Research on how healing mesenchymal cells morph and destroy muscles in models of spinal cord injury, ALS, and spinal muscular atrophy may reveal a potential way to treat motor neuron diseases, according to scientists.
In the study, published recently in Nature Cell Biology, scientists from Sanford Burnham Prebys Medical Discovery Institute (SBP), in collaboration with the Fondazione Santa Lucia IRCCS in Rome, explain that special repair cells called fibro-adipogenic progenitors (FAPs) help replace and repair tissue when a muscle is injured.
However, by studying the muscles of ALS patients and mouse models of motor neuron injury or disease, the scientists found that the FAP cells actually promoted muscle wasting and scarring. The cells activated a feedforward signaling pathway, IL-6-STAT3, creating an “always on” signal to the immune system. When the scientists blocked IL-6 and STAT signaling, muscle wasting and fibrosis halted, indicating a potential way to treat motor neuron diseases, explains a media release from Sanford Burnham Prebys Medical Discovery Institute.
“Characterizing the cell type that promotes muscle wasting and scarring in models of neuromuscular disorders is a critical step forward in our understanding of ALS and additional motor neuron diseases,” says Pier Lorenzo Puri, MD, professor in the Development, Aging and Regeneration Program at SBP, and senior author of the study, in the release.
“Now we can start working on designing medicines that target these cells or possibly use them as markers of disease progression, which can’t come soon enough for patients and their caregivers.”
By comparing mouse models of acute muscle injury and denervation, Puri and his team measured when key players in muscle repair, including macrophages (immune system cells that remove dead material), FAPs and muscle stem cells, appeared and at what levels. In models of acute injury, FAPs appeared in a timely sequence—after macrophage infiltration and before muscle stem cell activation—and left within the typical regeneration window of 5 to 7 days.
In contrast, in the denervation model, FAPs accumulated inside muscles at higher levels and never left. Additionally, inflammatory cell infiltration was not detected and muscle stem cells were not activated.
The scientists examined these strange FAPs more closely, and found that the cells had activated STAT3, resulting in elevated levels of IL-6, an inflammatory cytokine that stimulates muscle atrophy. The IL-6-STAT3 signaling appeared after a loss of connection between the motor neuron and muscle, called the neuromuscular junction, suggesting this link is essential for keeping FAPs under control, the release continues.
“This study highlights an interesting and promising pathway initiated in response to the loss of neuromuscular junctions; and when blocked, reduced muscle wasting in model systems of ALS,” states Lucie Bruijn, PhD, chief scientist at The ALS Association, per the release. “Further studies to understand this pathway in people with ALS and optimization of potential lead molecules will be important in developing this therapeutic approach for ALS.”
[Source(s): Sanford Burnham Prebys Medical Discovery Institute]