While past studies have suggested that plasticity exists between dermal fibroblasts and adipocytes, it remains unknown whether fat actively contributes to fibrosis in scarring. We show that adipocytes convert to scar-forming fibroblasts in response to Piezo-mediated mechanosensing to drive wound fibrosis. We establish that mechanics alone are sufficient to drive adipocyte-to-fibroblast conversion. By leveraging clonal-lineage-tracing in combination with scRNA-seq, Visium, and CODEX, we define a mechanically naive fibroblast-subpopulation that represents a transcriptionally intermediate state between adipocytes and scar-fibroblasts. Finally, we show that Piezo1 or Piezo2-inhibition yields regenerative healing by preventing adipocytes activation to fibroblasts, in both mouse-wounds and a novel human-xenograft-wound model. Importantly, Piezo1-inhibition induced wound regeneration even in pre-existing established scars, a finding that suggests a role for adipocyte-to-fibroblast transition in wound remodeling, the least-understood phase of wound healing. Adipocyte-to-fibroblast transition may thus represent a therapeutic target for minimizing fibrosis via Piezo-inhibition in organs where fat contributes to fibrosis.
There is undisputable benefit in translating basic science research concretely into clinical practice, and yet, the vast majority of therapies and treatments fail to achieve approval. The rift between basic research and approved treatment continues to grow, and in cases where a drug is granted approval, the average time from initiation of human trials to regulatory marketing authorization spans almost a decade. Albeit with these hurdles, recent research with deferoxamine (DFO) bodes significant promise as a potential treatment for chronic, radiation-induced soft tissue injury. DFO was originally approved by the Food and Drug Administration (FDA) in 1968 for the treatment of iron overload. However, investigators more recently have posited that its angiogenic and antioxidant properties could be beneficial in treating the hypovascular and reactive-oxygen species-rich tissues seen in chronic wounds and radiation-induced fibrosis (RIF). Small animal experiments of various chronic wound and RIF models confirmed that treatment with DFO improved blood flow and collagen ultrastructure. With a well-established safety profile, and now a strong foundation of basic scientific research that supports its potential use in chronic wounds and RIF, we believe that the next steps required for DFO to achieve FDA marketing approval will include large animal studies and, if those prove successful, human clinical trials. Though these milestones remain, the extensive research thus far leaves hope for DFO to bridge the gap between bench and wound clinic in the near future.
Background: Migraine surgery at 1 of 6 identified “trigger sites” of a target cranial sensory nerve has rapidly grown in popularity since 2000. This study summarizes the effect of migraine surgery on headache severity, headache frequency, and the migraine headache index score which is derived by multiplying migraine severity, frequency, and duration. Materials and Methods: This is a PRISMA-compliant systematic review of 5 databases searched from inception through May 2020 and is registered under the PROSPERO ID: CRD42020197085. Clinical trials treating headaches with surgery were included. Risk of bias was assessed in randomized controlled trials. Meta-analyses were performed on outcomes using a random effects model to determine the pooled mean change from baseline and when possible, to compare treatment to control. Results: 18 studies met criteria including 6 randomized controlled trials, 1 controlled clinical trial, and 11 uncontrolled clinical trials treated 1143 patients with pathologies including migraine, occipital migraine, frontal migraine, occipital nerve triggered headache, frontal headache, occipital neuralgia, and cervicogenic headache. Migraine surgery reduced headache frequency at 1 year postoperative by 13.0 days per month as compared to baseline ( I2 = 0%), reduced headache severity at 8 weeks to 5 years postoperative by 4.16 points on a 0 to 10 scale as compared to baseline ( I2 = 53%), and reduced migraine headache index at 1 to 5 years postoperative by 83.1 points as compared to baseline ( I2 = 2%). These meta-analyses are limited by a small number of studies that could be analyzed, including studies with high risk of bias. Conclusion: Migraine surgery provided a clinically and statistically significant reduction in headache frequency, severity, and migraine headache index scores. Additional studies, including randomized controlled trials with low risk-of-bias should be performed to improve the precision of the outcome improvements.
Wound healing results in the formation of scar tissue which can be associated with functional impairment, psychological stress, and significant socioeconomic cost which exceeds 20 billion dollars annually in the United States alone. Pathologic scarring is often associated with exaggerated action of fibroblasts and subsequent excessive accumulation of extracellular matrix proteins which results in fibrotic thickening of the dermis. In skin wounds, fibroblasts transition to myofibroblasts which contract the wound and contribute to remodeling of the extracellular matrix. Mechanical stress on wounds has long been clinically observed to result in increased pathologic scar formation, and studies over the past decade have begun to uncover the cellular mechanisms that underly this phenomenon. In this article, we will review the investigations which have identified proteins involved in mechano-sensing, such as focal adhesion kinase, as well as other important pathway components that relay the transcriptional effects of mechanical forces, such as RhoA/ROCK, the hippo pathway, YAP/TAZ, and Piezo1. Additionally, we will discuss findings in animal models which show the inhibition of these pathways to promote wound healing, reduce contracture, mitigate scar formation, and restore normal extracellular matrix architecture. Recent advances in single cell RNA sequencing and spatial transcriptomics and the resulting ability to further characterize mechanoresponsive fibroblast subpopulations and the genes that define them will be summarized. Given the importance of mechanical signaling in scar formation, several clinical treatments focused on reducing tension on the wound have been developed and are described here. Finally, we will look toward future research which may reveal novel cellular pathways and deepen our understanding of the pathogenesis of pathologic scarring. The past decade of scientific inquiry has drawn many lines connecting these cellular mechanisms that may lead to a map for the development of transitional treatments for patients on the path to scarless healing.
Background: Individuals with an extremity amputation are predisposed to persistent pain that reduces their quality of life. Residual limb pain is defined as pain that is felt in the limb after amputation. Methods: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review of 5 databases from inception to June 2020 was performed and is registered under the PROSPERO ID: CRD42020199297. Included studies were clinical trials with residual limb pain assessed at a minimum follow-up of 1 week. Meta-analyses of residual limb pain prevalence and severity were performed with subgroups of extremity and amputation etiology. Results: Twenty clinical trials met criteria and reported on a total of 1347 patients. Mean patient ages ranged from 38 to 77. Residual limb pain prevalence at 1 week, 1 month, 3 months, 6 months, 1 year, and 2 years, respectively, was 50%, 11%, 23%, 27%, 22%, and 24%. Mean residual limb pain severity at the 6 months or longer follow-up was 4.19 out of 10 for cancer amputations, 2.70 for traumatic amputations, 0.47 for vasculopathy amputations, 1.01 for lower extremity amputations, and 3.56 for upper extremity amputations. Conclusions: Residual limb pain severity varies according to the etiology of amputation and is more common after upper extremity amputation than lower extremity amputations. The most severe pain is reported by patients undergoing amputations due to cancer, followed by traumatic amputations, while vascular amputation patients report lower pain severity. Promising methods of reducing long-term pain are preoperative pain control, nerve or epidural blocks, use of memantine, calcitonin-containing blocks, and prophylactic nerve coaptations.
Agrin-NP/NHC treatment in vivo promotes neuromuscular junction reinnervation and improves functional recovery of forelimb grip strength. Our group has previously established the benefits of insulin-like growth factor 1 (IGF-1) nanoparticles on ameliorating the effects of chronic denervation. Future studies will combine Agrin-NPs and IGF-1-NPs and evaluate their hypothesized synergistic benefits.
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