ORIGINAL ARTICLE Treatment of avascular necrosis of the femoral head by hepatocyte growth factor-transgenic bone marrow stromalstem cells Q Wen 1 , L Ma 1 , Y-P Chen 2 , L Yang 2 , W Luo 1 and X-N Wang 3 1 Institute of Molecular Immunology, Southern Medical University, Guangzhou, People’s Republic of China; 2 Department of Imageology, Nanfang Hospital, Guangzhou, People’s Republic of China and 3 School of Biosciences and Bioengineering, South China University of Technology, Guangzhou, People’s Republic of China The treatmentof hormone-induced early-stage avascular necrosis of the femoral head (ANFH) with transplantation of hepatocyte growth factor (HGF)-transgenic bone marrow stromal stem cells (BMSCs) was examined. A rabbit model of hormone-induced early ANFH was first established. BMSCs were transplantedby core decompressionunder the guidance of computedtomography(CT). A supportive fibrinogendrug delivery mixture (FG) was tested for mechanical enhancement of stem celldelivery.Therapeutic efficacy was evaluated by CT, magnetic resonance imaging (MRI), CT perfusion imaging, ink artery infusion angiography, hematoxylin-and-eosin staining and immunohistochemical staining for extracellularsignal-regulatedkinase-1/2 of pathological sections.A regulararrangement of trabeculae and obvious bone regenerationwere observed in the animals receiving transplantedtransgenicBMSCs with FG. Newly generated capillaries were visible on the bone plates ofthe trabeculae, and the bone marrow was rich in hematopoietictissue. These results demonstrate that the combination ofcore decompression and trans- plantation of HGF transgenic autologous BMSCs enhanced blood vessel regenerationand bone reconstructionin the ANFH model. This study provides experimental data that motivate possible clinical use of this therapeutic strategy. Gene Therapy (2008) 15, 1523–1535; doi:10.1038/gt.2008.110; published online 17 July 2008 Keywords: avascular necrosis of the femoral head; hepatocyte growth factor; bone marrow stromal stem cells; fibrin glue Introduction Avascularnecrosisof the femoral head (ANFH) is a progressive pathological process thatprimarily afflicts people under 40 years of age. Without timely effective treatment, ANFH causes in situ avascular necrosis, and ultimately deforms the bone. The consequenceis impaired hip joint function and permanent disability. 1–3 Whether the etiology of ANFH is traumatic or aseptic nontraumatic,the basic cause is a vicious cycle of elevated intraosseouspressureand obstructed blood supply in the femoral head. ANFH is considered irreversible,and any diagnostic or therapeutic strategy for ANFH is best introduced in the early stage. Early intervention will reduce intraosseouspressure and improve the blood supply to the necrotic femoral head. Osseousrepair should be performed alongside supplemental interventions. The most widespread procedure used to treat early stages of ANFH is core decompression of the hip, which involves drilling a small hole in diseased, necrotic bone. The goal of core decompression isto decrease the intraosseous pressure and allow the regrowth of healthy bone tissue. 4 Although the efficacy of this procedure remains controversial, it has been used for more than three decades. 5,6 Reconstruction of blood circulation and stimulation of bone repair are important aspectsof healing that support this surgical intervention. Thus, the combination of core decompression with the delivery of angiogenic or osteoinductive agents may improve the results of this surgical procedure in the future. 7 Vasodilatationand drug intervention therapy to activate blood and remove stasis are currently used to treat existing blood vessels,which results in disease remission but are not permanent solutions. However, the induction of blood vessel regeneration and the construc- tion of a collateral circulation are the most effective ways to break the vicious pathological cycle of arterial disease or necrosis. Cytokine supplement therapy is a potential treatment for peripheral arterial disease. Hepatocyte growth factor (HGF), originally purified and cloned as a mitogen for hepatocytes, 8,9 is a novel member ofthe endothelium- specific growth factors, and it can stimulate angiogen- esis. Interestingly,HGF can stimulate a significantly higher level of DNA synthesis than basic fibroblast Received 14 January 2008; revised 14 May 2008; accepted 16 May 2008; published online 17 July 2008 Correspondence: Professor L Ma,Institute of Molecular Immuno- logy,Southern Medical University, No. 1838, Northern Guangzhou Avenue, Guangzhou,Guangdong,510515,People’s Republic of China. E-mail: maryhmz@126.com or X-N Wang, School of Biosciences and Bioengineering, South China University of Technology, Guangzhou, Guangdong, 510641, People’s Republic of China. E-mail: xnwang@21cn.net. Gene Therapy (2008) 15, 1523–1535 & 2008 Macmillan Publishers Limited All rights reserved 0969-7128/08 $32.00 www.nature.com/gt