Paracrine Mechanisms of Intravenous Bone Marrow-Derived Mononuclear Stem Cells in Chronic Ischemic Stroke

Abstract

Background: The emerging role of stem cell technology and transplantation has helped scientists to study their potential role in neural repair and regeneration. The fate of stem cells is determined by their niche, consisting of surrounding cells and the secreted trophic growth factors. This interim report evaluates the safety, feasibility and efficacy (if any) of bone marrow-derived mononuclear stem cells (BM-MNC) in chronic ischemic stroke by studying the release of serum vascular endothelial growth factor (VEGF) and brain-derived neurotrophic growth factor (BDNF).

Methods: Twenty stroke patients and 20 age-matched healthy controls were recruited with the following inclusion criteria: 3 months to 1.5 years from the index event, Medical Research Council (MRC) grade of hand muscles of at least 2, Brunnstrom stage 2-5, conscious, and comprehendible. They were randomized to one group receiving autologous BM-MNC (mean 60-70 million) and to another group receiving saline infusion (placebo). All patients were administered a neuromotor rehabilitation regime for 8 weeks. Clinical assessments [Fugl Meyer scale (FM), modified Barthel index (mBI), MRC grade, Ashworth tone scale] were carried out and serum VEGF and BDNF levels were assessed at baseline and at 8 weeks.

Results: No serious adverse events were observed during the study. There was no statistically significant clinical improvement between the groups (FM: 95% CI 15.2-5.35, p = 0.25; mBI: 95% CI 14.3-4.5, p = 0.31). VEGF and BDNF expression was found to be greater in group 1 compared to group 2 (VEGF: 442.1 vs. 400.3 pg/ml, p = 0.67; BDNF: 21.3 vs. 19.5 ng/ml) without any statistically significant difference.

Conclusion: Autologous mononuclear stem cell infusion is safe and tolerable by chronic ischemic stroke patients. The released growth factors (VEGF and BDNF) in the microenvironment could be due to the paracrine hypothesis of stem cell niche and neurorehabilitation regime.

Keywords: Autologous mononuclear stem cell infusion; Chronic ischemic stroke; Intravenous bone marrow-derived mononuclear stem cells.

Fig. 1

Mean FM score and mBI in groups 1 and 2 at 2 months (p > 0.05).

Fig. 2

Box plots showing VEGF in groups 1 and 2 at 8 weeks. No significant difference in the median values of VEGF was found in both groups (442.1 vs. 400.3 pg/ml; p = 0.67).

Fig. 3

Graph showing mean VEGF in ischemic stroke. All patients with LA disease were found to have a high mean baseline VEGF in groups 1 and 2 followed by SV. One patient with CE stroke had a VEGF level of 316.4 pg/ml, patients with undetermined (UND) or determined (DET) stroke each had a mean VEGF level of 245.5 or 256.7 pg/ml.

Fig. 4

a Association of serum VEGF according to stroke severity (severely and moderately affected patients) at baseline and at 2 months in groups 1 and 2. b Association of serum BDNF according to stroke severity (severely and moderately affected patients) at baseline and at 2 months in both groups.