Modified Autologous Skin Fibroblast

The following paper is quite interesting since for the first time it provides proof of concept data suggesting that skin derived fibroblasts could potentially be differentiated into osteogenic lineage!


Gene Therapy (2008) 15, 1330–1343; doi:10.1038/gt.2008.116; published online 17 July 2008

Ex vivo-transduced autologous skin fibroblasts expressing human Lim mineralization protein-3 efficiently form new bone in animal models
W Lattanzi1, C Parrilla2, A Fetoni2, G Logroscino3, G Straface4, G Pecorini4, E Stigliano5, A Tampieri6, R Bedini7, R Pecci7, F Michetti1,8, A Gambotto9, P D Robbins9 and E Pola3

1Department of Anatomy and Cell Biology, Università Cattolica del Sacro Cuore School of Medicine, Rome, Italy
2Department of Otolaryngology, Università Cattolica del Sacro Cuore School of Medicine, Rome, Italy
3Department of Orthopaedics, Università Cattolica del Sacro Cuore School of Medicine, Rome, Italy
4Department of Internal Medicine, Università Cattolica del Sacro Cuore School of Medicine, Rome, Italy
5Department of Pathology, Università Cattolica del Sacro Cuore School of Medicine, Rome, Italy
6Department of Science and Technology for Ceramics ISTEC-CNR National Council of Research, Faenza, Italy
7Technology and Health Department, Istituto Superiore di Sanità, Rome, Italy
8Latium Musculoskeletal Tissue Bank, Rome, Italy
9Department of Molecular Genetics and Biochemistry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Correspondence: Professor E Pola, Department of Orthopaedics and Traumatology, Università Cattolica del Sacro Cuore School of Medicine, L.go A. Gemelli, 8, Rome 168, Italy. E-mail: enrico.pola@rm.unicatt.it

Received 28 September 2007; Revised 6 June 2008; Accepted 8 June 2008; Published online 17 July 2008.

Abstract
Local gene transfer of the human Lim mineralization protein (LMP), a novel intracellular positive regulator of the osteoblast differentiation program, can induce efficient bone formation in rodents. To develop a clinically relevant gene therapy approach to facilitate bone healing, we have used primary dermal fibroblasts transduced ex vivo with Ad.LMP-3 and seeded on a hydroxyapatite/collagen matrix prior to autologous implantation. Here, we demonstrate that genetically modified autologous dermal fibroblasts expressing Ad.LMP-3 are able to induce ectopic bone formation following implantation of the matrix into mouse triceps and paravertebral muscles. Moreover, implantation of the Ad.LMP-3-modified dermal fibroblasts into a rat mandibular bone critical size defect model results in efficient healing, as determined by X-rays, histology and three-dimensional microcomputed tomography (3DCT). These results demonstrate the effectiveness of the non-secreted intracellular osteogenic factor LMP-3 in inducing bone formation in vivo. Moreover, the utilization of autologous dermal fibroblasts implanted on a biomaterial represents a promising approach for possible future clinical applications aimed at inducing new bone formation.