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TISSUE-SPECIFIC STEM CELLS

Widespread Distribution and Muscle Differentiation of Human Fetal Mesenchymal Stem Cells After Intrauterine Transplantation in Dystrophic mdx Mouse

^aExperimental Fetal Medicine Group, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London, United Kingdom;
^bCentre for Fetal Care, Queen Charlotte's & Chelsea Hospital, London, United Kingdom;
^cGene Therapy Research Group, Division of Biomedical Sciences, Imperial College London, London, United Kingdom;
^dDepartment of Haematology, Haemophilia Centre and Haemostasis Unit, Royal Free and University College Medical School, London, United Kingdom;
^eMuscle Cell Biology, MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom;
^fDepartment of Paediatrics, Imperial College London, London, United Kingdom

Correspondence: Jerry Chan, MRCOG, Ph.D., Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore & National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074. Telephone: 65-6772-2681; Fax: 65-6779-4753; e-mail: jerrychan{at}nus.edu.sg

Received October 30, 2006; accepted for publication December 15, 2006.
First published online in STEM CELLS EXPRESS   December 21, 2006.



Duchenne muscular dystrophy (DMD) is a common X-linked disease resulting from the absence of dystrophin in muscle. Affected boys suffer from incurable progressive muscle weakness, leading to premature death. Stem cell transplantation may be curative, but is hampered by the need for systemic delivery and immune rejection. To address these barriers to stem cell therapy in DMD, we investigated a fetal-to-fetal transplantation strategy. We investigated intramuscular, intravascular, and intraperitoneal delivery of human fetal mesenchymal stem cells (hfMSCs) into embryonic day (E) 14–16 MF1 mice to determine the most appropriate route for systemic delivery. Intramuscular injections resulted in local engraftment, whereas both intraperitoneal and intravascular delivery led to systemic spread. However, intravascular delivery led to unexpected demise of transplanted mice. Transplantation of hfMSCs into E14–16 mdx mice resulted in widespread long-term engraftment (19 weeks) in multiple organs, with a predilection for muscle compared with nonmuscle tissues (0.71% vs. 0.15%, p < .01), and evidence of myogenic differentiation of hfMSCs in skeletal and myocardial muscle. This is the first report of intrauterine transplantation of ontologically relevant hfMSCs into fully immunocompetent dystrophic fetal mice, with systemic spread across endothelial barriers leading to widespread long-term engraftment in multiple organ compartments. Although the low-level of chimerism achieved is not curative for DMD, this approach may be useful in other severe mesenchymal or enzyme deficiency syndromes, where low-level protein expression may ameliorate disease pathology.

Disclosure of potential conflicts of interest is found at the end of this article.

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