Transplantation of bone marrow stromal cells for peripheral nerve repair Chun-Jung Chen a,b, ⁎ , Yen-Chuan Ou c , Su-Lan Liao a , Wen-Ying Chen a,e , Shih-Yun Chen a,b , Ching-Wen Wu a , Chun-Chiang Wang a , Wen-Yi Wang d , Yong-San Huang e , Shan-Hui Hsu f a Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan b Institute of Biomedical Medicines, National Chung-Hsing University, Taichung, Taiwan c Division of Urology, Taichung Veterans General Hospital, Taichung, Taiwan d Graduate School of Nursing, Hung-Kuang University, Taichung, Taiwan e Department of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan f Department of Chemical Engineering, National Chung-Hsing University, Taichung, Taiwan Received 21 February 2006; revised 5 December 2006; accepted 6 December 2006 Available online 12 January 2007 Abstract Cell transplantation using bone marrow stromal cells (BMSCs) to alleviate neurological deficits has recently become the focus of research in regenerative medicine. Evidence suggests that secretion of various growth-promoting substances likely plays an important role in functional recovery against neurological diseases. In an attempt to identify a possible mechanism underlying the regenerative potential of BMSCs, this study investigated the production and possible contribution of neurotrophic factors by transected sciatic nerve defect in a rat model with a 15 mm gap. Cultured BMSCs became morphologically homogeneous with fibroblast-like shape after ex vivo expansion. We provided several pieces of evidence for the beneficial effects of implanted fibroblast-like BMSCs on sciatic nerve regeneration. When compared to silicone tube control animals, this treatment led to (i) improved walking behavior as measured by footprint analysis, (ii) reduced loss of gastrocnemius muscle weight and EMG magnitude, and (iii) greater number of regenerating axons within the tube. Cultured fibroblast-like BMSCs constitutively expressed trophic factors and supporting substances, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), collagen, fibronectin, and laminin. The progression of the regenerative process after BMSC implantation was accompanied by elevated expression of neurotrophic factors at both early and later phases. These results taken together, in addition to documented Schwann cell-like differentiation, provide evidence indicating the strong association of neurotrophic factor production and the regenerative potential of implanted BMSCs. © 2006 Elsevier Inc. All rights reserved. Keywords: Bone marrow stromal cells; Neurotrophic factor; Regeneration; Sciatic nerve; Schwann cells; Transplantation Introduction The ability of regenerating neurites to penetrate through the structurally altered extracellular matrix, surrounding tissues, and infiltrating cells at the injured site to reach synaptic targets plays an important role in the regeneration of peripheral nerves. Treatment of peripheral nerve defects is primarily aimed at recreating continuity of the nerve to allow axonal re-growth into the nerve stump distal to the lesion. Therapeutic approaches for the reconstruction of the peripheral nerve defects include end- to-end suturing, fascicular suturing, nerve grafts, and nerve conduits. Evidence indicates that nerve grafting is essential to the reconstruction of long nerve defect. Recently, cell transplantation has become the focus of attention, especially that of Schwann cells, and reliable outcomes have been achieved in the regeneration of the sciatic nerve (Bryan et al., 1996). In addition, the implantation of neural stem cells, bone marrow stromal cells (BMSCs), or fibroblasts has been shown to exert a beneficial effect on peripheral nerve regeneration (Shen et al., 1999; Dezawa et al., 2001; Cuevas et al., 2002, 2004; Murakami et al., 2003; Heine et al., 2004; Mimura et al., 2004). Thus, cell transplantation has been proposed as a method of improving peripheral nerve regeneration. Experimental Neurology 204 (2007) 443 – 453 www.elsevier.com/locate/yexnr ⁎ Corresponding author. Department of Education and Research, Taichung Veterans General Hospital, No. 160, Sec. 3, Taichung-Gang Rd., Taichung 407, Taiwan. Fax: +886 4 23592705. E-mail address: cjchen@vghtc.gov.tw (C.-J. Chen). 0014-4886/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2006.12.004