This targeting approach is especially valuable in diseases such as Duchenne muscular dystrophy (DMD) which is unpredictably ‘asynchronous’ ( 2), in which different muscles and even different groups of muscle fibers in the same muscle occur at different stages of injury and repair. Because inflammatory cells rapidly invade dystrophic muscle specifically at the times and locations where pathology is active, and afterwards they naturally reduce in numbers and activity when pathology attenuates, they provide a rapidly responsive, intrinsic system to target disease. Together, the findings show that macrophage-mediated delivery of transgenic LIF exerts differential effects on macrophage dispersion and muscle damage depending on the stage of dystrophic pathology.Ī recently developed strategy for targeting therapeutic molecules to dystrophic muscle exploits inflammatory cells as natural vectors to selectively express and deliver potentially beneficial proteins to diseased muscle ( 1).
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However, at later stages of the disease when macrophage numbers declined, they dispersed in the muscle, leading to reductions in muscle fiber damage, compared to non-transgenic mdx mice. Transgene expression also induced a shift in macrophage phenotype away from a CD206+, M2-biased phenotype that supports regeneration.
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The defect in inflammatory cell dispersion reflected impaired chemotaxis of macrophages to C-C motif chemokine ligand-2 and local increases of LIF production that produced large aggregations of cytolytic macrophages. Instead, transgene expression disrupted the normal dispersion of macrophages in dystrophic muscles, leading to transient increases in muscle damage in foci where macrophages were highly concentrated during early stages of pathology. However, transgene expression in inflammatory cells did not increase muscle growth or increase numbers of stem cells required for regeneration. We tested whether inflammatory cells expressing a LIF transgene under control of a leukocyte-specific, CD11b promoter provide a strategy to target LIF to sites of damage in the mdx mouse model of Duchenne muscular dystrophy, leading to increased numbers of muscle stem cells and improved muscle regeneration. However, systemic elevations of LIF can have negative, off-target effects. Because of its potency for expanding stem cell populations, delivery of exogenous LIF to diseased tissue could have therapeutic value. Leukemia inhibitory factor (LIF) can influence development by increasing cell proliferation and inhibiting differentiation.