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Duchenne muscular dystrophy (DMD) is a genetic disease characterized by progressive muscle weakness or dystrophy. DMD symptom onset occurs in early childhood, usually between ages 2 and 3. The disease primarily affects boys – in fact, in Europe and North America, DMD can be seen in approximately one out of every 3,500 boys – but in rare cases, it can also affect girls. Despite currently available treatments, patients with DMD become wheelchair-bound during adolescence and by early adulthood, they need assistance for eating, drinking, and eventually breathing.
Researchers from the Biomedical Research Centre at the University of British Columbia, have turned to better understanding the role of macrophages in order to explore ways of delaying the onset of DMD. Macrophages are proteins that either exist and regenerate in muscle tissues (called “tissue-resident macrophages”) or as white blood cells that travel through a body’s bloodstream (called “infiltrating macrophages”). Macrophages respond to and fight inflammation and disease in muscles, however the different roles of tissue-resident macrophages and infiltrating macrophages have thus far been difficult to distinguish.
A recent study outlines a way to tell tissue-resident macrophages apart from infiltrating macrophages. By surgically joining a mouse to another mouse whose macrophages have been bound to green fluorescent tracers, it becomes possible to distinguish the tissue-resident macrophages from the green fluorescent infiltrating macrophages when both mice are injured. This new insight could pave the way for scientists to better understand the role of tissue-resident macrophages on muscular dystrophy, which could help improve therapies for DMD. They also discovered the potential role of resident macrophages on beneficial tissue muscle metabolism.
We interviewed Dr. Farshad Babael-Jandaghi (DBJ), the primary author of the study to gain a better perspective on the research in this field.
CTS: For the sake of our readers, could you briefly describe the novelty of your recent findings on our understanding of muscular dystrpophy therapeutics?
DBJ: The treatment of muscular dystrophies is mainly limited to corticosteroids, which work through a mechanism that is not fully understood. Despite therapeutic interventions, patients with Duchenne Muscular Dystrophy (DMD) become wheelchair-bound during adolescence. Over the past two decades, many gene-therapy approaches for DMD have been in development. Although promising, the majority of these approaches are not yet available in clinical settings.
Twenty-five years ago, it was shown that fast-twitching muscle fibers are more profoundly affected in DMD and it was proposed that promoting slow muscle fiber function could be a therapeutic approach to delay DMD progression. However, so far, no therapeutic approach has been successfully developed to change the type of muscle fibers efficiently and safely. We believe the profound effect of CSF1R inhibitors (a class of drugs that has been widely investigated to treat cancer) on the type of muscle fibers has the potential to delay disease progression, helping people stay mobile and out of wheelchairs for longer.
We are planning to further explore the therapeutic potentials of CSF1R inhibitors on dystrophic rats, a superior animal model of human DMD. A promising aspect of the findings of this study is that, while developing a new drug to treat a disease can be a long process, the safety profile for this drug is already being proven in human studies, meaning we may be on a fast track to a new treatment for DMD.
CTS: What are the roles of resident and infiltrating macrophages?Infiltrating macrophages are the onese that ome
DBS: Resident macrophages exist in almost all adult tissues. One of their major roles is to remove dead cells or cells under stress in the tissues at steady state (healthy conditions). They also have a variety of tissue-specific roles that are required for proper functioning of healthy tissue.
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Infiltrating macrophages are the ones that come to the tissue from the blood following an injury, an infection, or other pathogenic (unhealthy) conditions. They help the body clear the ailment to regain its normal function. The number of infiltrating macrophages coming to the tissue following infection is much higher than the number of resident macrophages. Distinguishing between muscle resident macrophages and infiltrating macrophages after an injury was not previously possible, therefore the role of the time population of resident macrophages following an injury was underestimated. using several advanced approaches, this study allowed us to unveil the importance of resident macrophages in tissue regeneration.
CTS: How does the production and distribution of resident and infiltrating macrophages differ in people with DMD?
DBJ: This is an interesting question. As mentioned above, distinguishing between muscle resident macrophages and infiltrating macrophages after an injury was not previously possible. In this study, we have introduced several markers that can potentially be used to distinguish the two populations, enabling a better understanding of their numbers, distribution, and roles in different DMD Patients.
CTS: What information did you receive from the parabiosis (the surgical joining) of the two mice?
DBJ: Parabiosis, which involves surgically joining two organisms such that their physiological systems work together, enabled us to identify the cells in a tissue that are coming from the blood from the cells that are tissue-resident. Parabiosis was one of the techniques we used in this study to find markers that can potentially be used to distinguish the two populations.
What are some major challenges you face while conducting experiments with living specimens?
DBJ: To study the potential role of a biological factor such as a cell type or a molecule, we try to only change that one specific factor at a time. Achieving this goal in a living animal is very expensive and time-consuming. Furthermore, the complexity of the animal’s response to each alteration makes understanding the direct role of each factor very challenging.
CTS: What impacts do you hope the results of this study will have on the scientific community?
DBJ: This study introduced a new application for a class of drugs that has been widely investigated in cancer. Further, this study is one of a kind in linking tissue-resident macrophages to tissue metabolism. Therefore, we hope this study’s results broadly catch the interest of scientists working in different fields including tissue regeneration, stem cell biology, inflammation, cancer, and metabolic disorders.
This work was published in full in Science Translational Medicine.
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