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Enhancement of Human Adipose-Derived Stromal Cell Angiogenesis through Knockdown of a BMP-2 Inhibitor

Levi, Benjamin M.D.; Nelson, Emily R. B.S.; Hyun, Jeong S. M.D.; Glotzbach, Jason P. M.D.; Li, Shuli Ph.D.; Nauta, Allison M.D.; Montoro, Daniel T. B.S.; Lee, Min Ph.D.; Commons, George C. M.D.; Hu, Shijun Ph.D.; Wu, Joseph C. M.D., Ph.D.; Gurtner, Geoffrey C. M.D.; Longaker, Michael T. M.D., M.B.A.

Plastic & Reconstructive Surgery:
doi: 10.1097/PRS.0b013e3182361ff5
Experimental: Original Articles
Abstract

Background: Previous studies have demonstrated the role of noggin, a bone morphogenetic protein-2 inhibitor, in vascular development and angiogenesis. The authors hypothesized that noggin suppression in human adipose-derived stromal cells would enhance vascular endothelial growth factor secretion and angiogenesis in vitro and in vivo to a greater extent than bone morphogenetic protein-2 alone.

Methods: Human adipose-derived stromal cells were isolated from human lipoaspirate (n = 6) noggin was knocked down using lentiviral techniques. Knockdown was confirmed and angiogenesis was assessed by tubule formation and quantitative real-time polymerase chain reaction. Cells were seeded onto scaffolds and implanted into a 4-mm critical size calvarial defect. In vivo angiogenic signaling was assessed by immunofluorescence and immunohistochemistry.

Results: Human adipose-derived stromal cells with noggin suppression secreted significantly higher amounts of angiogenic proteins, expressed higher levels of angiogenic genes, and formed more tubules in vitro. In vivo, calvarial defects seeded with noggin shRNA human adipose-derived stromal cells exhibited a significantly higher number of vessels in the defect site than controls by immunohistochemistry (p < 0.05). In addition, bone morphogenetic protein-2–releasing scaffolds significantly enhanced vascular signaling in the defect site.

Conclusions: Human adipose-derived stromal cells demonstrate significant increases in angiogenesis in vitro and in vivo with both noggin suppression and BMP-2 supplementation. By creating a cell with noggin suppressed and by using a scaffold with increased bone morphogenetic protein-2 signaling, a more angiogenic niche can be created.

Author Information

Stanford and Los Angeles, Calif.

From the Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Plastic and Reconstructive Surgery Division, and the Department of Medicine and Radiology, Stanford University School of Medicine; the Institute for Stem Cell Biology and Regenerative Medicine, Stanford University; and the Division of Advanced Prosthodontics, Biomaterials, and Hospital Dentistry, University of California, Los Angeles, School of Dentistry.

Received for publication April 15, 2011; accepted June 17, 2011.

Ms. Nelson and Dr. Hyun contributed equally to this article.

Disclosure: The authors have no financial interest in any of the products or devices mentioned in this article.

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Michael T. Longaker, M.D., M.B.A.; Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, 257 Campus Drive, Stanford University, Stanford, Calif. 94305-5148, longaker@stanford.edu

©2012American Society of Plastic Surgeons