Transplantation of PSC-derived myogenic progenitors counteracts disease phenotypes in FSHD mice
Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant progressive myopathy caused by improper silencing of the DUX4 gene, leading to fibrosis, muscle atrophy, and fatty replacement. Approaches focused on muscle regeneration through the delivery of stem cells represent an attractive therapeutic option for muscular dystrophies. Scientists find that mouse pluripotent stem cell (PSC)-derived myogenic progenitors engraft muscle actively undergoing DUX4-mediated degeneration. Donor-derived muscle tissue displayed reduced fibrosis. Importantly, engrafted muscles showed improved contractile-specific force compared to non-transplanted controls. These data demonstrate the feasibility of replacing diseased muscle with PSC-derived myogenic progenitors in a mouse model for FSHD.
DUX4 may typically play some role in embryonic development, but its expression at later times is thought to be deleterious. In vitro, DUX4 expression leads to cell death, and mouse models have been generated to study FSHD pathology and test therapeutics.
To investigate the potential for cell transplantation in FSHD, researchers have used the doxycycline-regulated iDUX4pA-HSA mouse model in which low-level DUX4 can be induced in skeletal muscle. Successful modulation of Dux4 expression has been reported in a mouse model that recapitulates several disease phenotypes observed in patients with fibrosis, inflammation, and muscle atrophy. Another potential therapeutic approach is cell replacement, in which the diseased muscle is replaced with healthy myofibers and, ideally, new healthy muscle stem cells. Pluripotent stem cells (PSCs) are an attractive source since they can continually produce large amounts of differentiated tissue. Transplantation of PSC-derived myogenic progenitors has proven effective in several models of recessive muscular dystrophy, including DMD. iDUX4pA-HSA mice were pre-injured with cardiotoxin (CTX) and another cohort that remained uninjured. CTX injury is widely used for muscle engraftment assessment since it destroys existing muscle fibers, initiating a generalized regenerative program.
In summary, these findings represent an example of cell therapy in an FSHD model and demonstrate the benefits of PSC-based myogenic regenerative therapy for FSHD, providing proof of concept for the potential therapeutic application of cell transplantation for autonomous dominant Muscular dystrophy.
Azzag, K., Bosnakovski, D., Tungtur, S. et al. Transplantation of PSC-derived myogenic progenitors counteracts disease phenotypes in FSHD mice. npj Regen Med 7, 43 (2022). https://doi.org/10.1038/s41536-022-00249-0
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