Browsing by Author "Wehling-Henricks, Michelle"

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    Aging of the immune system and impaired muscle regeneration: A failure of immunomodulation of adult myogenesis
    (Elsevier, 2021) Tidball, James G.; Flores, Ivan; Welc, Steven S.; Wehling-Henricks, Michelle; Ochi, Eisuke; Anatomy, Cell Biology and Physiology, School of Medicine
    Skeletal muscle regeneration that follows acute injury is strongly influenced by interactions with immune cells that invade and proliferate in the damaged tissue. Discoveries over the past 20 years have identified many of the key mechanisms through which myeloid cells, especially macrophages, regulate muscle regeneration. In addition, lymphoid cells that include CD8+ T-cells and regulatory T-cells also significantly affect the course of muscle regeneration. During aging, the regenerative capacity of skeletal muscle declines, which can contribute to progressive loss of muscle mass and function. Those age-related reductions in muscle regeneration are accompanied by systemic, age-related changes in the immune system, that affect many of the myeloid and lymphoid cell populations that can influence muscle regeneration. In this review, we present recent discoveries that indicate that aging of the immune system contributes to the diminished regenerative capacity of aging muscle. Intrinsic, age-related changes in immune cells modify their expression of factors that affect the function of a population of muscle stem cells, called satellite cells, that are necessary for normal muscle regeneration. For example, age-related reductions in the expression of growth differentiation factor-3 (GDF3) or CXCL10 by macrophages negatively affect adult myogenesis, by disrupting regulatory interactions between macrophages and satellite cells. Those changes contribute to a reduction in the numbers and myogenic capacity of satellite cells in old muscle, which reduces their ability to restore damaged muscle. In addition, aging produces changes in the expression of molecules that regulate the inflammatory response to injured muscle, which also contributes to age-related defects in muscle regeneration. For example, age-related increases in the production of osteopontin by macrophages disrupts the normal inflammatory response to muscle injury, resulting in regenerative defects. These nascent findings represent the beginning of a newly-developing field of investigation into mechanisms through which aging of the immune system affects muscle regeneration.
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    Differential Effects of Myeloid Cell PPARδ and IL-10 in Regulating Macrophage Recruitment, Phenotype, and Regeneration following Acute Muscle Injury
    (American Association of Immunologists, 2020-09-15) Welc, Steven S.; Wehling-Henricks, Michelle; Antoun, Jacqueline; Ha, Tracey T.; Tous, Isabella; Tidball, James G.; Anatomy and Cell Biology, School of Medicine
    Changes in macrophage phenotype in injured muscle profoundly influence regeneration. In particular, the shift of macrophages from a pro-inflammatory (M1-biased) phenotype to a pro-regenerative (M2-biased) phenotype characterized by expression of CD206 and CD163 is essential for normal repair. According to the current canonical mechanism regulating for M1/M2 phenotype transition, signaling through PPARδ is necessary for obtaining the M2-biased phenotype. Our findings confirm that the murine myeloid cell targeted deletion of Ppard reduces expression in vitro of genes that are activated in M2-biased macrophages; however, the mutation in mice in vivo increased numbers of CD206+ M2-biased macrophages and did not reduce the expression of phenotypic markers of M2-biased macrophages in regenerating muscle. Nevertheless, the mutation impaired CCL2-mediated chemotaxis of macrophages and slowed revascularization of injured muscle. In contrast, null mutation of IL10 diminished M2-biased macrophages but produced no defects in muscle revascularization. Our results provide two significant findings. First, they illustrate that mechanisms that regulate macrophage phenotype transitions in vitro are not always predictive of mechanisms that are most important in vivo. Second, they show that mechanisms that regulate macrophage phenotype transitions differ in different in vivo environments.
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    Modulation of Klotho expression in injured muscle perturbs Wnt signalling and influences the rate of muscle growth
    (Wiley, 2020-01) Welc, Steven S.; Wehling-Henricks, Michelle; Kuro-o, Makoto; Thomas, Kyle A.; Tidball, James G.; Anatomy and Cell Biology, School of Medicine
    Skeletal muscle injuries activate a complex programme of myogenesis that can restore normal muscle structure. We tested whether modulating the expression of klotho influenced the response of mouse muscles to acute injury. Our findings show that klotho expression in muscle declines at 3 days post‐injury. That reduction in klotho expression coincided with elevated expression of targets of Wnt signalling (Ccnd1; Myc) and increased MyoD+ muscle cell numbers, reflecting the onset of myogenic cell differentiation. klotho expression subsequently increased at 7 days post‐injury with elevated expression occurring primarily in inflammatory lesions, which was accompanied by reduced expression of Wnt target genes (Ccnd1: 91%; Myc: 96%). Introduction of a klotho transgene maintained high levels of klotho expression over the course of muscle repair and attenuated the increases in Ccnd1 and Myc expression that occurred at 3 days post‐injury. Correspondingly, transgene expression reduced Wnt signalling in Pax7+ cells, reflected by reductions in Pax7+ cells expressing active β‐catenin, and reduced the numbers of MyoD+ cells at 3 days post‐injury. At 21 days post‐injury, muscles in klotho transgenic mice showed increased Pax7+ and decreased myogenin+ cell densities and large increases in myofibre size. Likewise, treating myogenic cells in vitro with Klotho reduced Myod expression but did not affect Pax7 expression. Muscle inflammation was only slightly modulated by increased klotho expression, initially reducing the expression of M2‐biased macrophage markers Cd163 and Cd206 at 3 days post‐injury and later increasing the expression of pan‐macrophage marker F480 and Cd68 at 21 days post‐injury. Collectively, our study shows that Klotho modulates myogenesis and that increased expression accelerates muscle growth after injury.
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    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
    (Oxford University Press, 2021) Flores, Ivan; Welc, Steven S.; Wehling-Henricks, Michelle; Tidball, James G.; Anatomy, Cell Biology and Physiology, School of Medicine
    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.
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    Myeloid cell-specific mutation of Spi1 selectively reduces M2-biased macrophage numbers in skeletal muscle, reduces age-related muscle fibrosis and prevents sarcopenia
    (Wiley, 2022) Wang, Ying; Welc, Steven S.; Wehling-Henricks, Michelle; Kong, Ying; Thomas, Connor; Montecino-Rodriguez, Enca; Dorshkind, Kenneth; Tidball, James G.; Anatomy, Cell Biology and Physiology, School of Medicine
    Intramuscular macrophages play key regulatory roles in determining the response of skeletal muscle to injury and disease. Recent investigations showed that the numbers and phenotype of intramuscular macrophages change during aging, suggesting that those changes could influence the aging process. We tested that hypothesis by generating a mouse model that harbors a myeloid cell-specific mutation of Spi1, which is a transcription factor that is essential for myeloid cell development. The mutation reduced the numbers of macrophages biased to the CD163+/CD206+ M2 phenotype in muscles of aging mice without affecting the numbers of CD68-expressing macrophages and reduced the expression of transcripts associated with the M2-biased phenotype. The mutation did not affect the colony-forming ability or the frequency of specific subpopulations of bone marrow hematopoietic cells and did not affect myeloid/lymphoid cell ratios in peripheral blood leukocyte populations. Cellularity of most myeloid lineage cells was not influenced by the mutation. The Spi1 mutation in bone marrow-derived macrophages in vitro also did not affect expression of transcripts that indicate the M2-biased phenotype. Thus, myeloid cell-targeted mutation of Spi1 influences macrophage phenotype in muscle but did not affect earlier stages of differentiation of cells in the macrophage lineage. The mutation reduced age-related muscle fibrosis, which is consistent with the reduction of M2-biased macrophages, and reduced expression of the pro-fibrotic enzyme arginase. Most importantly, the mutation prevented sarcopenia. Together, our observations indicate that intramuscular, M2-biased macrophages play significant roles in promoting detrimental, age-related changes in muscle.