Biology subjects

Baish, J. W.

Publications and source records attributed to Baish, J. W..

5 recordsLinked to original sources

bioRxiv2025

Selective Activation of NaV1.3 Restores Lymphatic Contractility in Age and Injury

BackgroundIntrinsic lymphatic contractility is essential for tissue fluid balance, immunity and organ function, yet no FDA-approved pharmacologic treatments specifically restore lymphatic contractility. Lymph is returned to the circulation by ion channel-driven cyclic contractions of collecting lymphatic vessels. Although voltage-gated sodium (NaV) channels drive cardiomyocyte excitability, their role in lymphatic muscle cell (LMC) physiology is not well defined. We identified NaV1.3, a NaV channel historically viewed as developmentally restricted and limited in adult tissues, as unexpectedly and selectively expressed in adult lymphatic muscle but absent from heart, vascular smooth muscle, and mature brain. We tested whether selective NaV1.3 activation restores impaired lymphatic pumping in aging and radiation injury. MethodsNaV1.3 expression in LMCs was confirmed through single-cell RNA sequencing analysis and immunostaining of mouse and human lymphatic vessels. Lymphatic contractility was quantified by in vivo fluorescence lymphangiography and interstitial fluid clearance was measured with a new bioluminescence assay. NaV1.3 function was assessed in young, aged, and radiation-injured mice. NaV1.3 knockout (Scn3a-/-) mice established the requirement of NaV1.3 for basal lymphatic excitability and responsiveness to the NaV1.3-specific activator, Tf2. ResultsIn mouse and human lymphatic vessels, NaV1.3 is expressed in adult LMCs. Although dispensable for basal lymphatic contractions, NaV1.3 acted as a pharmacologically recruitable reserve that amplified contractile output. Acute NaV1.3 activation with Tf2 increased lymphangion ejection fraction and accelerated interstitial fluid clearance. Tf2 fully restored lymphatic pumping in aged mice and partially rescued radiation-induced contractile deficits. All Tf2 responses were abolished in Scn3a-/- mice, confirming NaV1.3 dependence. ConclusionsNaV1.3 is a selectively druggable ion channel in adult lymphatic muscle that can be recruited to restore lymphatic pump function across aging and injury. Targeted NaV1.3 activation provides a molecular entry point for treating diseases characterized by lymphatic pump failure, a domain with no existing pharmacologic therapies.

physiology↗

bioRxiv2025

Efficient calculation of fluid transport in porous media with moving boundaries

A novel hybrid model combining the lattice Boltzmann (LB) and finite difference (FD) methods is proposed to simulate transport in through a junction of actively contracting lymphatic vessels, while also handling flow of interstitial liquid in the surrounding porous tissue. Details of the dynamically flexing walls and valves in the lymphatic vessel and its near vicinity are modeled using a high-resolution LB method, whereas overall efficiency was significantly improved by using low-resolution FD in the larger tissue domain distant from the vessel. Pressure and velocity conditions at the interface between subdomains of the two numerical methods are matched by imposing a partial bounce-back ratio in LB corresponding to the permeability coefficient{kappa} in Darcys law for flow through porous media. Parameters governing the match between the algorithms at their interface can be estimated from the Kozeny-Carman relationship for porous media and further refined with a simpler, parallel flow geometry that also serves to validate the method. Test calculations show that the hybrid method is roughly four times faster than the LB method and permits computation over significantly larger domains. This method should be applicable to a large range of problems involving fluid flow in porous media with embedded conduits that have non-stationary boundaries. Author summaryIt is generally acknowledged that the finite difference method (FDM) is faster and requires less memory than the lattice Boltzmann method (LBM) for comparable domain sizes. However, LBM performs better for simulating fluid flow near complex, deformable, or moving boundaries. For this reason, it can be beneficial to create hybrid models that combine FDM and LBM. In this work, we use such a hybrid model to simulate a contracting lymphatic bifurcation in fluid. Our goal is to demonstrate the models robustness and high efficiency.

bioengineering↗

bioRxiv2025

Overcoming impaired antigen presentation in tumor draining lymph nodes facilitates immunotherapy

Immunotherapies have revolutionized cancer care in recent decades, but approved therapies often fail and currently only target specific steps in the generation of anti-cancer immune responses. Notably, the majority of approved immunotherapies do not target antigen processing and presentation, which are key steps in the development of immune responses and harbor potential as targets to improve immunotherapy. Here, we demonstrate that breast tumors induce locoregional lymph node impairment in antigen presentation--but not in antigen processing--which limits anti-cancer antigen- specific T cell responses. Inhibition of the locoregional T cell response was due to a tumor-mediated reduction of the cytokine IL1{beta} in tumor draining lymph nodes, which impaired antigen presentation. Further, we tested the ability of dendritic cells in lymph nodes at various distances from the primary tumor to be activated utilizing an antigen- agnostic adjuvant delivery strategy. We observed improved anti-tumor T cell responses when the adjuvant was delivered to cancer antigen-positive lymph nodes distant from the tumor, suggesting these lymph nodes can be targeted to improve anti-cancer immune responses. When combined with immune checkpoint blockade, delivery of the adjuvant to distant lymph nodes led to long-term survival and protection from recurrence. Antigen presentation and T cell responses could also be recovered by exogenous delivery of IL1{beta} via intratumoral injection, with improved survival when combined with immune checkpoint blockade. Our study demonstrates that tumor- induced locoregional impairment of antigen presentation can be overcome by the appropriate introduction of immunological adjuvant to tumor-distant lymph nodes or by restoring IL1{beta} to the tumor-draining lymph node. These strategies can induce high- quality, durable immune responses and have clinical implications for expanding the efficacy of immunotherapies. SummaryBreast tumors induce locoregional lymph node impairments in antigen presentation, which can be remedied via either IL1{beta} delivery or antigen-agnostic adjuvant therapies to distant lymph nodes, facilitating better immunotherapy responses.

cancer biology↗

bioRxiv2023

Lymphatic muscle cells are unique cells that undergo aging induced changes

Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing. We have generated a comprehensive transcriptional single-cell atlas--including LMCs--of collecting lymphatic vessels in mouse dermis at various ages. We identified genes that distinguish LMCs from other types of muscle cells, characterized the phenotypical and transcriptomic changes in LMCs in aged vessels, and uncovered a pro-inflammatory microenvironment that suppresses the contractile apparatus in advanced-aged LMCs. Our findings provide a valuable resource to accelerate future research for the identification of potential drug targets on LMCs to preserve lymphatic vessel function as well as supporting studies to identify genetic causes of primary lymphedema currently with unknown molecular explanation.

cell biology↗

bioRxiv2023

Cancer immunotherapy responses persist after lymph node resection

Lymphatic transport facilitates the presentation of cancer antigens in tumor-draining lymph nodes (tdLNs), leading to T cell activation and the generation of systemic anti-cancer immune surveillance. Surgical removal of tdLNs to control cancer progression is routine in clinical practice. However, whether removing tdLNs impairs immune checkpoint blockade (ICB) is still controversial. Our analysis demonstrates that melanoma patients remain responsive to PD-1 checkpoint blockade after regional LN dissection. We were able to recapitulate the persistent response to ICB after regional LN resection in murine melanoma and mammary carcinoma models. Mechanistically, soluble antigen is diverted to distant LNs after tdLN dissection. Consistently, robust ICB responses in patients with head and neck cancer after primary tumor and tdLN resection correlated with the presence of reactive LNs in distant sites. These findings indicate that distant LNs sufficiently compensate for the removal of direct tdLNs and sustain the response to ICB.

cancer biology↗