Abstract
Clinical trials of cell therapy in stroke favor autologous cell transplantation. To date, feasibility studies have used bone marrow-derived mononuclear cells, but harvesting bone marrow cells is invasive thus complicating bedside treatment. We investigated the therapeutic potential of peripheral blood-derived mononuclear cells (PB-MNC) harvested from diabetic patients and stimulated by ephrin-B2 (PB-MNC+) (500,000 cells), injected intravenously 18–24 hours after induced cerebral ischemia in mice. Infarct volume, neurological deficit, neurogenesis, angiogenesis, and inflammation were investigated as were the potential mechanisms of PB-MNC+ cells in poststroke neurorepair. At D3, infarct volume was reduced by 60% and 49% compared to unstimulated PB-MNC and PBS-treated mice, respectively. Compared to PBS, injection of PB-MNC+ increased cell proliferation in the peri-infarct area and the subventricular zone, decreased microglia/macrophage cell density, and upregulated TGF-β expression. At D14, microvessel density was decreased and functional recovery was enhanced compared to PBS-treated mice, whereas plasma levels of BDNF, a major regulator of neuroplasticity, were increased in mice treated with PB-MNC+ compared to the other two groups. Cell transcriptional analysis showed that ephrin-B2 induced phenotype switching of PB-MNC by upregulating genes controlling cell proliferation, inflammation, and angiogenesis, as confirmed by adhesion and Matrigel assays. Conclusions. This feasibility study suggests that PB-MNC+ transplantation poststroke could be a promising approach but warrants further investigation. If confirmed, this rapid, noninvasive bedside cell therapy strategy could be applied to stroke patients at the acute phase.
Highlights
Providing appropriate treatment to all stroke patients remains a genuine challenge
We speculated that peripheral blood-derived mononuclear cells (PB-MNC) from type-2 diabetic patients, stimulated by ephrin-B2 (PB-MNC+) and transplanted into mice 18–24 hours after induction of experimental cerebral ischemia, would be more effective than PBS or unstimulated
Our results show that IV transplantation of PB-MNC+ significantly reduces cerebral infarct volume and increases plasma brain-derived neurotrophic factor (BDNF) levels compared to mice receiving PB-MNC or PBS
Summary
Providing appropriate treatment to all stroke patients remains a genuine challenge. Sixteen million strokes occur every year [1], one every four minutes. 25% of patients die, 40% remain disabled, and 25% develop dementia. Stroke represents a considerable economic burden, with costs reaching 8.3 billion euros per year in France Diabetes is a known independent risk factor for stroke, increasing its incidence threefold and worsening both the severity of the event and strokerelated mortality [2]. These observations are all the more alarming considering the anticipated doubling of the prevalence of diabetes by 2030 (World Health Organization, 2012)
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