Human umbilical cord blood cells transfected with VEGF and L(1)CAM do not differentiate into neurons but transform into vascular endothelial cells and secrete neuro-trophic factors to support neuro-genesis-a novel approach in stem cell therapy

• Published in: Neurochemistry international Vol. 53; no. 6-8; pp. 389 - 394
• Main Authors: Rizvanov, Albert A, Kiyasov, Andrey P, Gaziziov, Ilnaz M, Yilmaz, Tatyana S, Kaligin, Maxim S, Andreeva, Dina I, Shafigullina, Aigul K, Guseva, Darya S, Kiselev, Sergey L, Matin, Keyvan, Palotás, András, Islamov, Rustem R
• Format: Journal Article
• Language: English
• Published: England 01-12-2008
• Subjects: Animals; Cell Differentiation - genetics; Cell Movement - physiology; Cell Proliferation; Cells, Cultured; Endothelial Cells - metabolism; Endothelial Cells - secretion; Female; Genetic Vectors; Graft Survival - physiology; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - secretion; Humans; Male; Mice; Mice, Transgenic; Neovascularization, Physiologic - genetics; Nerve Growth Factors - metabolism; Nerve Growth Factors - secretion; Neural Cell Adhesion Molecule L1 - genetics; Neurogenesis - physiology; Spinal Cord - cytology; Spinal Cord - physiology; Stem Cell Transplantation - methods; Transfection - methods; Treatment Outcome; Vascular Endothelial Growth Factor A - genetics
• ISSN: 0197-0186
• DOI: 10.1016/j.neuint.2008.09.011

Genetically modified mono-nuclear cell fraction from human umbilical cord blood (HUCB) expressing human vascular endothelial growth factor (VEGF) and mouse neural L(1) cell adhesion molecule (L(1)CAM) were used for gene-stem cell therapy of transgenic (G)93(A) mice adopted as an animal amyotrophic lateral sclerosis (ALS) model. We generated non-viral plasmid constructs, expressing human VEGF(165) (pcDNA-VEGF) and mouse neural L(1) cell adhesion molecule (pcDNA-mL(1)CAM). Mono-nuclear fraction of HUCB cells were transiently transfected by electro-poration with a mixture of expression plasmids (pcDNA-VEGF+pcDNA-mL(1)CAM). Sixteen transgenic female and male mice were randomly assigned to three groups: (1) transplantation of genetically modified HUCB cells expressing L(1) and VEGF (n=6), (2) transplantation of un-transfected HUCB cells (n=5), and (3) control group (n=5). In first two experimental groups 1x10(6) cells were injected retro-orbitally in pre-symptomatic 22-25-week-old (G)93(A) mice. Our results demonstrate that HUCB cells successfully grafted into nervous tissue of ALS mice and survived for over 3 months. Therefore, genetically modified HUCB cells migrate in the spinal cord parenchyma, proliferate, but instead of transforming into nerve cells, they differentiate into endothelial cells forming new blood vessels. We propose that: (A) expression of mouse neural L(1)CAM is responsible for increased homing and subsequent proliferation of transplanted cells at the site of neuro-degeneration, (B) expression of human VEGF directs HUCB cell differentiation into endothelial cells, and (C) neuro-protective effect may stem from the delivery of various neuro-trophic factors from newly formed blood vessels.