Effect of age and gender on recovery after stroke in rats treated with bone marrow mononuclear cells

Coelho, Bárbara de Paula; Giraldi-Guimarães, Arthur

doi:10.1016/j.neures.2014.08.007

Cited by 15 publications

(9 citation statements)

References 37 publications

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“…In this study, TTC staining was used for histological analyses of the lesion area 2 h after TCI ( Fig 3 ) and confirmed the extension of the lesion into the cortical and subcortical regions. This sensitivity analysis of TTC has been described in previous studies with the same ischemic model [ 15 , 16 ]. The ischemic lesion by the thermocoagulation model compromised all cortical layers around the vessel coagulated at five to seven days after induction detectable by TTC and histological analysis [ 11 , 14 , 16 ], keeping the integrity of the medial cortex, corpus callosum, striatum, and subventricular zone due to blood supply by anterior and middle cerebral arteries [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…The small brain lesion caused by sham surgery did not change the brain volume in this group and did not cover deep cortical areas ( Fig 4B ). The ischemic lesion was detected and measured from the thermal dissipation in the tissue by induction as reported in studies that used the same focal ischemic cerebral model [ 12 – 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…The hot probe (ESD-900 model, Instrutherm, Brazil) had digital control for temperature (150°C–480°C), 50 W, and ± 1°C of accuracy and maintained constant temperature. After 30 min of TCI at 400°C, vessel lesions were evaluated macroscopically through the color changes in the region targeted, from light red to dark red to indicate complete thermocoagulation of blood [ 11 – 15 , 19 – 22 ]. Thus TCI was performed for 30 min at the three temperatures.…”

Section: Methodsmentioning

confidence: 99%

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Evaluation of temperature induction in focal ischemic thermocoagulation model

et al. 2018

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The thermocoagulation model, which consists of focal cerebral ischemia with craniectomy, is helpful in studying permanent ischemic brain lesions and has good reproducibility and low mortality. This study analyzed the best conditions for inducing a focal ischemic lesion by thermocoagulation. We investigated parameters such as temperature and thermal dissipation in the brain tissue during induction and analyzed real-time blood perfusion, histological changes, magnetic resonance imaging (MRI), and motor behavior in a permanent ischemic stroke model. We used three-month-old male Wistar rats, weighing 300–350 g. In the first experiment, the animals were divided into four groups (n = 5 each): one sham surgery group and three ischemic lesion groups having thermocoagulation induction (TCI) temperatures of 200°C, 300°C, and 400°C, respectively, with blood perfusion (basal and 30 min after TCI) and 2,3,5-Triphenyl-tetrazolium chloride (TTC) evaluation at 2 h after TCI. In the second experiment, five groups (n = 5 each) were analyzed by MRI (basal and 24 h after TCI) and behavioral tests (basal and seven days after TCI) with the control group added for the surgical effects. The MRI and TTC analyses revealed that ischemic brain lesions expressively evolved, especially at TCI temperatures of 300°C and 400°C, and significant motor deficits were observed as the animals showed a decrease frequency of movement and an asymmetric pattern. We conclude that a TCI temperature of 400°C causes permanent ischemic stroke and motor deficit.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Evaluation of temperature induction in focal ischemic thermocoagulation model

et al. 2018

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“…We do know that diabetic microangiopathy has the potential to interfere with repair mechanisms [ 29 ] and the cerebral “diabetic state” may generate inflammation that affects the global response to cell transplantation. BM-MNC have been tested in older mice and found to be beneficial in this population [ 40 ], though not in spontaneously hypertensive rats [ 4 , 41 ]. Transplantation in diabetic mice should be the next step in the development of such cell therapy strategies.…”

Section: Discussionmentioning

confidence: 99%

Diabetic Ephrin-B2-Stimulated Peripheral Blood Mononuclear Cells Enhance Poststroke Recovery in Mice

Hilal

Poittevin

Pasteur-Rousseau

et al. 2018

Stem Cells International

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Clinical trials of cell therapy in stroke favor autologous cell transplantation. To date, feasibility studies have used bone marrow-derived mononuclear cells, but harvesting bone marrow cells is invasive thus complicating bedside treatment. We investigated the therapeutic potential of peripheral blood-derived mononuclear cells (PB-MNC) harvested from diabetic patients and stimulated by ephrin-B2 (PB-MNC+) (500,000 cells), injected intravenously 18–24 hours after induced cerebral ischemia in mice. Infarct volume, neurological deficit, neurogenesis, angiogenesis, and inflammation were investigated as were the potential mechanisms of PB-MNC+ cells in poststroke neurorepair. At D3, infarct volume was reduced by 60% and 49% compared to unstimulated PB-MNC and PBS-treated mice, respectively. Compared to PBS, injection of PB-MNC+ increased cell proliferation in the peri-infarct area and the subventricular zone, decreased microglia/macrophage cell density, and upregulated TGF-β expression. At D14, microvessel density was decreased and functional recovery was enhanced compared to PBS-treated mice, whereas plasma levels of BDNF, a major regulator of neuroplasticity, were increased in mice treated with PB-MNC+ compared to the other two groups. Cell transcriptional analysis showed that ephrin-B2 induced phenotype switching of PB-MNC by upregulating genes controlling cell proliferation, inflammation, and angiogenesis, as confirmed by adhesion and Matrigel assays. Conclusions. This feasibility study suggests that PB-MNC+ transplantation poststroke could be a promising approach but warrants further investigation. If confirmed, this rapid, noninvasive bedside cell therapy strategy could be applied to stroke patients at the acute phase.

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“…A study on BM MNC revealed that cells derived from younger (24 ± 1 years), but not from older donors (68 ± 1 years) induce neuroprotection in an organotypic in vitro ischemia model . Aged BM cells are further believed to exert less neovascularization what might be critical if used for CVD treatment. Another study showed that age‐ and sex‐matched syngeneic transplantation of BM cells resulted in decreased, but not absent efficacy of BM cell transplantation after stroke with increasing age in otherwise healthy Wistar rats .…”

Section: Age and Frequent Comorbidities Affect Cell‐based Cvd Therapiesmentioning

confidence: 99%

Concise Review: Increasing the Validity of Cerebrovascular Disease Models and Experimental Methods for Translational Stem Cell Research

et al. 2017

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Interspecies differences, anatomical and physiological aspects, as wells as simplified study designs contribute to an overestimation of treatment effects and limit the transferability of experimental results into clinical applications. Confounders of cell therapies for cerebrovascular disorders (CVD) include common CVD comorbidities, frequent medications potentially affecting endogenous and transplanted stem cells, as well as age-and immune-system-related effects. All those can contribute to a substantial modeling bias, ultimately limiting the prospective quality of preclinical research programs regarding the clinical value of a particular cell therapy. In this review, we discuss the nature and impact of most relevant confounders. We provide suggestions on how they can be considered to enhance the validity of CVD models in stem cell research. Acknowledging substantial and sometimes surprising effects of housing conditions, chronobiology, and intersex differences will further augment the translational value of animal models. We finally discuss options for the implementation of high-quality functional and imaging readout protocols. Altogether, this might help to gain a more holistic picture about the therapeutic impact of a particular cell therapy for CVD, but also on potential side and off-site effects of the intervention. STEM CELLS 2017;35:1141-1153 SIGNIFICANCE STATEMENTThis review summarizes most important aspects that may affect stem cell and cell therapy impact in cerebrovascular disease research. We discuss relevant mechanisms potentially impacting stem cell efficacy, safety, as well as relevant options to increase the predictive value of translational research programs. Importantly, the review also covers so far underrepresented areas such as chronobiology, comorbidities, polypharmacology (effects of drugs on stem cell efficacy and behavior), as well as potential species-specific aspects of stem cell performance.

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Effect of age and gender on recovery after stroke in rats treated with bone marrow mononuclear cells

Cited by 15 publications

References 37 publications

Evaluation of temperature induction in focal ischemic thermocoagulation model

Evaluation of temperature induction in focal ischemic thermocoagulation model

Diabetic Ephrin-B2-Stimulated Peripheral Blood Mononuclear Cells Enhance Poststroke Recovery in Mice

Concise Review: Increasing the Validity of Cerebrovascular Disease Models and Experimental Methods for Translational Stem Cell Research

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