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

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 (106 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.

Autologous Bone Marrow Mononuclear Cells Exert Broad Effects on Short- and Long-Term Biological and Functional Outcomes in Rodents with Intracerebral Hemorrhage

“…As seen in young rats, MNCs in this model reduced brain edema and brain atrophy and improved spatial learning and memory produced by ICH. Although we did not repeat the neurogenesis and angiogenesis experiments on aged rats in the present study, recent studies provide evidence that recovery of motor and spatial memory impairment by cellular therapy was associated with the improvement of neurogenesis and angiogenesis, even in aged rats after stroke [57,58].…”

“…However, we did not determine the different populations of MNCs that migrated to the perihematomal area. Another important issue is that differences in labeling techniques (eg, Qtracker vs. GFP) might lead to different biodistribution results [56,57].…”

New GABAergic Neurogenesis in the Hippocampal CA1 Region of a Gerbil Model of Long‐Term Survival after Transient Cerebral Ischemic Injury

“…Over the past several years, stroke-stimulated endogenous neurogenesis has been applied as one of effective strategies for the treatment of stroke associated with aging (2,36). Cerebral ischemia is known to stimulate the proliferation and differentiation of neural precursor cells, which have a potential to enable regeneration and restoration; however, the functional relation of this phenomenon is not clear because of the poor survival and low neuronal differentiation rate of newly born cells in the brain, especially, in the aged brain (8,15).…”

G-CSF as an Adjunctive Therapy with Umbilical Cord Blood Cell Transplantation for Traumatic Brain Injury

“…These effects were hypothesized to involve, at least partially, enhancement of proliferation and differentiation of bone marrow stem cells resulting in improved host brain regeneration and functional recovery (132). Recently, effects of G-CSF treatment alone or in combination with bone marrow mesenchymal stem cells (BM-MSCs) after stroke were evaluated in aged rats (5). Although the combination therapy produced remarkable angiogenesis in the formerly infarct core and beyond in the "islet of regeneration," it did not afford better neuroprotection and recovery poststroke compared with G-CSF treatment alone (5).…”

“…Recently, effects of G-CSF treatment alone or in combination with bone marrow mesenchymal stem cells (BM-MSCs) after stroke were evaluated in aged rats (5). Although the combination therapy produced remarkable angiogenesis in the formerly infarct core and beyond in the "islet of regeneration," it did not afford better neuroprotection and recovery poststroke compared with G-CSF treatment alone (5). That effects of G-CSF were more robust than those exerted by combination treatment with BM-MSCs is consistent with the previous observation on survival-enhancing capacity and beneficial effects on functional outcomes of G-CSF treatment in aged rats (80).…”