Cartilage repair in a rat model of osteoarthritis through intraarticular transplantation of muscle-derived stem cells expressing bone morphogenetic protein 4 and soluble Flt-1.
OBJECTIVE
The control of angiogenesis during chondrogenic differentiation is an important issue affecting the use of stem cells in cartilage repair, especially with regard to the persistence of regenerated cartilage. This study was undertaken to investigate the effect of vascular endothelial growth factor (VEGF) stimulation and the blocking of VEGF with its antagonist, soluble Flt-1 (sFlt-1), on the chondrogenesis of skeletal muscle-derived stem cells (MDSCs) in a rat model of osteoarthritis (OA).


METHODS
We investigated the effect of VEGF on cartilage repair in an immunodeficiency rat model of OA after intraarticular injection of murine MDSCs expressing bone morphogenetic protein 4 (BMP-4) in combination with MDSCs expressing VEGF or sFlt-1.


RESULTS
In vivo, a combination of sFlt-1- and BMP-4-transduced MDSCs demonstrated better repair without osteophyte formation macroscopically and histologically following OA induction, when compared with the other groups. Higher differentiation/proliferation and lower levels of chondrocyte apoptosis were also observed in sFlt-1- and BMP-4-transduced MDSCs compared with a combination of VEGF- and BMP-4-transduced MDSCs or with BMP-4-transduced MDSCs alone. In vitro experiments with mixed pellet coculture of MDSCs and OA chondrocytes revealed that BMP-4-transduced MDSCs produced the largest pellets, which had the highest gene expression of not only type II collagen and SOX9 but also type X collagen, suggesting formation of hypertrophic chondrocytes.


CONCLUSIONS
Our results demonstrate that MDSC-based therapy involving sFlt-1 and BMP-4 repairs articular cartilage in OA mainly by having a beneficial effect on chondrogenesis by the donor and host cells as well as by preventing angiogenesis, which eventually prevents cartilage resorption, resulting in persistent cartilage regeneration and repair.
Matsumoto
Tomoyuki
T
Stem Cell Research Center, Children's Hospital of Pittsburgh, and University of Pittsburgh, Pittsburgh, Pennsylvania 15213-2582, USA.
Cooper
Gregory M
GM
Gharaibeh
Burhan
B
Meszaros
Laura B
LB
Li
Guangheng
G
Usas
Arvydas
A
Fu
Freddie H
FH
Huard
Johnny
J
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000032:analysis* / Q000494:pharmacology; D002358:Cartilage, Articular / Q000502:physiology*; D020219:Chondrogenesis / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010003:Osteoarthritis / Q000601:surgery*; D051381:Rats; D011923:Rats, Nude; D012038:Regeneration / Q000502:physiology; D033581:Stem Cell Transplantation; D014161:Transduction, Genetic; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis* / Q000502:physiology
D055415:Bone Morphogenetic Protein 4; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1