Exogenously Regulated Stem Cell-Mediated Gene Therapy for Bone Regeneration

Regulated expression of transgene production and function is of great importance for gene therapy. Such regulation can potentially be used to monitor and control complex biological processes. We report here a regulated stem cell-based system for controlling bone regeneration, utilizing genetically e...

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Bibliographic Details
Published in:Molecular therapy 2001-04, Vol.3 (4), p.449-461
Main Authors: Moutsatsos, Ioannis K., Turgeman, Gadi, Zhou, Shuanhu, Kurkalli, Basan Gowda, Pelled, Gadi, Tzur, Liat, Kelley, Pamela, Stumm, Natalie, Mi, Sha, Müller, Ralph, Zilberman, Yoram, Gazit, Dan
Format: Article
Language:English
Subjects:
Adenoviruses
Angiogenesis
Animals
Anti-Bacterial Agents - pharmacology
Antibodies
Bone Development - genetics
Bone Morphogenetic Protein 2
Bone Morphogenetic Proteins - genetics
bone regeneration
Bone Regeneration - genetics
Cell Differentiation
Cell Line
Chick Embryo
Cloning
Doxycycline - pharmacology
Female
Fracture Healing
Fractures
Gene expression
Gene therapy
Genetic Therapy - methods
Genetic Vectors
Humans
Immunohistochemistry
Mice
Mice, Inbred BALB C
Mice, Inbred C3H
Microscopy, Fluorescence
Neovascularization, Physiologic
Proteins
Recombinant Proteins - genetics
Reverse Transcriptase Polymerase Chain Reaction
Signal transduction
Stem cells
Stem Cells - metabolism
tetracycline regulation
Transforming Growth Factor beta
Transgenes
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Summary:Regulated expression of transgene production and function is of great importance for gene therapy. Such regulation can potentially be used to monitor and control complex biological processes. We report here a regulated stem cell-based system for controlling bone regeneration, utilizing genetically engineered mesenchymal stem cells (MSCs) harboring a tetracycline-regulated expression vector encoding the osteogenic growth factor human BMP-2. We show that doxycycline (a tetracycline analogue) is able to control hBMP-2 expression and thus control MSC osteogenic differentiation both in vitro and in vivo. Following in vivo transplantation of genetically engineered MSCs, doxycycline administration controlled both bone formation and bone regeneration. Moreover, our findings showed increased angiogenesis accompanied by bone formation whenever genetically engineered MSCs were induced to express hBMP-2 in vivo. Thus, our results demonstrate that regulated gene expression in mesenchymal stem cells can be used as a means to control bone healing.
ISSN:1525-0016
1525-0024
DOI:10.1006/mthe.2001.0291