Artikel
Development of a three-dimensional extracellular matrix for the transplantation of tumor targeting neural stem cells in an orthotopic glioma model
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Autoren
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N. Schmidt
- Klinik für Neurochirurgie, Universitäts-Krankenhaus Eppendorf
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K. Hansen
- Klinik für Neurochirurgie, Universitäts-Krankenhaus Eppendorf
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F. Zeigler
- Histogen Inc., San Diego, CA, USA
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F.J. Müller
- ZIP-Kiel, Center for Psychiatry, Universitätsklinikum Schleswig Holstein, Campus Kiel, Kiel, Deutschland
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K. Lamszus
- Klinik für Neurochirurgie, Universitäts-Krankenhaus Eppendorf
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M. Westphal
- Klinik für Neurochirurgie, Universitäts-Krankenhaus Eppendorf
| Veröffentlicht: | 20. Mai 2009 |
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Gliederung
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Objective: Neural stem cells (NSC) display inherent tumor-tropic properties that can be exploited for targeted delivery of therapeutic genes to invasive glioma cells. Optimized transplantation efficiency is essential for developing effective NSC-based glioma therapies especially when applied to the challenging surgical resection cavity. Stem cell transplantation using biomaterial-based devices is considered promising to reduce the poor survival and limited integration of grafted cells in various neurological disorders reported so far.
Methods: We report the development of a three-dimensional extracellular matrix preparation (3DECM) which is based on ECM purified from tissue-engineered skin cultures containing laminin-coated collagen fibers. We determined the in vitro growth characteristics of murine neural stem cells encased in 3DECM and assessed their proliferation rate (MIB5) and differentiation status (Nestin, GFAP, MAP2, NF) by immunohistochemistry. The migration pattern of DiI-labeled NSC after intracerebral transplantation within a 3DECM pellet was determined using the syngenic C57BL6/GL261 glioma xenograft model (n=4).
Results: The 3DECM preparation allowed the in vitro expansion of NSC encased within the 3DECM (MIB Index 39±4%) while retaining their uncommited differentiation status. The semisolid consistency of the NSC-containing 3DECM pellets allowed simple handling during the surgical procedure of intracerebral implantation and ensured a continuous contact with the surrounding brain parenchyma as assessed by histology. When implanted into the right forebrain DiI-labeled NSC were able to migrate out of the 3DECM to a targeted contralateral growing glioma and to enrich within the tumor mass after one week. In absence of a tumor, the NSC stayed near the contact zone of the 3DECM/brain parenchyma with no distant NSC migration.
Conclusions: Here we demonstrate proof-of-concept of a matrix supported intracerebral transplantation of glioma targeting NSC. In contrast to injections of cell suspensions, an intracerebral application of NSC within a semisolid 3DECM has the potential to increase transplantation efficiency by reducing metabolic stress and providing mechanical support especially when administered in a surgical resection cavity.
