Regenerative medicine 2.0: extracellular vesicle-based therapeutics for musculoskeletal tissue regeneration.

In recent years, extracellular vesicles (EVs) have emerged as prominent mediators of the homeostasis, repair, and regeneration of musculoskeletal tissues including bone, skeletal muscle, and cartilage. Accordingly, the therapeutic potential of EVs for regenerative medicine applications has not gone unnoticed. The use of EVs for the treatment of musculoskeletal injury and disease in veterinary species is a nascent but rapidly expanding area of research. Recent studies in this area have demonstrated the safety and feasibility of EV products in dogs and horses. While early clinical responses to EV-based therapeutics in companion animals have been favorable, more rigorously designed, sufficiently powered, and placebo-controlled clinical trials are required to fully elucidate the clinical benefits and best-use scenarios for EV therapeutics in veterinary medicine. Additionally, clinical translation of EV-based therapeutics will require Good Manufacturing Practice-compliant methods to scale up and purify EV products. Despite these challenges, EVs hold great promise in the regenerative medicine landscape, particularly in the treatment of musculoskeletal injury and disease in companion animals.

Regulation of axial and head patterning during planarian regeneration by a commensal bacterium.

Some animals, such as planaria, can regenerate complex anatomical structures in a process regulated by genetic and biophysical factors, but additional external inputs into regeneration remain to be uncovered. Microbial communities inhabiting metazoan organisms are important for metabolic, immune, and disease processes, but their instructive influence over host structures remains largely unexplored. Here, we show that Aquitalea sp. FJL05, an endogenous commensal bacterium of Dugesia japonica planarians, and one of the small molecules it produces, indole, can influence axial and head patterning during regeneration, leading to regeneration of permanently two-headed animals. Testing the impact of indole on planaria tissues via RNA sequencing, we find that indole alters the regenerative outcomes in planarians through changes in expression to patterning genes, including a downregulation of Wnt pathway genes. These data provide a unique example of the product of a commensal bacterium modulating transcription of patterning genes to affect the host's anatomical structure during regeneration.

The Bacterial Metabolite Indole Inhibits Regeneration of the Planarian Flatworm Dugesia japonica.

Planarian flatworms have been used for over a century as models for regeneration. Planarians live in aquatic environments with constant exposure to microbes, but the mechanisms by which bacteria may mediate planarian regeneration are largely unknown. We characterized the microbiome of laboratory populations of the planarian Dugesia japonica and determined how individual bacteria impact D. japonica regeneration. Eight to ten taxa in the phyla Bacteroidetes and Proteobacteria consistently occur across planarian colonies housed in different research laboratories. Individual members of the D. japonica microbiome can delay regeneration including the development of eye spots and blastema formation. The microbial metabolite indole is produced in significant quantities by two bacteria that are consistently found in the D. japonica microbiome and contributes to delays in regeneration. Collectively, these results provide a baseline understanding of the bacteria associated with the planarian D. japonica and demonstrate how metabolite production by host-associated microbes can affect regeneration.

Planarian regeneration in space: Persistent anatomical, behavioral, and bacteriological changes induced by space travel.

Regeneration is regulated not only by chemical signals but also by physical processes, such as bioelectric gradients. How these may change in the absence of the normal gravitational and geomagnetic fields is largely unknown. Planarian flatworms were moved to the International Space Station for 5 weeks, immediately after removing their heads and tails. A control group in spring water remained on Earth. No manipulation of the planaria occurred while they were in orbit, and space-exposed worms were returned to our laboratory for analysis. One animal out of 15 regenerated into a double-headed phenotype-normally an extremely rare event. Remarkably, amputating this double-headed worm again, in plain water, resulted again in the double-headed phenotype. Moreover, even when tested 20 months after return to Earth, the space-exposed worms displayed significant quantitative differences in behavior and microbiome composition. These observations may have implications for human and animal space travelers, but could also elucidate how microgravity and hypomagnetic environments could be used to trigger desired morphological, neurological, physiological, and bacteriomic changes for various regenerative and bioengineering applications.

The identification of fall history using maximal and rapid isometric torque characteristics of the hip extensors in healthy, recreationally active elderly females: a preliminary investigation.

BACKGROUND AND AIMS: Maximal and rapid torque characteristics of the hip extensor muscles play an important role in fall prevention and other balance-related performances; however, few studies have investigated the ability of these variables at identifying fall-history status in healthy, recreationally active elderly adults. This study aimed to examine the effectiveness of maximal and rapid isometric torque characteristics of the hip extensor muscles to differentiate between healthy, recreationally active elderly females with (fallers) and without (non-fallers) a history a falls. METHODS: Six elderly female fallers (mean ± SD: age = 73 ± 7 year; mass = 68 ± 16 kg; height = 160 ± 5 cm) and nine elderly female non-fallers (age = 71 ± 7 year; mass = 66 ± 16 kg; height = 157 ± 6 cm) performed two isometric maximal voluntary contractions (MVCs) of the hip extensor muscles. Peak torque (PT) and absolute and relative rate of torque development (RTD) at the early (0-50 ms) and late (100-200 ms) phases of muscle contraction were examined during each MVC. RESULTS: Absolute and relative RTD at 0-50 ms were greater (P = 0.039 and 0.011, respectively) in the non-fallers compared to the fallers. However, no group-related differences (P = 0.160-0.573) were observed for PT nor absolute and relative RTD at 100-200 ms. CONCLUSIONS: Early rapid strength production of the hip extensor muscles may be a sensitive and effective measure for discriminating between elderly females of different fall histories. These findings may provide important insight regarding implications for the assessment of fall risk and in the development of proper training programs aimed at minimizing the occurrence of falls and other balance-related injuries in the elderly.