Segmental bone defects and nonunions are relatively common in the craniofacial skeleton. Osteogenic proteins, including bone morphogenetic protein-2 and 4 (BMP-2,4), can promote bone healing in segmental bone defects, but the osteogenic proteins' short half-lives and rapid clearance by the bloodstream limit the success of this technology. Gene therapy and tissue engineering approaches that can achieve high expression levels of these proteins may help to further improve craniofacial bone healing. Our recently isolated clonal population of muscle-derived stem cells (mcl3 cells) that can express stem cell markers, differentiate into both myogenic and osteogenic lineages, and, more importantly, improve bone healing in a calvarial bone defect may be an ideal cell population to mediate gene transfer of osteogenic proteins. The long-term goal of this proposed project is the development of gene therapy approaches based on this novel population of muscle-derived stem cells to efficiently deliver the osteogenic proteins and improve craniofacial bone healing. The mechanism by which these muscle-derived stem cells differentiate into osteogenic lineages under the influence of BMP-2 and BMP-4 will be tested and compared. In addition, we propose to characterize designated approaches of muscle-based tissue engineering using the muscle-derived stem cells in an ex vivo gene transfer of osteogenic proteins in combination with a scaffold to improve bone healing in a mouse calvarial defect. We will investigate the persistence of osteogenic protein expression, the presence of immune response and undesirable side effects related to the overexpression of these proteins, and the biological effects on fracture healing. The use of vascular endothelial growth factor (VEGF), a well-known angiogenic factor, to further improve bone healing will be also characterized. Although this proposed research will focus on muscle-based tissue engineering to regenerate a calvarial defect, this technology ultimately will be applied to other craniofacial sites, as well as appendicular bones. The proposed research will enhance and expand our knowledge of bone healing and develop a clinically relevant treatment based on new molecular therapeutics to treat osseous deficiencies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE013420-01A2
Application #
6370466
Study Section
Special Emphasis Panel (ZRG1-SSS-M (01))
Program Officer
Kousvelari, Eleni
Project Start
2001-08-01
Project End
2006-06-30
Budget Start
2001-08-01
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$248,031
Indirect Cost
Name
Children's Hosp Pittsburgh/Upmc Health Sys
Department
Type
DUNS #
044304145
City
Pittsburgh
State
PA
Country
United States
Zip Code
15224
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Gao, Xueqin; Usas, Arvydas; Lu, Aiping et al. (2016) Cyclooxygenase-2 deficiency impairs muscle-derived stem cell-mediated bone regeneration via cellular autonomous and non-autonomous mechanisms. Hum Mol Genet 25:3216-3231
Tian, Ke; Qi, Min; Wang, Limin et al. (2015) Two-stage therapeutic utility of ectopically formed bone tissue in skeletal muscle induced by adeno-associated virus containing bone morphogenetic protein-4 gene. J Orthop Surg Res 10:86
Gao, Xueqin; Usas, Arvydas; Proto, Jonathan D et al. (2014) Role of donor and host cells in muscle-derived stem cell-mediated bone repair: differentiation vs. paracrine effects. FASEB J 28:3792-809
Gao, Xueqin; Usas, Arvydas; Tang, Ying et al. (2014) A comparison of bone regeneration with human mesenchymal stem cells and muscle-derived stem cells and the critical role of BMP. Biomaterials 35:6859-70
Li, Hongshuai; Johnson, Noah Ray; Usas, Arvydas et al. (2013) Sustained release of bone morphogenetic protein 2 via coacervate improves the osteogenic potential of muscle-derived stem cells. Stem Cells Transl Med 2:667-77
Gao, Xueqin; Usas, Arvydas; Lu, Aiping et al. (2013) BMP2 is superior to BMP4 for promoting human muscle-derived stem cell-mediated bone regeneration in a critical-sized calvarial defect model. Cell Transplant 22:2393-408
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Meszaros, Laura B; Usas, Arvydas; Cooper, Gregory M et al. (2012) Effect of host sex and sex hormones on muscle-derived stem cell-mediated bone formation and defect healing. Tissue Eng Part A 18:1751-9
Gharaibeh, Burhan; Chun-Lansinger, Yuri; Hagen, Tanya et al. (2012) Biological approaches to improve skeletal muscle healing after injury and disease. Birth Defects Res C Embryo Today 96:82-94

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