, and function effectively via paracrine effects or cell differentiation. However, others have reported that, after intravenous delivery, most BMMNCs are initially trapped in the lungs or liver [14, 42].…”

Section: Discussionmentioning

confidence: 99%

“…BBB leakage, however, may also make it easier for BMMNCs to enter the ischemic brain. Previous studies have shown that BMMNCs could not penetrate the healthy rat brain, but were able to migrate into the infarct area after MCAO [7, 9]. We hypothesized that supplying exogenous VEGF would facilitate the migration of BMMNCs into the chronically ischemic brain of 2VO rats, thus enhancing their therapeutic efficacy.…”

Section: Introductionmentioning

confidence: 93%

“…Among many cell types, bone marrow mononuclear cells (BMMNCs) are particularly attractive for acute ischemic stroke treatment because they are composed of different kinds of stem cells, can be rapidly isolated without cultivation, and can be used in autologous applications [6]. Several research groups have shown that BMMNC transplantation can significantly improve neurologic outcome from ischemic stroke in animal models by cell differentiation [7, 8], secretion of trophic factors [9], and possible immunomodulation [10]. Some phase I/II clinical trials also have shown that BMMNC transplantation can improve clinical outcomes of patients with middle cerebral artery occlusion (MCAO) [11–14].…”

Section: Introductionmentioning

confidence: 99%

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Preconditioning with VEGF Enhances Angiogenic and Neuroprotective Effects of Bone Marrow Mononuclear Cell Transplantation in a Rat Model of Chronic Cerebral Hypoperfusion

Wang

et al. 2015

Mol Neurobiol

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Bone marrow mononuclear cell (BMMNC) transplantation is a promising therapy for brain ischemia. However, BMMNCs are few in number, and a limited time window is available during which they can penetrate the blood–brain barrier (BBB) and migrate to the brain. We investigated whether vascular endothelial growth factor (VEGF) can facilitate BMMNC migration into the ischemic brain and enhance their therapeutic effect in a rat model of chronic cerebral hypoperfusion. First, we assessed the impact of VEGF on the BBB of rats that had undergone permanent bilateral occlusion of the common carotid arteries (2VO). Then, we transplanted BMMNCs into 2VO rats pretreated with intracerebroventricular VEGF or vehicle. We examined cognitive function with the Morris water maze test, BMMNC migration by immunofluorescence analysis, and cytokine levels in the peripheral blood by enzyme-linked immunosorbent assay (ELISA). Angiogenesis and neural degeneration were evaluated by staining tissue with Ki67/lectin or Fluoro-Jade B. We found that at a dose of 0.2 μg/rat, VEGF significantly increased BBB permeability without causing brain edema in 2VO rats. VEGF+BMMNC-treated rats had more BMMNC migration in the ischemic brain, better learning and memory, greater proliferation of vessels, and fewer degenerating neurons than did BMMNC-treated rats. Pretreatment with VEGF receptor inhibitor SU5416 significantly decreased BMMNC migration and abolished the therapeutic effect of BMMNC transplantation. We conclude that preconditioning with an appropriate dose of VEGF can enhance the therapeutic efficacy of BMMNC transplantation in 2VO rats, possibly by facilitating BMMNC migration into the ischemic brain.

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“…1 Cellbased therapies, either transplantation of exogenous cells or stimulation of endogenous cells, are considered a promising means of treating stroke. [2][3][4][5][6] Approaches using bone marrowderived cells (BMCs) are particularly attractive because BMCs can be easily obtained and permit autologous transplantation. 7 Besides transplantation of exogenous cells, endogenous BMCs can be mobilized by the granulocyte colony-stimulating factor (G-CSF).…”

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confidence: 99%

Combining Growth Factor and Bone Marrow Cell Therapy Induces Bleeding and Alters Immune Response After Stroke in Mice

Strecker

Olk

Hoppen

et al. 2016

Stroke

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Background and Purpose-Bone marrow cell (BMC)-based therapies, either the transplantation of exogenous cells or stimulation of endogenous cells by growth factors like the granulocyte colony-stimulating factor (G-CSF), are considered a promising means of treating stroke. In contrast to large preclinical evidence, however, a recent clinical stroke trial on G-CSF was neutral. We, therefore, aimed to investigate possible synergistic effects of co-administration of G-CSF and BMCs after experimental stroke in mice to enhance the efficacy compared with single treatments. Methods-We used an animal model for experimental stroke as paradigm to study possible synergistic effects of co-administration of G-CSF and BMCs on the functional outcome and the pathophysiological mechanism. Results-G-CSF treatment alone led to an improved functional outcome, a reduced infarct volume, increased blood vessel stabilization, and decreased overall inflammation. Surprisingly, the combination of G-CSF and BMCs abrogated G-CSFs' beneficial effects and resulted in increased hemorrhagic infarct transformation, altered blood-brain barrier, excessive astrogliosis, and altered immune cell polarization. These increased rates of infarct bleeding were mainly mediated by elevated matrix metalloproteinase-9-mediated blood-brain barrier breakdown in G-CSF-and BMCs-treated animals combined with an increased number of dilated and thus likely more fragile vessels in the subacute phase after cerebral ischemia. Conclusions-Our results provide new insights into both BMC-based therapies and immune cell biology and help to understand potential adverse and unexpected side effects.

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Bone marrow mononuclear cells exert long-term neuroprotection in a rat model of ischemic stroke by promoting arteriogenesis and angiogenesis

Cited by 55 publications

References 43 publications

Cerebral ischemia increases bone marrow CD4+CD25+FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system

Cerebral ischemia increases bone marrow CD4+CD25+FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system

Preconditioning with VEGF Enhances Angiogenic and Neuroprotective Effects of Bone Marrow Mononuclear Cell Transplantation in a Rat Model of Chronic Cerebral Hypoperfusion

Combining Growth Factor and Bone Marrow Cell Therapy Induces Bleeding and Alters Immune Response After Stroke in Mice

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