Biology subjects

Mesfin, J. M.

Publications and source records attributed to Mesfin, J. M..

5 recordsLinked to original sources

bioRxiv2025

Infusible Extracellular Matrix Biomaterial Enhances Cell-Specific Pro-Repair Responses Following Acute Myocardial Infarction

To mitigate the pathological effects of myocardial infarction, we developed and investigated pro-reparative decellularized extracellular matrix (ECM) biomaterials: an intravascularly infusible ECM (iECM). However, the cellular and molecular mechanisms by which iECM mediates repair are unknown because investigations have relied on bulk techniques. Here, we leverage single nucleus RNA sequencing (snRNAseq) to measure pro-repair in various cell types across acute timepoints (1, 3 and 7 days post infusion). In iECM, we found pro-reparative macrophage activation, fibroblast remodeling, increased vasculaure development, lymphangiogenesis, cardioprotection, and neurogenesis. These findings were validated through spatial transcriptomics. Thus, we define the pro-reparative nature of decellularized ECM biomaterials on cardiac cell types and elucidate previously undiscovered therapeutic pathways, further demonstrating the potential of iECM as an MI therapy as well as display the wealth of data generated from next-generation sequencing.

bioengineering↗

bioRxiv2025

Uncovering the Regional and Cell Specific Bioactivity of Injectable Extracellular Matrix Biomaterials in Myocardial Infarction through Spatial and Single Nucleus Transcriptomics

Myocardial infarction (MI) remains a global health concern. To mitigate MI pathophysiology, we previously investigated a pro-reparative decellularized extracellular matrix (ECM) hydrogel for treating subacute and chronic MI. Despite increasing interest in biomaterial scaffolds, single cell and spatially resolved transcriptomics have not been used to probe their therapeutic activity in the heart. Here, we utilize spatial transcriptomics and single nucleus RNA sequencing to delineate the regional and cell-specific bioactivity of ECM biomaterials. ECM hydrogel subacute treatment induced cardiac resident macrophage preservation, fibroblast activation, and increased lymphatic, vasculature, smooth muscle and cardiomyocyte development as well as neurogenesis. Chronic treatment elicited macrophage polarization, cardiomyocyte and vasculature development, alongside fibroblast development. When comparing treatment timepoints, subacute administration had stronger immune modulation, while the chronic timepoint demonstrated higher cardiac development markers. Both subacute and chronic administration were associated with fibroblast activation and vasculature development. Thus, we elucidate undiscovered therapeutic targets of the ECM hydrogel, further demonstrating the potential of ECM biomaterials as an MI therapy.

bioengineering↗

bioRxiv2024

An Infusible Extracellular Matrix Biomaterial Improves Survival in a Model of Severe Systemic Inflammation

Excess systemic inflammation can often be lethal in septic and trauma patients due to onset of multiple organ dysfunction syndrome (MODS). As of right now, there are no effective immunomodulatory therapeutics that can promote survival within this patient population. Pro-regenerative extracellular matrix (ECM) biomaterials have shown success for treatment of local inflammation but have not been fully explored for treating systemic inflammation. Here, we demonstrate efficacy of an intravenously delivered infusible ECM (iECM) material, which promotes increased survival in a murine model of MODS by decreasing systemic mediators of inflammation. Lung and kidney failure are associated with higher mortality in MODS compared to other organ failures, and we demonstrate that iECM localizes primarily to kidney and lung tissues during systemic inflammation induced by endotoxin. iECM successfully lowered vascular permeability within lung tissue and lowered levels of inflammatory cytokine signaling such as IL-6, verified via ELISA and gene expression analyses. We also demonstrated that immune cell infiltration into lung tissue was modulated with iECM treatment, with an increase in neutrophil retention in the lung and decreases in pro-inflammatory macrophage presence. In summation, iECM improves survival from severe systemic inflammation by decreasing the local and systemic inflammatory signaling pathways that contribute to MODS. These results provide a strong rationale for translational studies of iECM treatment in systemic inflammatory syndromes, including sepsis and trauma.

bioengineering↗

bioRxiv2022

MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas

Combining multiple therapeutic strategies in NRAS/BRAF mutant melanoma - namely MEK/BRAF kinase inhibitors, immune checkpoint inhibitors, and targeted immunotherapies - may offer an improved survival benefit by overcoming limitations associated with any individual therapy. Still, optimal combination, order, and timing of administration remains under investigation. Here, we measure how MEK inhibition (MEKi) alters anti-tumor immunity by utilizing quantitative immunopeptidomics to profile changes in the peptide MHC (pMHC) repertoire. These data reveal a collection of tumor antigens whose presentation levels are selectively augmented following therapy, including several epitopes present at over 1000 copies-per-cell. We leveraged the tunable abundance of MEKi-modulated antigens by targeting 4 epitopes with pMHC-specific T cell engagers and antibody drug conjugates, enhancing cell killing in tumor cells following MEK inhibition. These results highlight drug treatment as a means to enhance immunotherapy efficacy by targeting specific upregulated pMHCs and provide a methodological framework for identifying, quantifying, and therapeutically targeting additional epitopes of interest. SIGNIFICANCEKinase inhibitor treatment in NRAS/BRAF mutant melanoma can sensitize tumors to immunotherapy, in part through an increase in average surface presentation of peptide MHC molecules. Here, we demonstrate that MEK inhibition selectively boosts epitope abundance of select tumor-associated antigens in vitro and in vivo, enhancing targeted immunotherapy efficacy against these treatment-modulated epitopes.

cancer biology↗

bioRxiv2020

Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition

Peptides bound to class I major histocompatibility complexes (MHC) play a critical role in immune cell recognition and can trigger an antitumor immune response in cancer. Surface MHC levels can be modulated by anticancer agents, altering immunity. However, understanding the peptide repertoires response to treatment remains challenging and is limited by quantitative mass spectrometry-based strategies lacking robust normalization controls. We describe a novel approach that leverages recombinant heavy isotope-coded peptide MHCs (hipMHCs) and multiplex isotope tagging to quantify peptide repertoire alterations using low sample input. HipMHCs improve quantitative accuracy of peptide repertoire changes by normalizing for variation across analyses and enable absolute quantification using internal calibrants to determine copies per cell of MHC antigens, which can inform immunotherapy design. Applying this platform in melanoma to profile the immunopeptidome response to CDK4/6 inhibition and interferon gamma, known modulators of antigen presentation, we uncovered treatment-specific alterations, connecting the intracellular response to extracellular immune presentation.

immunology↗