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 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.
Moutsatsos
I K
IK
Molecular Pathology Laboratory, Hebrew University-Hadassah Medical and Gene Therapy Center, Jerusalem, Israel.
Turgeman
G
G
Zhou
S
S
Kurkalli
B G
BG
Pelled
G
G
Tzur
L
L
Kelley
P
P
Stumm
N
N
Mi
S
S
Müller
R
R
Zilberman
Y
Y
Gazit
D
D
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001846:Bone Development / Q000235:genetics; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D001861:Bone Regeneration / Q000235:genetics*; D002454:Cell Differentiation; D002460:Cell Line; D002642:Chick Embryo; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D017102:Fracture Healing; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008856:Microscopy, Fluorescence; D018919:Neovascularization, Physiologic; D011994:Recombinant Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta; D019076:Transgenes
D000900:Anti-Bacterial Agents; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D004318:Doxycycline