Vasculogenesis in Experimental Stroke After Human Cerebral Endothelial Cell Transplantation

Sounds interesting.  What will your doctor do to initiate human clinical trials?
http://stroke.ahajournals.org/content/44/12/3473.abstract?etoc

1. Hiroto Ishikawa, MD, PhD;
2. Naoki Tajiri, PT, PhD;
3. Kazutaka Shinozuka, PhD;
4. Julie Vasconcellos, BS;
5. Yuji Kaneko, PhD;
6. Hong J. Lee, PhD;
7. Osamu Mimura, MD, PhD;
8. Mari Dezawa, MD, PhD;
9. Seung U. Kim, MD, PhD;
10. Cesar V. Borlongan, PhD

+ Author Affiliations

1. From the Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL (H.I., N.T., K.S., J.V., Y.K., C.V.B.); Department of Ophthalmology, Hyogo College of Medicine, Nishinomiya, Japan (H.I., O.M.); Medical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea (H.J.L.); Department of Stem Cell Biology and Histology and Department of Anatomy and Anthropology, Tohoku University Graduate School of Medicine, Sendai, Japan (M.D.); and Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada (S.U.K.).

1. Correspondence to Cesar V. Borlongan, PhD, Department of Neurosurgery and Brain Repair, University of South Florida, 12901 Bruce B. Downs Blvd MDC78, Tampa, FL 33612. E-mail cborlong@health.usf.edu

Abstract

Background and Purpose—Despite the reported functional recovery in transplanted stroke models and patients, the mechanism of action underlying stem cell therapy remains not well understood. Here, we examined the role of stem cell–mediated vascular repair in stroke.

Methods—Adult rats were exposed to transient occlusion of the middle cerebral artery and 3 hours later randomly stereotaxically transplantated with 100K, 200K, or 400K human cerebral endothelial cell 6 viable cells or vehicle. Animals underwent neurological examination and motor test up to day 7 after transplantation then euthanized for immunostaining against neuronal, vascular, and specific human antigens. A parallel in vitro study cocultured rat primary neuronal cells with human cerebral endothelial cell 6 under oxygen-glucose deprivation and treated with vascular endothelial growth factor (VEGF) and anti-VEGF.

Results—Stroke animals that received vehicle infusion displayed typical occlusion of the middle cerebral artery–induced behavioral impairments that were dose-dependently reduced in transplanted stroke animals at days 3 and 7 after transplantation and accompanied by increased expression of host neuronal and vascular markers adjacent to the transplanted cells. Some transplanted cells showed a microvascular phenotype and juxtaposed to the host vasculature. Infarct volume in transplanted stroke animals was significantly smaller than vehicle-infused stroke animals. Moreover, rat neurons cocultured with human cerebral endothelial cell 6 or treated with VEGF exhibited significantly less oxygen-glucose deprivation–induced cell death that was blocked by anti-VEGF treatment.

Conclusions—We found attenuation of behavioral and histological deficits coupled with robust vasculogenesis and neurogenesis in endothelial cell–transplanted stroke animals, suggesting that targeting vascular repair sets in motion a regenerative process in experimental stroke possibly via the VEGF pathway.

Endothelial Cell–Dependent Regulation of Arteriogenesis

Now if we can just get our researchers to figure out how to put arteriogenesis together with angiogenesis or vasculogenesis and new stem cells for the brain to fill in those dead areas. Sounds pretty damn simple to me. A great stroke association would tackle and solve something like that. Nothing ventured, nothing gained.
Maybe leptin administration;

Delayed leptin administration after stroke induces neurogenesis and angiogenesis

http://circres.ahajournals.org/content/113/9/1076.abstract.html?etoc

1. Filipa Moraes,
2. Julie Paye,
3. Feilim Mac Gabhann,
4. Zhen W. Zhuang,
5. Jiasheng Zhang,
6. Anthony A. Lanahan,
7. Michael Simons

+ Author Affiliations

1. From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, New Haven, CT (F.M., Z.W.Z., J.Z., A.A.L., M.S.); Dartmouth College, Hanover, NH (J.P.); Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD (F.M.G.); and Department of Cell Biology, Yale University School of Medicine, New Haven, CT (M.S.). The online-only Data Supplement is available with this article at http://circres.ahajournals.org/lookup/suppl/doi:10.1161/CIRCRESAHA.113.301340/-/DC1.

1. Correspondence to Michael Simons, MD, Cardiovascular Medicine, Yale University School of Medicine, PO Box 802017, 333 Cedar St, New Haven, CT 06520-2017. E-mail michael.simons@yale.edu

Abstract

Rationale: Arteriogenesis is the process of formation of arterial conduits. Its promotion is an attractive therapeutic strategy in occlusive atherosclerotic diseases. Despite the functional and clinical importance of arteriogenesis, the biology of the process is poorly understood. Synectin, a gene previously implicated in the regulation of vascular endothelial cell growth factor signaling, offers a unique opportunity to determine relative contributions of various cell types to arteriogenesis.

Objective: We investigated the cell-autonomous effects of a synectin knockout in arterial morphogenesis.

Methods and Results: A floxed synectin knockin mouse line was crossbred with endothelial-specific (Tie2, Cdh5, Pdgfb) and smooth muscle myosin heavy chain–specific Cre driver mouse lines to produce cell type–specific deletions. Ablation of synectin expression in endothelial, but not smooth muscle cells resulted in the presence of developmental arterial morphogenetic defects (smaller size of the arterial tree, reduced number of arterial branches and collaterals) and impaired arteriogenesis in adult mice.

Conclusions: Synectin modulates developmental and adult arteriogenesis in an endothelial cell–autonomous fashion. These findings show for the first time that endothelial cells are central to both developmental and adult arteriogenesis and provide a model for future studies of factors involved in this process.

Saneron and Henry Ford Health: Cell Therapy Combo Aids Stroke

This might be difficult for your doctor to acquire the day you have a stroke so you better tell your doctor to stock up. 

Saneron and Henry Ford Health: Cell Therapy Combo Aids Stroke 

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.
The study was published in a recent issue of Neuroscience (227:223-231)
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 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.
Funding for the study came from grants from the National Institute on Aging, RO1 AG031811,National Institute of Neurological Disorder and Stroke, PO1 NS23393 and 1R41NS064708, and from the American Heart Association, grant 09GRNT2300151.

Membrane Trafficking and Endothelial-Cell Dynamics During Angiogenesis

Only 28 pages and I learned something new, vasculogenesis vs angiogenesis, I wonder which is more applicable for us survivors that have lots of dead area. Cool diagrams in the pdf, sections listed, details at the link.

http://cdn.intechweb.org/pdfs/31164.pdf
1. Introduction
The formation of new blood vessels, or neovascularization, involves multiple processes,
including cell proliferation and migration, cell-cell and cell-matrix adhesion, and tube
morphogenesis. Neovascularization can occur through one of two events: vasculogenesis,
the de novo formation of blood vessels from angioblasts; or angiogenesis, the extension of
new vessels from a pre-existing vasculature. Among these, angiogenesis in particular is
relevant throughout life; its dysregulation has been causally related to several disorders that
involve malignancy, inflammation, and ischemia. Angiogenesis is thought to depend on a
set of signaling proteins – including certain kinases, integrins and vascular endothelial
growth factor receptor-2 (VEGFR2) – that are enriched in specific plasma membrane
domains. Both physiological and pathological angiogenesis rely on intracellular trafficking,
a process that governs signaling by such proteins, as well as cell motility.
In this chapter, we discuss our current understanding of angiogenesis from the perspective
of trafficking of the membrane components that are responsible for endothelial-cell (EC) dynamics.
2. Angiogenesis: Mechanism and importance

Fig. 1. Schematic representation of a mature blood vessel. Endothelial cells at the luminal
side line tubular blood vessel. The smooth muscle cells and the pericytes that remain in
contact with the endothelial cell lining through the basement membrane strengthen this
tubular structure.
2.1 Vasculogenesis
2.2 Angiogenesis
2.3 Pathological angiogenesis
3. Ligands and receptors in angiogenesis
3.1 The VEGF-VEGFR system coordinates the process of angiogenesis
3.1.1 VEGF
3.2 VEGF receptors
3.2.1 VEGFR1
3.2.2 VEGFR2
3.2.3 VEGFR3
3.2.4 Neuropilins (NRP)
3.3 Role of the extracellular matrix (ECM) in endothelial-cell interactions during angiogenesis
3.4 Role of Integrin in endothelial-cell dynamics during angiogenesis
4. Membrane trafficking
4.1 Biosynthetic/secretory pathway
4.2 Endocytic and exocytic pathways
4.3 Endocytic trafficking of VEGFR2
4.4 Secretory transport of VEGFR2
4.5 VEGFR2 trafficking and angiogenesis