Neural stem cells exert a neuroprotective action by changing the ischemic microenvironment

Principato Maria-Cristina, Carmen Capone, Simona Frigerio, Stefano Fumagalli, Maurizio Gelati, Claudio Storini, Mery Montinaro, Marco De Curtis, Eugenio Parati, De Simoni Maria-Grazia

Research output: Contribution to journalArticle

Abstract

Cell replacement strategies are particularly promising candidate therapies for stroke, a condition in which a widespread loss of different cell types occurs that in principle may benefit from exogenous stem cells replacement of lost or damaged cells. In the present study we have used a murine model of focal, transient ischemia to investigate if: 1) infused NSC are able to decrease ischemic injury and restore brain function; 2) these cells induce changes in the environment in which they are infused; 3) changes in brain environment consequent to transient ischemia are relevant for NSC action. Neurosphere-derived stem cells were obtained from brains of C57BL/6 newborn mice. NSC were infused intracerebroventricularly 4h or 7d after 30min focal ischemia obtained by intraluminal MCAO. Behaviour was evaluated in an open field paradigm at day 7 or 14 after ischemia/reperfusion. The impairment in the numbers of rears and of contacts with objects, measures related to exploratory behavior and sensory-motor activity respectively, observed in ischemic mice, was significantly improved in ischemic mice receiving NSC. Neuronal loss, evaluated in striatum and in cortex, was significantly reduced at day 7 and day 14 in ischemic mice infused with NSC at 4h compared to controls and to ischemic mice receiving NSC at 7d. Infusion of adult fibroblasts in the same experimental conditions was not effective. Assessment of infused NSC distribution revealed that they migrated from the ventricle to the brain parenchyma, they were observable up to day 14, but they progressively decreased in number. In mice receiving NSC at day 7 and in sham-operated mice, few cells located near the injection site could be observed only at 24h, indicating that the survival of these cells in brain tissue relates to the ischemic environment. The mRNA expression of trophic factors such as IGF-1, VEGF-A, TGF-alpha1, BDNF and SDF-1beta increased 24h after NSC infusion in ischemic mice treated with NSC at 4h compared to sham-operated and to mice receiving NSC at 7d. Ischemic brains infused with NSC showed higher activation of microglia/macrophages compared to sham-operated mice receiving NSC or to ischemic brains receiving saline injection showing that microglia/macrophages activation is required for NSC action. In conclusion, neurosphere-derived NSC are able to reduce functional impairment and neuronal damage after ischemia/reperfusion injury. The reciprocal interaction between NSC and the ischemic environment is crucial for NSC protective actions. Indeed NSC survival is enhanced by the ischemic environment and NSC can induce the activation of chemokine and neurotrophic factors. NSC protective effects also relates to the interaction with activated microglia/macrophage. Based on these observations we propose that NSC exert their protective effect by a bystander control of the ischemic environment.

Original languageEnglish
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue numberSUPPL. 1
Publication statusPublished - Nov 13 2007

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Neural Stem Cells
Brain
Microglia
Ischemia
Macrophage Activation
Stem Cells
Bystander Effect
Chemokine CXCL12
Injections
Exploratory Behavior
Brain-Derived Neurotrophic Factor
Nerve Growth Factors
Reperfusion Injury
Insulin-Like Growth Factor I
Chemokines
Brain Injuries
Vascular Endothelial Growth Factor A
Reperfusion
Cell Survival
Motor Activity

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

Cite this

Neural stem cells exert a neuroprotective action by changing the ischemic microenvironment. / Maria-Cristina, Principato; Capone, Carmen; Frigerio, Simona; Fumagalli, Stefano; Gelati, Maurizio; Storini, Claudio; Montinaro, Mery; De Curtis, Marco; Parati, Eugenio; Maria-Grazia, De Simoni.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 27, No. SUPPL. 1, 13.11.2007.

Research output: Contribution to journalArticle

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AU - Maria-Cristina, Principato

AU - Capone, Carmen

AU - Frigerio, Simona

AU - Fumagalli, Stefano

AU - Gelati, Maurizio

AU - Storini, Claudio

AU - Montinaro, Mery

AU - De Curtis, Marco

AU - Parati, Eugenio

AU - Maria-Grazia, De Simoni

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N2 - Cell replacement strategies are particularly promising candidate therapies for stroke, a condition in which a widespread loss of different cell types occurs that in principle may benefit from exogenous stem cells replacement of lost or damaged cells. In the present study we have used a murine model of focal, transient ischemia to investigate if: 1) infused NSC are able to decrease ischemic injury and restore brain function; 2) these cells induce changes in the environment in which they are infused; 3) changes in brain environment consequent to transient ischemia are relevant for NSC action. Neurosphere-derived stem cells were obtained from brains of C57BL/6 newborn mice. NSC were infused intracerebroventricularly 4h or 7d after 30min focal ischemia obtained by intraluminal MCAO. Behaviour was evaluated in an open field paradigm at day 7 or 14 after ischemia/reperfusion. The impairment in the numbers of rears and of contacts with objects, measures related to exploratory behavior and sensory-motor activity respectively, observed in ischemic mice, was significantly improved in ischemic mice receiving NSC. Neuronal loss, evaluated in striatum and in cortex, was significantly reduced at day 7 and day 14 in ischemic mice infused with NSC at 4h compared to controls and to ischemic mice receiving NSC at 7d. Infusion of adult fibroblasts in the same experimental conditions was not effective. Assessment of infused NSC distribution revealed that they migrated from the ventricle to the brain parenchyma, they were observable up to day 14, but they progressively decreased in number. In mice receiving NSC at day 7 and in sham-operated mice, few cells located near the injection site could be observed only at 24h, indicating that the survival of these cells in brain tissue relates to the ischemic environment. The mRNA expression of trophic factors such as IGF-1, VEGF-A, TGF-alpha1, BDNF and SDF-1beta increased 24h after NSC infusion in ischemic mice treated with NSC at 4h compared to sham-operated and to mice receiving NSC at 7d. Ischemic brains infused with NSC showed higher activation of microglia/macrophages compared to sham-operated mice receiving NSC or to ischemic brains receiving saline injection showing that microglia/macrophages activation is required for NSC action. In conclusion, neurosphere-derived NSC are able to reduce functional impairment and neuronal damage after ischemia/reperfusion injury. The reciprocal interaction between NSC and the ischemic environment is crucial for NSC protective actions. Indeed NSC survival is enhanced by the ischemic environment and NSC can induce the activation of chemokine and neurotrophic factors. NSC protective effects also relates to the interaction with activated microglia/macrophage. Based on these observations we propose that NSC exert their protective effect by a bystander control of the ischemic environment.

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