Functional Overloading of Dystrophic Mice Enhances Muscle-Derived Stem Cell Contribution to Muscle Contractile Capacity
Presented as an abstract to Engineering Tissues: Replace, Repair, Regenerate, March 8–11, 2007, Hilton Head, SC.
Abstract
Ambrosio F, Ferrari RJ, Fitzgerald GK, Carvell G, Boninger ML, Huard J. Functional overloading of dystrophic mice enhances muscle-derived stem cell contribution to muscle contractile capacity. Arch Phys Med Rehabil
Objectives
To evaluate the effect of functional overloading on the transplantation of muscle derived stem cells (MDSCs) into dystrophic muscle and the ability of transplanted cells to increase dystrophic muscle's ability to resist overloading-induced weakness.
Design
Cross-sectional.
Setting
Laboratory.
Animals
Male mice (N=10) with a dystrophin gene mutation.
Interventions
MDSCs were intramuscularly transplanted into the extensor digitorum longus muscle (EDL). Functional overloading of the EDL was performed by surgical ablation of the EDL's synergist.
Main Outcome Measures
The total number of dystrophin-positive fibers/cross-section (as a measure of stem cell engraftment), the average number of CD31+ cells (as a measure of capillarity), and in vitro EDL contractile strength. Independent t tests were used to investigate the effect of overloading on engraftment, capillarity, and strength. Paired t tests were used to investigate the effect of MDSC engraftment on strength and capillarity.
Results
MDSC transplantation protects dystrophic muscles against overloading-induced weakness (specific twitch force: control 4.5N/cm2±2.3; MDSC treated 7.9N/cm2±1.4) (P=.02). This improved force production following overloading is concomitant with an increased regeneration by transplanted MDSCs (MDSC: 26.6±20.2 dystrophin-positive fibers/cross-section; overloading + MDSC: 170.6±130.9 dystrophin-positive fibers/cross-section [P=.03]). Overloading-induced increases in skeletal muscle capillarity is significantly correlated with increased MDSC engraftment (R2=.80, P=.01).
Conclusions
These findings suggest that the functional contribution of transplanted MDSCs may rely on activity-dependent mechanisms, possibly mediated by skeletal muscle vascularity. Rehabilitation modalities may play an important role in the development of stem cell transplantation strategies for the treatment of muscular dystrophy.
cOrthopedic Surgery, University of Pittsburgh, Pittsburgh, PA
dStem Cell Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA
Reprint requests to Fabrisia Ambrosio, PhD, MPT, Dept of Physical Medicine & Rehabilitation, Ste 202, 3471 5th Ave, Pittsburgh, PA 15213
Supported in part by the Competitive Medical Research Fund of the University of Pittsburgh; the K12 for Physical and Occupational Therapists–A Comprehensive Opportunities in Rehabilitation Research Training program (grant no. 1K12HD055931-01); the Henry J. Mankin Endowed Chair for the Orthopedic Research at the University of Pittsburgh; the William F. and Jean W. Donaldson Chair at Children's Hospital of Pittsburgh, Pittsburgh, PA; and the NIH (grant no. 5R01 AR49684).
An organization with which 1 or more of the authors is associated has received or will receive financial benefits from a commercial party having a direct financial interest in the results of the research supporting this article.
ABSTRACT