Homing properties of adipose-derived stem cells to intracerebral glioma and the effects of adenovirus infection.
The inevitable clinical recurrence of high grade gliomas after standard treatment is due to the highly diffuse infiltrating parts of these tumors, which remain after surgery and respond poorly to radiation and chemotherapy. It has been proposed to employ the homing capacity of neural stem cells (NSCs) to different types of intracerebral pathology for selective targeting of glioma cells, and delivery of transgenic expressed therapeutics. This approach has been successful in a number of preclinical experimental studies, however, a major drawback for clinical translation has been the limitation of harvesting and ex vivo expansion of NSCs in patients. Here we demonstrate that adipose derived stem cells (ASCs), which are easily harvested in relatively large quantities in humans, display the same tropism for gliomas as NSCs in vitro and in vivo. Both ipsilateral as well as contralateral injection of these cells in brains of glioma-bearing mice, led to extensive homing to the tumor by the ASCs. The potential of loading these cellular vehicles with transgenes was assessed using adenoviral vectors. ASCs could be infected with adenoviral vectors, albeit at very high MOI. Insertion of the arg-gly-asp (RGD) motif into the adenovirus fiber knob, thereby redirecting primary attachment of the virus to integrins, resulted in a striking 7000-fold increase in infection efficiency. However, in vivo migration of adenovirus-infected ASCs was not observed, most likely due to an inflammatory response to these cells which was not observed with control non-infected ASCs. These results indicate that ASCs are an interesting candidate for further development for cell-based therapy of gliomas, however adenoviruses are not appropriate vectors for delivery of transgenes in this context.
Department of Neurosurgery, VU University Medical Centre, P.O. box 7057, 1007 MB, Amsterdam, The Netherlands.
Martine
M
Lamfers
Sander
S
Idema
Florine
F
van Milligen
Tabitha
T
Schouten
Paul
P
van der Valk
Peter
P
Vandertop
Clemens
C
Dirven
David
D
Noske
D000256:Adenoviridae / Q000235:genetics*; D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology* / Q000821:virology; D002465:Cell Movement; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005822:Genetic Vectors; D005910:Glioma / Q000276:immunology / Q000473:pathology* / Q000821:virology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D014162:Transfection; D019076:Transgenes / Q000502:physiology; D018523:Tropism; D023041:Xenograft Model Antitumor Assays