Engineered heart muscles in non-human primates sustain heart remuscularization
Related Articles
Myoblast-derived ADAMTS-like 2 promotes skeletal muscle regeneration after injury
Skeletal muscle regeneration and functional recovery after minor injuries requires the activation of muscle-resident myogenic muscle stem cells (i.e. satellite cells) and their subsequent differentiation into myoblasts, myocytes, and ultimately myofibers. We recently identified secreted ADAMTS-like 2 (ADAMTSL2) as a pro-myogenic regulator of muscle development, where it promoted myoblast differentiation. Since myoblast differentiation is a key process in skeletal muscle regeneration, we here examined the role of ADAMTSL2 during muscle regeneration after BaCl2 injury. Specifically, we found that muscle regeneration was delayed after ablation of ADAMTSL2 in myogenic precursor cells and accelerated following injection of pro-myogenic ADAMTSL2 protein domains. Mechanistically, ADAMTSL2 regulated the number of committed myoblasts, which are the precursors for myocytes and regenerating myofibers. Collectively, our data support a role for myoblast-derived ADAMTSL2 as a positive regulator of muscle regeneration and provide a proof-of-concept for potential therapeutic applications.
Use of HSALR female mice as a model for the study of myotonic dystrophy type I
HSALR mice are the most broadly used animal model for studying myotonic dystrophy type I (DM1). However, so far, HSALR preclinical studies have often excluded female mice or failed to document the biological sex of the animals. This leaves an unwanted knowledge gap concerning the differential development of DM1 in males and females, particularly considering that the disease has a different clinical presentation in men and women. Here we compared typical functional measurements, histological features, molecular phenotypes and biochemical plasma profiles in the muscles of male and female HSALR mice in search of any significant between-sex differences that could justify this exclusion of female mice in HSALR studies and, critically, in candidate therapy assays performed with this model. We found no fundamental differences between HSALR males and females during disease development. Both sexes presented comparable functional and tissue phenotypes, with similar molecular muscle profiles. The only sex differences and significant interactions observed were in plasma biochemical parameters, which are also intrinsically variable in patients with DM1. In addition, we tested the influence of age on these measurements. We therefore suggest including female HSALR mice in regular DM1 studies, and recommend documenting the sex of animals, especially in studies focusing on metabolic alterations. This will allow researchers to detect and report any potential differences between male and female HSALR mice, especially regarding the efficacy of experimental treatments that could be relevant to patients with DM1.
Incomplete elimination of viral genomes is associated with chronic inflammation in nonhuman primate livers after AAV-mediated gene transfer
The liver is a unique organ where immunity can be biased toward ineffective response notably in the context of viral infections. Chronic viral hepatitis depends on the inability of the T-cell immune response to eradicate antigen. In the case of recombinant Adeno-Associated-Virus, used for therapeutic gene transfer, conflicting reports describe tolerance induction to different transgene products while other studies have shown conventional cytotoxic CD8+ T cell responses with a rapid loss of transgene expression. We performed a 1 year follow up of 6 non-human primates after all animals received an rAAV8 vector carrying the GFP transgene at doses of 7×1012 vg/kg. We report that despite anti-GFP peripheral cellular response and loss of hepatic transgene expression, we were still able to detect persisting viral genomes in the liver until 1-year post-injection. These viral genomes were associated with liver inflammation, fibrosis and signs of CD8 T cell exhaustion, including high expression of PD-1. Our study shows that AAV8-mediated gene transfer can results to loss of transgene expression in liver and chronic inflammation several months after gene transfer.
Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
Streptococcus abundance and oral site tropism in humans and non-human primates reflects host and lifestyle differences
The genus Streptococcus is highly diverse and a core member of the primate oral microbiome. Streptococcus species are grouped into at least eight phylogenetically-supported clades, five of which are found almost exclusively in the oral cavity. We explored the dominant Streptococcus phylogenetic clades in samples from multiple oral sites and from ancient and modern-day humans and non-human primates and found that clade dominance is conserved across human oral sites, with most Streptococcus reads assigned to species falling in the Sanguinis or Mitis clades. However, minor differences in the presence and abundance of individual species within each clade differentiated human lifestyles, with loss of S. sinensis appearing to correlate with toothbrushing. Of the non-human primates, only baboons show clade abundance patterns similar to humans, suggesting that a habitat and diet similar to that of early humans may favor the growth of Sanguinis and Mitis clade species.
Responses