Researchers from the University of Illinois developed a novel therapeutic approach using dystrophin expressing chimeric (DEC) cells derived from myoblasts of normal and Duchenne muscular dystrophy (DMD) donors with clinical potential to mitigate multiorgan failure in DMD patients.
“We confirmed that systemic-intraosseous transplant of DEC cells resulted in increased dystrophin expression, reduction of mdx pathology, and amelioration of cardiac, pulmonary, and skeletal muscle’s function,” the study authors concluded.
Ejection fraction and fractional shortening values were preserved in DEC cell‑injected mice. In contrast, vehicle-injected controls experienced hypertrophy of the posterior left ventricular wall with significant decline in ejection fraction and fractional shortening.
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DEC cell transplantation reduced cardiac muscle fibrosis and inflammation. When compared with vehicle-injected controls, treated mice showed less fibrotic collagenous tissue and inflammatory foci, as well as normalized fiber size and lack of large inflammatory infiltrates.
Siemionow et al found a significant dose-dependent improvement in the respiratory function of DEC cell-injected mice, including reduced enhanced pause (Pehn) and expiration time, increased tidal volume and respiratory frequency, strengthened diaphragm contraction, and decreased interstitial fibrosis and inflammation of the diaphragm.
A significant dose-dependent effect was also observed on skeletal muscle’s architecture and function. DEC cell transplantation increased muscle mass, enhanced muscle strength, reduced muscle fatigue, and diminished skeletal muscle’s fibrosis and inflammation. Feret’s diameter measurement in gastrocnemius muscles revealed enlarged diameter and a shift toward larger fiber size in DEC cell-injected mice.
These findings were accompanied by a dose-dependent increase in the expression of dystrophin in heart, diaphragm, and gastrocnemius muscles, and a decrease of centrally nucleated fibers, a hallmark of the mdx pathology, in diaphragm and gastrocnemius muscles.
To establish the therapeutic model, the researchers developed an ex vivo cell fusion technology to create human DEC cell lines from normal and DMD-affected donors. DEC cells (0.5 x 106 or 1 x 106) were directly injected into the femur of male mdx/scid mice, a conventional DMD animal model. Age-matched male mdx/scid mice injected with vehicles were assigned to the control group. Long-term engraftment, dystrophin expression, and effects on heart, diaphragm, and gastrocnemius muscles were analyzed at 90 days post‑transplantation.
Siemionow M, Langa P, Harasymczuk M, et al. Human dystrophin expressing chimeric (DEC) cell therapy ameliorates cardiac, respiratory, and skeletal muscle’s function in Duchenne muscular dystrophy. Stem Cells Trans Med. Published online July 22, 2021. doi:10.1002/sctm.21-0054