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Bone marrow cell transplantation time-dependently reverses G-CSF effects after stroke in hypertensive rats

: Pösel, C.; Wagner, D.C.; Scheibe, J.; Kranz, A.; Bothe, V.; Lange, F.; Schäbitz, W.R.; Minnerup, J.; Boltze, J.


Journal of cerebral blood flow and metabolism 36 (2016), Supplement 1, pp.304-305
ISSN: 0271-678X
ISSN: 1559-7016
International Symposium on Cerebral Blood Flow, Metabolism and Function <27, 2015, Vancouver>
International Conference on Quantification of Brain Function with PET <12, 2015, Vancouver>
Fraunhofer IZI ()

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic cytokine and preclinically proven, potent neuroprotectant1. A potential reason for the clinical failure of G-CSF may be that relevant G-CSF effects such as the mobilization of mononuclear hematopoietic stem and progenitor cells from the bone-marrow may take too long in humans (up to 9 days2) to counter the initial stroke consequences. Systemic transplantation of bone marrow mononuclear cells (BMMNC) is feasible within a relatively short time after stroke onset and may provide an external resource of aforementioned stem and progenitor cells and thereby “bridge the gap” until G-CSF comes to full effect.
Male spontaneously hypertensive rats (SHR) were randomly assigned into 4 groups after permanent middle cerebral artery occlusion. Groups 1-3 received i.p. G-CSF treatment (50µg/kg) for 5d starting 1h after stroke onset. Groups 2 and 3 received 1.5x107/kg BMMNC i.v. at 6 or 48h following stroke. Group 4 received placebo treatment. Functional deficits (adhesive removal test), infarct volume, edema (T2 TSE MRI) were repeatedly assessed for one month. Peripheral leukocyte counts and BMMNC biodistribution were analyzed by flow cytometry during the first week after stroke. All experiments were conducted randomized and blinded.
G-CSF mono-treatment reduced functional deficits (p<0.05) and partially reversed post-stroke immune depression (overall leuko-/monocyte as well as B-, NK, and T-cell counts; p<0.01) and expectedly increased peripheral leukocyte counts massively (p<0.01). G-CSF but did not affect infarct volume or edema. BMMNC co-transplantation at 6h did not further improve functional deficits (p>0.05 each). Surprisingly, BMMNC transplantation at 48h abolished G-CSF effects. Early biodistribution studies (at 52 hours after stroke onset) revealed splenic accumulation of granulocytes and BMMNC as well as a granulocyte overload in the peripheral circulation and the brain (p<0.05).
Although therapeutic effects of G-CSF mono-treatment were observed in SHR, the G-CSF/BMMNC co-treatment did not provide additional functional benefits. Splenic accumulation of transplanted BM MNC may have impaired peripheral granulocyte clearance. Subsequently, increased granulocyte numbers in the circulation and the post-stroke brain prompted a pro-inflammatory bias of the innate immune system’s response to stroke, ultimately abolishing G-CSF effects3. These surprising findings indicate that systemic effects of experimental stroke therapies need to be carefully considered when assessing the therapeutic potential of such novel approaches.