Abstract
Bone marrow-derived mononuclear cells (BM MNC) have been effectively used to treat experimental stroke. Most of the preclinical trials have been performed in young and healthy laboratory animals, even though age and hypertension are major risk factors for stroke. To determine the influence of age on the properties of BM MNCs after cerebral ischemia, we compared the efficacy of aged and young BM MNC in an in vitro model of cerebral hypoxia and in an adapted in vivo model of stroke. Human BM MNCs were obtained from healthy young or aged donors and either co-cultured with rat hippocampal slices exposed to oxygen glucose deprivation (OGD), or transplanted intravenously 24 h after permanent middle cerebral artery occlusion in aged (18 months) spontaneously hypertensive rats (SHR). Efficacy was examined by quantification of hippocampal cell death, or respectively, by neurofunctional tests and MR investigations. Co-cultivation with young, but not with aged BM MNCs significantly reduced the hippocampal cell death after OGD. Transplantation of both young and old BM MNCs did not reduce functional deficits or ischemic lesion volume after stroke in aged SHR. These results suggest a significant impact of age on the therapeutic efficacy of BM MNCs after cerebral ischemia.
Highlights
Cerebral ischemia is one of the leading causes for mortality and disability in industrialized countries, and its treatment is seriously restricted by a tight therapeutic time frame
Age-related changes in cell functionality In the first set of experiments we examined whether age has a significant impact on the functional characteristics of Bone marrow derived mononuclear cells (BM MNC)
The ability of BM MNCs derived from young donors with an average age of 24 years to form erythroid burst forming units (BFU-E) and granulocyte/monocyte forming units (CFU-GM) was significantly higher than that from donors with an average age of 68 years (Figure 1A-B)
Summary
Cerebral ischemia is one of the leading causes for mortality and disability in industrialized countries, and its treatment is seriously restricted by a tight therapeutic time frame. Bone marrow derived mononuclear cells (BM MNC) are promising candidates for acute stroke treatment, since these cells can be harvested and re-transplanted acutely. BM MNC transplantation in experimental models of brain ischemia and spinal cord injury resulted in a significantly improved functional recovery [5,6,7], and the therapeutic time window for these effects seems to be between 3 h-72 h after stroke onset [8]. Age and comorbidities have to be considered if autologous approaches are intended, since the receiving tissue and the donor tissue (i.e. the bone marrow) is subjected to aging processes and might be altered in its functionality. We investigated the therapeutic efficacy of human BM MNCs obtained from aged or young donors in an ex vivo model of hypoxia-ischemia and in an in vivo model of stroke using aged hypertensive rats
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