The Multifaceted Functions of TRPV4 and Calcium Oscillations in Tissue Repair.

The transient receptor potential vanilloid 4 (TRPV4) specifically functions as a mechanosensitive ion channel and is responsible for conveying changes in physical stimuli such as mechanical stress, osmotic pressure, and temperature. TRPV4 enables the entry of cation ions, particularly calcium ions, into the cell. Activation of TRPV4 channels initiates calcium oscillations, which trigger intracellular signaling pathways involved in a plethora of cellular processes, including tissue repair. Widely expressed throughout the body, TRPV4 can be activated by a wide array of physicochemical stimuli, thus contributing to sensory and physiological functions in multiple organs. This review focuses on how TRPV4 senses environmental cues and thereby initiates and maintains calcium oscillations, critical for responses to organ injury, tissue repair, and fibrosis. We provide a summary of TRPV4-induced calcium oscillations in distinct organ systems, along with the upstream and downstream signaling pathways involved. In addition, we delineate current animal and disease models supporting TRPV4 research and shed light on potential therapeutic targets for modulating TRPV4-induced calcium oscillation to promote tissue repair while reducing tissue fibrosis.

Fibroblasts - the cellular choreographers of wound healing.

Injuries to our skin trigger a cascade of spatially- and temporally-synchronized healing processes. During such endogenous wound repair, the role of fibroblasts is multifaceted, ranging from the activation and recruitment of innate immune cells through the synthesis and deposition of scar tissue to the conveyor belt-like transport of fascial connective tissue into wounds. A comprehensive understanding of fibroblast diversity and versatility in the healing machinery may help to decipher wound pathologies whilst laying the foundation for novel treatment modalities. In this review, we portray the diversity of fibroblasts and delineate their unique wound healing functions. In addition, we discuss future directions through a clinical-translational lens.

Diversity of Fibroblasts and Their Roles in Wound Healing.

Wound healing disorders are a societal, clinical, and healthcare burden and understanding and treating them is a major challenge. A particularly important cell type in the wound healing processes is the fibroblast. Fibroblasts are not homogenous; however, there are diverse functional fibroblast subtypes coming from different embryonic origins and residing in dispersed anatomic locations including distinct classes of fibroblasts at various skin depths. In this review, we discuss the implications of fibroblast heterogeneity, with a focus on the fundamental physiological functions of the fibroblast subtypes that govern wound repair and clinical degrees of healing. A better understanding of these diverse functional fibroblast populations will likely lead to novel therapies to enhance wound healing and inhibit excessive scarring.

A Novel Missense Variant of HOXD13 Caused Atypical Synpolydactyly by Impairing the Downstream Gene Expression and Literature Review for Genotype-Phenotype Correlations.

Synpolydactyly (SPD) is a hereditary congenital limb malformation with distinct syndactyly designated as SPD1, SPD2, and SPD3. SPD1 is caused by mutations of HOXD13, which is a homeobox transcription factor crucial for limb development. More than 143 SPD patients have been reported to carry HOXD13 mutations, but there is a lack of genotype-phenotype correlation. We report a novel missense mutation of c. 925A > T (p.I309F) in an individual with atypical synpolydactyly inherited from her father with mild clinodactyly and three other different alanine insertion mutations in HOXD13 identified by whole exome sequencing (WES) in 12 Chinese SPD families. Unlike polyalanine extension, which tends to form α-helix and causes protein aggregation in the cytoplasm as shown by molecular simulation and immunofluorescence, the c. 925A > T mutation impairs downstream transcription of EPHA7. We compiled literature findings and analyzed genotype-phenotype features in 173 SPD individuals of 53 families, including 12 newly identified families. Among the HOXD13-related individuals, mutations were distributed in three regions: polyalanine, homeobox, and non-homeobox. Polyalanine extension was the most common variant (45%), followed by missense mutations (32%) mostly in the homeobox compared with the loss-of-function (LOF) variants more likely in non-homeobox. Furthermore, a more severe degree and classic SPD were associated with polyalanine mutations although missense variants were associated with brachydactyly and syndactyly in hands and feet and LOF variants with clinodactyly in hands. Our study broadens the HOXD13 mutation spectrum and reveals the profile of three different variants and their severity of SPD, the genotype-phenotype correlation related to the HOXD13 mutation site provides clinical insight, including for genetic counseling.

A volar approach to on-top plasty for correction of radial polydactyly: a case series of 21 patients.

Correction of unequal radial polydactyly in which neither thumb duplicates possess both well-developed proximal and distal components, remains challenging. Current techniques using on-top plasty techniques require circumferential incisions, often resulting in postoperative swelling and dorsal scars. We described our experience using a volar approach to achieve better aesthetic and functional results. Twenty-one patients underwent this surgery between 2008 and 2018, with a mean follow-up of 5.1 years. The mean flexion-extension arc for the metacarpophalangeal joint was 75° and that of the interphalangeal joint was 43°. Mean percentage of key, tripod and tip pinch strength were 77%, 79% and 77%, respectively, when compared with the contralateral side. The Vancouver Scar Scale showed an average score of 1.2. We conclude from our study that the volar approach to on-top plasty is a good technique for the correction of unequal radial polydactyly, with good functional and aesthetic results.Level of evidence: IV.

Functional and aesthetic reconstruction of digital flexion contractures with full-thickness plantar skin grafts in children.

Hand burns are frequently seen in children, often resulting in digital flexion contractures. Traditional split-thickness or full-thickness skin grafts leave notably different skin texture and hyperpigmentation. The purpose of this study was to describe our operation for treating digital flexion contractures with full-thickness plantar skin grafts, and to evaluate the appearance and function outcomes. Hematoxylin and eosin staining, Masson trichrome staining and Melan A (marker of melanocyte) staining were used to evaluate palmar skin, plantar skin, groin skin and burn scars. Full-thickness plantar skin grafts were performed between 2008 and 2015 in 24 hand burn patients with digital flexion contracture. The average age at the time of surgery was 39.3 months and the average follow-up period was 5.5 years. The functional and cosmetic results were assessed. Plantar skin shared similar attributes with palmar skin histologically. Both plantar skin and palmar skin did not express melan A. All of the skin grafts survived well without hematoma, infection and necrosis. The grafts resembled the adjacent normal skin in regards to appearance and texture. The average TAM (total active movement) degree for the fingers was improved from 152.3° to 238.5°. The average VSS (Vancouver Scar Scale) score decreased dramatically from 10.4 to 1.1. Twenty one of twenty four patients (21/24, 87.5%) were very satisfied with function and appearance, and three in twenty four (3/24, 12.5%) were somewhat satisfied. This study indicates that full-thickness plantar skin grafts can achieve a satisfactory appearance and good function for hand burn child patients with digital flexion contractures.

A Novel Frameshift Mutation of GLI3 Causes Isolated Postaxial Polydactyly.

BACKGROUND: GLI3 encodes a transcription factor in the sonic hedgehog signaling pathway, which is essential in regulating the human limb bud development, especially on the anteroposterior axis. Mutations in GLI3 have been confirmed to be associated with various human congenital malformations, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, and isolated polydactyly. A robust gene-phenotype relationship between GLI3 and Greig cephalopolysyndactyly syndrome and Pallister-Hall syndrome has been well elucidated, and less is known about GLI3 mutation-caused isolated polydactyly. This study intended to perform a mutation analysis of GLl3 in a family with isolated polydactyly. METHODS: A 3-generation Chinese family with 19 members was recruited in this study, of which the proband and her mother were affected with polydactyly. The whole-exon sequencing was performed to find mutations, and Sanger sequencing was performed to validate the mutations. RESULTS: We found a novel heterozygous frameshift mutation of GLI3 (c.1180C > TT, p.P394fs18x) in the proband of a Chinese family with isolated postaxial polydactyly. No mutation was detected in the proband's father or another 2 patients with sporadic preaxial polydactyly. CONCLUSIONS: By systematically reviewing the gene-phenotype relationship, we found that GLI3 p.P394fs18x mutation might be specific for isolated postaxial polydactyly.

Morphological and neurophysiological impairment of the nerve in type II macrodactyly.

BACKGROUND: Macrodactyly is a congenital malformation characterized by aggressive overgrowth of multiple tissues, including subcutaneous fat, nerves, and bones in digits or limbs. In type II macrodactyly, the peripheral nerve is enlarged; however, the morphological and functional characteristics of the affected peripheral nerves have rarely been evaluated. METHODS: In this research, six macrodactyly patients and three polydactyly patients (control) were studied. Pre-operative sensory nerve action potential and intra-operative nerve action potential tests were performed. The microstructure and ultrastructure of the enlarged nerves were observed and neurofilament (NF) expression was evaluated using immunofluorescent staining. RESULTS: Axon impairment of the digital nerves originating from the median nerve (MN) was observed. A compensatory reinnervation from the ulnar nerve (UN) was found in two of the six patients, and significant morphological changes were observed in the enlarged nerve. The myelinated nerve fibers decreased, the lamellar structure of the myelin sheath changed, and the density of the NFs of the unmyelinated fibers decreased. There was aberrant distribution of NFs in the macrodactylous nerve tissues. In patients with compensatory UN reinnervation, the number of myelinated and unmyelinated fibers increased to normal levels; however, the diameter of the myelinated fibers apparently decreased. CONCLUSIONS: The morphology and function of the macrodactylous enlarged nerve was impaired in type II macrodactyly patients; however, the unaffected UN partially compensated for the lost function of the affected MN under specific situations. Electrophysiological tests should be performed to determine the function of the affected nerve and surgical treatment for type II macrodactyly could be refined.