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Open Access Research

Inhibition of CD26/DPP-IV enhances donor muscle cell engraftment and stimulates sustained donor cell proliferation

Maura H Parker1*, Carol Loretz1, Ashlee E Tyler2, Lauren Snider2, Rainer Storb13 and Stephen J Tapscott24*

Author Affiliations

1 Program in Transplantation Biology, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Mailstop D1-100, Seattle, WA, 98109-1024, USA

2 Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Mailstop C3-168, Seattle, WA, 98109-1024, USA

3 Department of Medicine, Health Sciences Building RR-512, University of Washington, 1959 NE Pacific Street, Box 356420, Seattle, WA, 98195, USA

4 Department of Neurology, Health Sciences Building RR-650, University of Washington, 1959 NE Pacific Street, Box 356465, Seattle, WA, 98195, USA

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Skeletal Muscle 2012, 2:4  doi:10.1186/2044-5040-2-4

Published: 16 February 2012

Abstract

Background

Transplantation of myogenic stem cells possesses great potential for long-term repair of dystrophic muscle. In murine-to-murine transplantation experiments, CXCR4 expression marks a population of adult murine satellite cells with robust engraftment potential in mdx mice, and CXCR4-positive murine muscle-derived SP cells home more effectively to dystrophic muscle after intra-arterial delivery in mdx5cv mice. Together, these data suggest that CXCR4 plays an important role in donor cell engraftment. Therefore, we sought to translate these results to a clinically relevant canine-to-canine allogeneic transplant model for Duchenne muscular dystrophy (DMD) and determine if CXCR4 is important for donor cell engraftment.

Methods

In this study, we used a canine-to-murine xenotransplantation model to quantitatively compare canine muscle cell engraftment, and test the most effective cell population and modulating factor in a canine model of DMD using allogeneic transplantation experiments.

Results

We show that CXCR4 expressing cells are important for donor muscle cell engraftment, yet FACS sorted CXCR4-positive cells display decreased engraftment efficiency. However, diprotin A, a positive modulator of CXCR4-SDF-1 binding, significantly enhanced engraftment and stimulated sustained proliferation of donor cells in vivo. Furthermore, the canine-to-murine xenotransplantation model accurately predicted results in canine-to-canine muscle cell transplantation.

Conclusions

Therefore, these results establish the efficacy of diprotin A in stimulating muscle cell engraftment, and highlight the pre-clinical utility of a xenotransplantation model in assessing the relative efficacy of muscle stem cell populations.

Keywords:
muscular dystrophy; cell transplantation; xenotransplant; canine; CXCR4; diprotin A