Bone Marrow Cell Transplantation Time-Dependently Abolishes Efficacy of Granulocyte Colony-Stimulating Factor After Stroke in Hypertensive Rats

Abstract

Background and Purpose— We aimed to determine a possible synergistic effect of granulocyte colony-stimulating factor (G-CSF) and bone marrow–derived mononuclear cells (BM MNC) after stroke in spontaneously hypertensive rats. Methods— Male spontaneously hypertensive rats were subjected to middle cerebral artery occlusion and randomly assigned to daily injection of 50 μg/kg G-CSF for 5 days starting 1 hour after stroke (groups 1, 2, and 3) with additional intravenous transplantation of 1.5×10E7 BM MNC per kilogram at 6 hours (group 2) or 48 hours (group 3) after stroke, or control treatment (group 4). Circulating leukocyte counts and functional deficits, infarct volume, and brain edema were repeatedly assessed in the first week and first month. Results— G-CSF treatment led to a significant neutrophilia, to a reversal of postischemic depression of circulating leukocytes, and to a significantly improved functional recovery without affecting the infarct volume or brain edema. BM MNC cotransplantation was neutral after 6 hours, but reversed the functional effect of G-CSF after 48 hours. Short-term investigation of combined G-CSF and BM MNC treatment at 48 hours indicated splenic accumulation of granulocytes and transplanted cells, accompanied by a significant rise of granulocytes in the circulation and the ischemic brain. Conclusions— G-CSF improved functional recovery in spontaneously hypertensive rats, but this effect was abolished by cotransplantation of BM MNC after 48 hours. In the spleen, transplanted cells may hinder the clearance of granulocytes that were massively increased by G-CSF. Increased circulation and infiltration of granulocytes into the ischemic brain may be detrimental for stroke outcome.

Combining Growth Factor and Bone Marrow Cell Therapy Induces Bleeding and Alters Immune Response After Stroke in Mice

“…41 In this previous study, we found that G-CSF+BMC treatment results in accumulation of endogenous granulocytes and grafted cells within the spleen, which in turn led to splenic overload, granulocyte clearance failure, and increase of circulating and intracerebral granulocytes. In the present study, we also observed increased granulocyte numbers within the ischemic lesion of G-CSF+BMC-treated animals, but not in mice treated with G-CSF alone.…”

Concise Review: Increasing the Validity of Cerebrovascular Disease Models and Experimental Methods for Translational Stem Cell Research

“…Unpredictable immunomodulatory effects are not only probable for allogenically or xenogenically transplanted cells but also for cells being manufactured to induce special genes or a pluripotent state . Even freshly isolated autologous cells such as BM‐derived mononuclear cells (BM MNC) or adipose tissue‐derived cells were influenced by centrifugation and exposition to media that cumulatively alter their phenotype and could induce immunologically relevant apoptosis . Aforementioned factors, leading to an undetermined extend of immunomodulation, cannot be simply categorized into beneficial or adverse.…”

Is Immunomodulation a Principal Mechanism Underlying How Cell-Based Therapies Enhance Stroke Recovery?

“…Evidence shows that exogenous cells administered shortly after stroke are exposed to lesser hostile environments and are able to exert better neuroprotective effects as compared with longer time windows after stroke [94][95][96]. NSCs transplanted at 48 h showed better survival than those transplanted at 1 to 2 weeks, because of an increased exposure to well-established inflammatory milieu in latter group [95].…”

“…NSCs transplanted at 48 h showed better survival than those transplanted at 1 to 2 weeks, because of an increased exposure to well-established inflammatory milieu in latter group [95]. Pösel et al [94] showed significant functional improvement in rat stroke models treated with monotherapy of granulocyte colony-stimulating factor (G-CSF), as well as combination therapy of G-CSF and bone marrow MNCs at 6 h poststroke. When bone marrow MNCs were given at 48 h, the beneficial effect of G-CSF therapy was completely abolished [94].…”

“…Pösel et al [94] showed significant functional improvement in rat stroke models treated with monotherapy of granulocyte colony-stimulating factor (G-CSF), as well as combination therapy of G-CSF and bone marrow MNCs at 6 h poststroke. When bone marrow MNCs were given at 48 h, the beneficial effect of G-CSF therapy was completely abolished [94]. These studies show that timing of cell therapy can play a vital role in functional outcome.…”