Myeloid cell-mediated targeting of LIF to dystrophic muscle causes transient increases in muscle fiber lesions by disrupting the recruitment and dispersion of macrophages in muscle
Year: 2021
Type: article
Abstract: Leukemia inhibitory factor (LIF) can influence development by increasing cell proliferation and inhibiting differentiation. Because of its potency for expanding stem cell populations, delivery of exogenous LIF to diseased tissue could have therapeutic value. However, systemic elevations of LIF can have negative, off-target effects. 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, transgene expression in inflammatory cells did not increase muscle growth or increase numbers of stem cells required for regeneration. 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. 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. Transgene expression also induced a shift in macrophage phenotype away from a CD206+, M2-biased phenotype that supports regeneration. 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. 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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddab230
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,922
Awards: G1528649053, Targeting leukemia inhibitory factor to dystrophic muscle via a macrophage-specific transgene, G3508371607, Targeting Therapeutic Molecules to Dystrophic Muscle via the Immune System, G6099097669, Myeloid-cell mediated mechanisms driving muscle growth and regeneration, Modulating Skeletal Muscle Regeneration by Delivery of Myeloid Lineage Cells, Immune cell regulation of the regeneration of dystrophic muscle
OpenAlex ID: W3195996828