Human engineered skeletal muscle of hypaxial origin from pluripotent stem cells with advanced function and regenerative capacity

Human pluripotent stem cell derived muscle models show great potential for translational research. Here, we describe developmentally inspired methods for derivation of skeletal muscle cells and their utility in three-dimensional skeletal muscle organoid formation as well as skeletal muscle tissue engineering. Key steps include the directed differentiation of human pluripotent stem cells to embryonic muscle progenitors of hypaxial origin followed by primary and secondary fetal myogenesis into hypaxial muscle with development of a satellite cell pool and evidence for innervation in vitro. Skeletal muscle organoids faithfully recapitulate all steps of embryonic myogenesis in 3D. Tissue engineered muscle exhibits organotypic maturation and function, advanced by thyroid hormone. Regenerative competence was demonstrated in a cardiotoxin injury model with evidence of satellite cell activation as underlying mechanism. Collectively, we introduce a hypaxial muscle model with canonical properties of bona fide skeletal muscle in vivo to study muscle development, maturation, disease, and repair.

An enigmatic braincase from Five Points, Ohio (Westphalian D) further supports a stem tetrapod position for aïstopods

ABSTRACTWe describe a new specimen of the aïstopodOestocephalusfrom Five Points, Ohio, which preserves much of the posterior braincase. The specimen, the largest aïstopod skull described, preserves the postorbital region to the occiput. The posterior braincase has coossified the basioccipital, exoccipitals, and opisthotic. The parasphenoid is rostrally restricted, toothless, and highly vaulted along the cultriform process. The lateral walls of the cultriform process are further reinforced by large longitudinally running, ventral flanges from the parietals. Two large endochondral ventral projections from the basioccipital, previously interpreted as basal tuberosities for hypaxial muscle insertion, are here instead interpreted as articulations for the branchial skeleton. This interpretation is further supported by traces of vasculature that is consistent with what is seen in gill-bearing species. A model for the reorganisation of the basicranial region on the transition from hyomandibula to stapes is proposed, which suggests that gills, or gill-support skeletal elements, might be further distributed along the tetrapod stem than previously thought. These data further support the placement of aïstopods in the tetrapod stem group and require a reconsideration of our understanding of early tetrapod evolution.