Tissue-resident macrophages specifically express Lactotransferrin and Vegfc during ear pinna regeneration in spiny mice.

The details of how macrophages control different healing trajectories (regeneration vs. scar formation) remain poorly defined. Spiny mice (Acomys spp.) can regenerate external ear pinnae tissue, whereas lab mice (Mus musculus) form scar tissue in response to an identical injury. Here, we used this dual species system to dissect macrophage phenotypes between healing modes. We identified secreted factors from activated Acomys macrophages that induce a pro-regenerative phenotype in fibroblasts from both species. Transcriptional profiling of Acomys macrophages and subsequent in vitro tests identified VEGFC, PDGFA, and Lactotransferrin (LTF) as potential pro-regenerative modulators. Examining macrophages in vivo, we found that Acomys-resident macrophages secreted VEGFC and LTF, whereas Mus macrophages do not. Lastly, we demonstrate the requirement for VEGFC during regeneration and find that interrupting lymphangiogenesis delays blastema and new tissue formation. Together, our results demonstrate that cell-autonomous mechanisms govern how macrophages react to the same stimuli to differentially produce factors that facilitate regeneration.

Neural crest cells give rise to non-myogenic mesenchymal tissue in the adult murid ear pinna.

Despite being a major target of reconstructive surgery, development of the external ear pinna remains poorly studied. As a craniofacial organ highly accessible to manipulation and highly conserved among mammals, the ear pinna represents a valuable model for the study of appendage development and wound healing in the craniofacial complex. Here we provide a cellular characterization of late gestational and postnatal ear pinna development in Mus musculus and Acomys cahirinus and demonstrate that ear pinna development is largely conserved between these species. Using Wnt1-cre;ROSAmT/mG mice we find that connective tissue fibroblasts, elastic cartilage, dermal papilla cells, dermal sheath cells, vasculature, and adipocytes in the adult pinna are derived from cranial crest. In contrast, we find that skeletal muscle and hair follicles are not derived from neural crest cells. Cellular analysis using the naturally occurring short ear mouse mutant shows that elastic cartilage does not develop properly in distal pinna due to impaired chondroprogenitor proliferation. Interestingly, while chondroprogenitors develop in a mostly continuous sheet, the boundaries of cartilage loss in the short ear mutant strongly correlate with locations of vasculature-conveying foramen. Concomitant with loss of elastic cartilage we report increased numbers of adipocytes, but this seems to be a state acquired in adulthood rather than a developmental abnormality. In addition, chondrogenesis remains impaired in the adult mid-distal ear pinna of these mutants. Together these data establish a developmental basis for the study of the ear pinna with intriguing insights into the development of elastic cartilage.

Design and development of a novel expanding flexible rod device (FRD) for stability in the lumbar spine: A finite-element study.

The aim of this study is to design a novel expanding flexible rod device, for pedicle screw fixation to provide dynamic stability, based on strength and flexibility. Three-dimensional finite-element models of lumbar spine (L1-S) with flexible rod device on L3-L4-L5 levels are developed. The implant material is taken to be Ti-6Al-4V. The models are simulated under different boundary conditions, and the results are compared with intact model. In natural model, total range of motion under 10 Nm moment were found 66.7°, 24.3° and 13.59°, respectively during flexion-extension, lateral bending and axial rotation. The von Mises stress at intact bone was 4 ± 2 MPa and at bone, adjacent to the screw in the implanted bone, was 6 ± 3 MPa. The von Mises stress of disc of intact bone varied from 0.36 to 2.13 MPa while that of the disc between the fixed vertebra of the fixation model reduced by approximately 10% for flexion and 25% for extension compared to intact model. The von Mises stresses of pedicle screw were 120, 135, 110 and 90 MPa during flexion, extension, lateral bending, and axial rotation, respectively. All the stress values were within the safe limit of the material. Using the flexible rod device, flexibility was significantly increased in flexion/extension but not in axial rotation and lateral bending. The results suggest that dynamic stabilization system with respect to fusion is more effective for homogenizing the range of motion of the spine.

Comparative analysis of ear-hole closure identifies epimorphic regeneration as a discrete trait in mammals.

Why mammals have poor regenerative ability has remained a long-standing question in biology. In regenerating vertebrates, injury can induce a process known as epimorphic regeneration to replace damaged structures. Using a 4-mm ear punch assay across multiple mammalian species, here we show that several Acomys spp. (spiny mice) and Oryctolagus cuniculus completely regenerate tissue, whereas other rodents including MRL/MpJ 'healer' mice heal similar injuries by scarring. We demonstrate ear-hole closure is independent of ear size, and closure rate can be modelled with a cubic function. Cellular and genetic analyses reveal that injury induces blastema formation in Acomys cahirinus. Despite cell cycle re-entry in Mus musculus and A. cahirinus, efficient cell cycle progression and proliferation only occurs in spiny mice. Together, our data unite blastema-mediated regeneration in spiny mice with regeneration in other vertebrates such as salamanders, newts and zebrafish, where all healthy adults regenerate in response to injury.