Researchers at the Henry Ford Health System (Detroit, MI) and colleagues at Saneron CCEL Therapeutics, Inc. of Tampa, Florida, have found that when human umbilical cord blood cells (HUCBCs) were transplanted into test rats modeled with stroke, the addition of Simvastatin to the HUCBCs significantly increased the therapeutic benefit of the HUCBCs.
According to N. Kuzmin-Nichols, Saneron president and COO, the combination treatment, delivered 24 hours after the test animals were subjected to simulated stroke, showed an interactive effect in improving neurological outcome. When compared with monotherapy, the combination therapy increased densities of key blood vessels, arteries, and smooth muscle cells in vascular walls.
“HUCBCs are a source for blood stem cells, endothelial cell precursors, mensenchymal cell progenitors, and other multipotent and pluripotent stem cells,” said Kuzmin-Nichols. “They offer a promising therapy for stroke. However, when HUCBCs are used alone, and injected via a vascular route for brain repair, success has been limited.”
Because the drug Simvastatin has been demonstrated to be a neurorestorative and neuroprotective agent in ischemic brain injury, the research team hypothesized that the combination of therapeutic doses of Simvastatin and HUCBCs would increase the expression of Angiopoietin-1(Ang-1, a protein with important roles in vascular development and blood vessel growth) and its receptor Tie2 (a cell-surface receptor that binds with Ang-1). Both Ang-1 and Tie2 promote vascular stabilization and artery growth and could enhance blood vessel remodeling (angiogenesis) after stroke, said the researchers.
According to the researchers, HUCBCs contain a “ready supply” of neurotrophic and angiogenic factors that induce neurogenesis (neural cell repair) and angiogenesis (blood vessel growth), both of which are critical to promoting neurological recovery post stroke. While transplanted HUCBCs have been found to selectively migrate to the injured brain, past and recent research has discovered that few transplanted HUCBCs express neural cell characteristics, and few find their way to the ischemic region of the brain.
“Our study using subtherapeutic monotherapy doses did not show significant improvement in either vasculogenesis or functional outcome,” said Dr. Jieli Chen (pictured) of Henry Ford Hospital and the study corresponding author. “However, the combination of HUCBCs and Simvastatin did show an interactive effect with a significant improvement in neurological outcome. The combination also amplified endogenous angiogenesis and arteriogenesis, and enhanced vascular remodeling.”
Their in vitro experiments showed that combination treatment and Ang-1 significantly increased capillary-like tube formation and arterial cell migration while anti-Ang-1 significantly reduced combination treatment-induced tube formation and artery cell migration.
Dr. Chen noted that combination treatment likely increases the signaling between the brain vasculature and parenchymal cells that facilitate the migration of HUCBCs into the injured cerebral tissue. This signaling may be attributed to the increased expression of stromal derived factor (SDF-1) in brain vascular and parenchymal cells and its receptor (CXCR4) in HUCBCs.
The researchers concluded that their findings “indicate that the combination of sub-therapeutic doses of Simvastatin and HUCBCs increases Ang1/Tie2 and thereby enhances vascular remodeling that contribute to improved functional outcome after stroke.”
“Our results in this preclincial study support further exploration of the use of combination therapies - such as those combining Simvastatin and HUCBCs - for stroke treatment,” said Kuzmin-Nichols.
Illustration: Henry Ford Health System.
Abstract (Neuroscience; Volume 227, 27 December 2012, Pages 223–231.)