Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.

BACKGROUND: Mutations in PIEZO1 (Piezo type mechanosensitive ion channel component 1) cause human lymphatic malformations. We have previously uncovered an ORAI1 (ORAI calcium release-activated calcium modulator 1)-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion. METHODS: Various mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration. RESULTS: Piezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as KLF2 (Krüppel-like factor 2), DTX1 (Deltex E3 ubiquitin ligase 1), DTX3L (Deltex E3 ubiquitin ligase 3L,) and NOTCH1 (Notch receptor 1), which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting. Finally, we assessed a potential therapeutic value of Piezo1 activation in lymphatic regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed postsurgical lymphedema development. CONCLUSIONS: Piezo1 is an upstream mechanosensor for the lymphatic mechanotransduction pathway and regulates lymphatic growth in response to external physical stimuli. Piezo1 activation presents a novel therapeutic opportunity for preventing postsurgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.

Platelet-Rich Plasma Treatment for the Lumbar Spine: A Review and Discussion of Existing Gaps.

BACKGROUND: Platelet-rich plasma (PRP) is obtained by centrifuging autologous whole blood to extract a layer concentrated with platelets, growth factors found in platelet granules, and cytokines. These components work together to promote and facilitate the healing process at sites of injury. An increasing number of clinical studies are assessing the efficacy of PRP as a treatment for lower back pain. OBJECTIVES: Lumbar back pain is a significant cause of years lived with disability. This paper conducts a thorough review of clinical studies on intradiscal, facet-joint, epidural, and mixed-target PRP interventions in the lumbar spine. Furthermore, gaps in the current literature regarding lumbar spinal PRP injections are identified to help guide future clinical trials. STUDY DESIGN: Literature review. METHODS: An initial search was conducted using Ovid MEDLINE, focusing on PRP injections in the spine. Boolean operators were used to combine MeSH terms and key words such as "spine," "lumbar spine," "thoracic spine," "cervical spine," "intervertebral disc," "platelet-rich plasma," and "inject." The search revealed an absence of papers about PRP injections into the cervical and thoracic spine, so the review was written with a specific focus on the lumbar spine. For the purposes of this paper, the selected manuscripts were separated into categories of intradiscal, facet-joint, epidural, and mixed-target PRP injections. RESULTS: A multitude of case reports, case series, prospective clinical studies, and randomized controlled trials have yielded results supporting the use of intradiscal, facet-joint, and epidural PRP injections in the lumbar spine. However, a handful of papers suggest that PRP lacks efficacy in improving lumbar back pain and function. With the relative dearth of literature assessing the effects of spinal PRP injections, additional double-blinded randomized trials are needed. Important findings from available studies include the observation of PRP's increased efficacy over time, the correlation of the number of targeted injection sites with the efficacy of PRP injections, and the correlation of platelet count with PRP injections' efficacy. LIMITATIONS: There exists wide variability in PRP preparation protocols and in the methods of assessing PRP's therapeutic benefits between each study that evaluates PRP's effects in the lumbar spine. CONCLUSIONS: All clinical studies evaluating PRP as a form of treatment for the lumbar spine should include full transparency and details about the methods used for PRP preparation and injection. Future double-blinded randomized trials can fill in existing gaps by assessing the effects of platelet concentration and dose on the extent of clinical improvement as well as by establishing an expected timeline for clinical improvement after PRP injections. Cross-study standardization of which pain scoring systems to utilize for study evaluation would increase comparability among different papers.

Terminating Cancer by Blocking VISTA as a Novel Immunotherapy: Hasta la vista, baby.

VISTA is an up-and-coming immune checkpoint molecule that can become the target of new cancer immunotherapy treatments. Immune cells in the tumor microenvironment can largely influence the progression of cancer through inhibitory and stimulatory pathways. Indeed, VISTA is expressed on many immune cells, including T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and dendritic cells. VISTA has predominantly been shown to act in an immune-suppressing manner that enables cancer progression. This review will delve into results from preclinical murine studies of anti-VISTA monoclonal antibody treatments, bring together recent studies that detect VISTA expression on immune cells from patient tumors of various cancers, and discuss ongoing clinical trials involving VISTA.