Granulocyte Colony-stimulating Factor and Bone Marrow Mononuclear Cells for Stroke Treatment in the Aged Brain

Abstract

Ischemic stroke swiftly induces a wide spectrum of pathophysiological sequelae, particularly in the aged brain. The translational failure of experimental therapies, might partially be related to monotherapeutic approaches, not address potential counter-mechanisms sufficiently or within the best time window. For example, therapeutic effects relying on stem/progenitor cell mobilization by granulocyte-colony stimulating factor (G-CSF), require approximately a week to become manifest, which is potentially beyond the optimal timing. Here, We tested the hypothesis that treating post-stroke aged rats with the combination of bone marrow-derived mononuclear cells (BM MNC) and G-CSF improves the long term (56 days) functional outcome by compensating the delay before G-CSF effects come to full effect. 1x10(6) syngeneic BM MNC per kg bodyweight (BW) with G-CSF (50 µg/kg, given intraperitoneal by via the jugular vein to aged Sprague- Dawley rats, six hours post-stroke. This process was repeated daily, for a 28 day period. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunohistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period. Daily G-CSF treatment led to a robust and consistent improvement of neurological function, but did not alter final infarct volumes. The combination of G-CSF and BM MNC, did not further improve post-stroke recovery. The lack of an additional benefit may be due to interaction between both approaches, and to a lesser extent, in the insensitivity of the aged brains' regenerative mechanisms. Also considering recent findings on other tandem approaches involving G-CSF in animal models featuring relevant co-morbidities, we conclude that such combination therapies are not the optimal approach to treat the acutely injured aged brain.

Stem Cell‐Based Therapies for Ischemic Stroke: Preclinical Results and the Potential of Imaging‐Assisted Evaluation of Donor Cell Fate and Mechanisms of Brain Regeneration

“…Similarly, Buga et al. who used a G‐CSF and a combined G‐CSF–BMMNC therapy to improve the functional outcome after transplantation in aged stroke animals were also unable to observe an increased functional improvement by using the combination treatment . The use of iPSCs in aged rats was described by Tatarishivili et al.…”

“…149 Similarly, Buga et al who used a G-CSF and a combined G-CSF-BMMNC therapy to improve the functional outcome after transplantation in aged stroke animals were also unable to observe an increased functional improvement by using the combination treatment. 290 The use of iPSCs in aged rats was described by Tatarishivili et al who showed that almost 50% of the engrafted iPSC-derived long-term expendable neuroepithelial cells survived 8 weeks posttransplantation and caused functional improvement in the aged rats. 170 Moreover, these cells differentiated toward neuroblast-like cells, compared to the BM-MSCs described in Refs.…”

Granulocyte-Colony Stimulating Factor (G-CSF) for stroke: an individual patient data meta-analysis

“…Similarly, G-CSF and SCF combined induced significant and sustained functional recovery in stroke rats with administration as late as 3.5 months post ictus32. More recently, however, experimental studies assessed G-CSF in post-stroke aged rats in combination with bone marrow-derived mononuclear cells33 and pre-differentiated mesenchymal cells34; 28 days of combined treatment did not enhance recovery in comparison to G-CSF alone in either experiment, further questioning the capability of the aged brain to respond to regenerative therapies.…”

Genetic Aspects of Inflammation and Immune Response in Stroke

“…Balseanu et al, demonstrated in a stroke rat model that daily intravenous injection of G-CSF led to robust and consistent improvement of neurological functions, which in a combination with a single intravenous administration of mesenchymal stromal cells (MSC) increased the neurogenesis in the subventricular zone and improved microvessel density in the formerly infarct core and perilesional area of treated aged rats, but had no beneficial effect on the infarct volume or mortality [ 90 ]. The same group revealed that the combination of G-CSF with bone marrow-derived mononuclear cells (BM MNC) in aged rats led to the no advantage over G-CSF treatment alone, suggesting that different outcomes might be achieved depending on the type of cells used [ 91 ]. Ren et al confirmed the neuroprotective effect of G-CSF gene therapy in rodents and suggested a translational possibility of this research strategy in humans by exprimation of the G-CSF gene into an adenovirus that is safe and known to infect brain cells efficiently [ 92 ].…”