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First published online December 21, 2006
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2006-0694v1
25/4/875    most recent
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Submitted on October 30, 2006
Accepted on December 15, 2006

Tissue-Specific Stem Cells

Widespread distribution and muscle differentiation of human fetal mesenchymal stem cells after intrauterine transplantation in dystrophic mdx mouse

Jerry Chan 1*, Simon N. Waddington 2, Keelin O'Donoghue 1, Hitoshi Kurata 3, Pascale V. Guillot 3, Cecilia Gotherstrom 3, Michael Themis 4, Jennifer E. Morgan 5, Nicholas M. Fisk 1

1 Experimental Fetal Medicine Group, Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom;Centre for Fetal Care, Queen Charlotte's & Chelsea Hospital, London, United Kingdom
2 Gene Therapy Research Group, Division of Biomedical Sciences, Imperial College London, London, United Kingdom; Department of Haematology, Haemophilia Centre and Haemostasis Unit, Royal Free and University College Medical School, London, United Kingdom
3 Experimental Fetal Medicine Group, Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
4 Gene Therapy Research Group, Division of Biomedical Sciences, Imperial College London, London, United Kingdom
5 Muscle Cell Biology, MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom; Department of Paediatrics, Imperial College London, Hammersmith Campus, London, United Kingdom

* To whom correspondence should be addressed. E-mail: jerrychan{at}nus.edu.sg.


  Abstract

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 (hfMSC) into E14-16 MF1 mice to determine the most appropriate route for systemic delivery. Intramuscular injections resulted in local engraftment, while both intraperitoneal and intravascular delivery led to systemic spread. However, intravascular delivery led to unexpected demise of transplanted mice.

Transplantation of hfMSC into E14-16 mdx mice resulted in wide-spread long-term engraftment (19 weeks) in multiple organs, with a predilection for muscle compared to non-muscle tissues (0.71 v. 0.15%, p<0.01), and evidence of myogenic differentiation of hfMSC in skeletal and myocardial muscle.

This is the first report of intrauterine transplantation of an ontologically-relevant hfMSC into fully immuno-competent dystrophic fetal mice, with systemic spread across endothelial barriers leading to widespread long-term engraftment in multiple organ compartments. While 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.




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