Combination treatment of stroke with sub-therapeutic doses of Simvastatin and human umbilical cord blood cells enhances vascular remodeling and improves functional outcome

Abstract

Human umbilical cord blood cells (HUCBCs) have been employed as a restorative treatment for experimental stroke. In this study, we investigated whether transplantation of sub-therapeutic doses of HUCBCs and Simvastatin enhances cerebral vascular remodeling after stroke. Adult male Wistar rats (n=34) were subjected to transient middle cerebral artery occlusion (MCAo) and treated with: phosphate buffered solution (PBS, gavaged daily for 7 days); Simvastatin (0.5mg/kg, gavaged daily for 7 days); HUCBCs (1x106, injected once via tail vein); and combination Simvasatin with HUCBCs, starting at 24 h after MCAo. There was no significant difference between Simvastatin- or HUCBC-monotherapy and MCAo-alone group. Combination treatment 24 h post-stroke significantly increased the perimeter of von Willebrand factor (vWF)-positive vessels, the diameter and density of alpha smooth muscle actin ( SMA)-positive arteries, and the percentage of BrdU-positive endothelial cells (ECs) in the ischemic boundary zone (IBZ) compared with MCAo-alone or HUCBC-monotherapy 14 days after MCAo (p<0.05, n=8/group); Combination treatment significantly increased the densities of vWF-vessels and SMA-arteries as well as the densities of BrdU-ECs and BrdU-positive smooth muscle cells (SMCs) in vascular walls in the IBZ compared with Simvastatin-monotherapy. Moreover, the increased BrdU-ECs and BrdU-SMCs were significantly correlated with neurological functional outcome 14 days after MCAo. Combination treatment also significantly increased the expression of Angiopoietin-1 (Ang1), Tie2 and Occludin in the IBZ (p<0.05, n=8/group). The in vitro experiments showed that combination treatment and Ang1 significantly increased capillary-like tube formation and arterial cell migration; anti-Ang1 significantly reduced combination treatment induced tube-formation and artery cell migration (p<0.05, n=6/group). These findings indicated that combination of sub-therapeutic doses of Simvastatin and HUCBCs treatment of stroke increases Ang1/Tie2 and Occludin expression in the ischemic brain, amplifies endogenous angiogenesis and arteriogenesis, and enhances vascular remodeling which in concert may contribute to functional outcome after stroke.

Transplantation of Cryopreserved Human Umbilical Cord Blood Mononuclear Cells Does Not Induce Sustained Recovery after Experimental Stroke in Spontaneously Hypertensive Rats

“…The results of this study are in clear contrast with previously reported findings from our 3 and other groups 6,28 that indicated a noticeable benefit of experimental HUCB MNC transplantation after stroke. However, next to a considerable body of indications corroborating the therapeutic efficacy of HUCB MNC after stroke, some investigators were unable to reproduce therapeutic findings, especially when applying more demanding functional tests as in the present study.…”

“…Thus, direct release of human neurotrophins by cord blood cells as shown in in vitro experiments 27 cannot be ruled out by our study design and might account for discrepancies with the literature. 10,28 But even if present, it would not have had an effect on the primary and secondary endpoints assessed. Moreover, we performed analysis of growth factor mRNA expression only up to 2 days after stroke, as previous studies suggested that gene expression functionally related to processes of brain plasticity is initiated very quickly after stroke.…”

Umbilical cord blood donation: public or private?

“…UCB cells have produced functional recovery and vascular remodeling after stroke. 56 UCB has shown promise and is in clinical trials for the treatment of patients with chronic spinal cord injury. 57 The IV infusions of human UCB ameliorated the consequences of prenatal hypoxic injury in a baby rabbit model of hypoxic ischemic encephalopathy.…”

G-Protein–Coupled Receptor 91 and Succinate Are Key Contributors in Neonatal Postcerebral Hypoxia-Ischemia Recovery

“…[9][10][11] In this context, prompt revascularization of stroke is associated with improved outcome. [12][13][14] For instance in humans, elevated levels of vascular endothelial growth factor (VEGF) are observed after stroke, and increased microvascular density correlates with a better outcome. 15,16 In animal models, intracerebral injections of proangiogenic factors greatly enhance motor functions.…”