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Multimodal Approaches for Regenerative Stroke Therapies: Combination of Granulocyte Colony-Stimulating Factor with Bone Marrow Mesenchymal Stem Cells is Not Superior to G-CSF Alone.

Balseanu AT, Buga AM, Catalin B, Wagner DC, Boltze J, Zagrean AM, Reymann K, Schaebitz W, Popa-Wagner A - Front Aging Neurosci (2014)

Bottom Line: Functional recovery was tested during the entire post-stroke survival period of 56 days.The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the "islet of regeneration." However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery.We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time.

View Article: PubMed Central - PubMed

Affiliation: Center of Clinical and Experimental Medicine, University of Medicine and Pharmacy of Craiova , Craiova , Romania.

ABSTRACT
Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods of cellular therapy that can enhance the endogenous restorative mechanisms of the injured brain. Since stroke afflicts mostly the elderly, it is highly desirable to test the efficacy of cell therapy in the microenvironment of aged brains that is generally refractory to regeneration. In particular, stem cells from the bone marrow allow an autologous transplantation approach that can be translated in the near future to the clinical practice. Such a bone marrow-derived therapy includes the grafting of stem cells as well as the delayed induction of endogenous stem cell mobilization and homing by the stem cell mobilizer granulocyte colony-stimulating factor (G-CSF). We tested the hypothesis that grafting of bone marrow-derived pre-differentiated mesenchymal cells (BM-MSCs) in G-CSF-treated animals improves the long-term functional outcome in aged rodents. To this end, G-CSF alone (50 μg/kg) or in combination with a single dose (10(6) cells) of rat BM MSCs was administered intravenously to Sprague-Dawley rats at 6 h after transient occlusion (90 min) of the middle cerebral artery. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunhistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period of 56 days. Daily treatment for post-stroke aged rats with G-CSF led to a robust and consistent improvement of neurological function after 28 days. The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the "islet of regeneration." However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery. We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time.

No MeSH data available.


Related in: MedlinePlus

Phenotyping of human BMSCs. In the ipsilateral hemisphere, the injected human BMSCs were localized in the corpus callosum as shown for CD166-positive cells [(A), arrows] and CD105-positive cells [(F), arrows]. In our model, the cells most likely entered the injured brain via the lateral ventricle as shown by the CD166-positive cells (B). A fraction (about 1%) of the injected CD166- and CD105-positive cells reached the infarcted area [(C,E), arrows] where they were intermingled with surviving or degenerating neuronal nuclei [(C), arrowheads]. Noteworthy was also the presence of immunopositivity for human nuclei [(D), arrows] that were dispersed between the rat nuclei in the infarcted area [(D), arrowheads]. Cc, corpus callosum; IC, infarct core; LV, lateral ventricle; PI, periinfract.
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Figure 4: Phenotyping of human BMSCs. In the ipsilateral hemisphere, the injected human BMSCs were localized in the corpus callosum as shown for CD166-positive cells [(A), arrows] and CD105-positive cells [(F), arrows]. In our model, the cells most likely entered the injured brain via the lateral ventricle as shown by the CD166-positive cells (B). A fraction (about 1%) of the injected CD166- and CD105-positive cells reached the infarcted area [(C,E), arrows] where they were intermingled with surviving or degenerating neuronal nuclei [(C), arrowheads]. Noteworthy was also the presence of immunopositivity for human nuclei [(D), arrows] that were dispersed between the rat nuclei in the infarcted area [(D), arrowheads]. Cc, corpus callosum; IC, infarct core; LV, lateral ventricle; PI, periinfract.

Mentions: In the ipsilateral hemisphere, the injected human BM MSCs were detected in the corpus callosum as shown for CD166-positive cells (Figure 4A, arrows) and CD105-positive cells (Figure 4F, arrows). In our model the cell probably entered the injured brain via the lateral ventricle as shown by the CD166-positive cells (Figure 4B). A fraction (about 1%) of the injected CD166- and CD105-positive cells reached the infarcted area (Figures 4C,E, arrows) where they were intermingled with surviving or degenerating neuronal nuclei (Figure 4C, arrowheads). Noteworthy was also the presence of immunopositivity for human nuclei (Figure 4D, arrows) that were dispersed between the rat nuclei in the infarcted area (Figure 4D, arrowheads).


Multimodal Approaches for Regenerative Stroke Therapies: Combination of Granulocyte Colony-Stimulating Factor with Bone Marrow Mesenchymal Stem Cells is Not Superior to G-CSF Alone.

Balseanu AT, Buga AM, Catalin B, Wagner DC, Boltze J, Zagrean AM, Reymann K, Schaebitz W, Popa-Wagner A - Front Aging Neurosci (2014)

Phenotyping of human BMSCs. In the ipsilateral hemisphere, the injected human BMSCs were localized in the corpus callosum as shown for CD166-positive cells [(A), arrows] and CD105-positive cells [(F), arrows]. In our model, the cells most likely entered the injured brain via the lateral ventricle as shown by the CD166-positive cells (B). A fraction (about 1%) of the injected CD166- and CD105-positive cells reached the infarcted area [(C,E), arrows] where they were intermingled with surviving or degenerating neuronal nuclei [(C), arrowheads]. Noteworthy was also the presence of immunopositivity for human nuclei [(D), arrows] that were dispersed between the rat nuclei in the infarcted area [(D), arrowheads]. Cc, corpus callosum; IC, infarct core; LV, lateral ventricle; PI, periinfract.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4066299&req=5

Figure 4: Phenotyping of human BMSCs. In the ipsilateral hemisphere, the injected human BMSCs were localized in the corpus callosum as shown for CD166-positive cells [(A), arrows] and CD105-positive cells [(F), arrows]. In our model, the cells most likely entered the injured brain via the lateral ventricle as shown by the CD166-positive cells (B). A fraction (about 1%) of the injected CD166- and CD105-positive cells reached the infarcted area [(C,E), arrows] where they were intermingled with surviving or degenerating neuronal nuclei [(C), arrowheads]. Noteworthy was also the presence of immunopositivity for human nuclei [(D), arrows] that were dispersed between the rat nuclei in the infarcted area [(D), arrowheads]. Cc, corpus callosum; IC, infarct core; LV, lateral ventricle; PI, periinfract.
Mentions: In the ipsilateral hemisphere, the injected human BM MSCs were detected in the corpus callosum as shown for CD166-positive cells (Figure 4A, arrows) and CD105-positive cells (Figure 4F, arrows). In our model the cell probably entered the injured brain via the lateral ventricle as shown by the CD166-positive cells (Figure 4B). A fraction (about 1%) of the injected CD166- and CD105-positive cells reached the infarcted area (Figures 4C,E, arrows) where they were intermingled with surviving or degenerating neuronal nuclei (Figure 4C, arrowheads). Noteworthy was also the presence of immunopositivity for human nuclei (Figure 4D, arrows) that were dispersed between the rat nuclei in the infarcted area (Figure 4D, arrowheads).

Bottom Line: Functional recovery was tested during the entire post-stroke survival period of 56 days.The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the "islet of regeneration." However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery.We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time.

View Article: PubMed Central - PubMed

Affiliation: Center of Clinical and Experimental Medicine, University of Medicine and Pharmacy of Craiova , Craiova , Romania.

ABSTRACT
Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods of cellular therapy that can enhance the endogenous restorative mechanisms of the injured brain. Since stroke afflicts mostly the elderly, it is highly desirable to test the efficacy of cell therapy in the microenvironment of aged brains that is generally refractory to regeneration. In particular, stem cells from the bone marrow allow an autologous transplantation approach that can be translated in the near future to the clinical practice. Such a bone marrow-derived therapy includes the grafting of stem cells as well as the delayed induction of endogenous stem cell mobilization and homing by the stem cell mobilizer granulocyte colony-stimulating factor (G-CSF). We tested the hypothesis that grafting of bone marrow-derived pre-differentiated mesenchymal cells (BM-MSCs) in G-CSF-treated animals improves the long-term functional outcome in aged rodents. To this end, G-CSF alone (50 μg/kg) or in combination with a single dose (10(6) cells) of rat BM MSCs was administered intravenously to Sprague-Dawley rats at 6 h after transient occlusion (90 min) of the middle cerebral artery. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunhistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period of 56 days. Daily treatment for post-stroke aged rats with G-CSF led to a robust and consistent improvement of neurological function after 28 days. The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the "islet of regeneration." However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery. We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time.

No MeSH data available.


Related in: MedlinePlus