Biology subjects

Momin, N.

Publications and source records attributed to Momin, N..

4 recordsLinked to original sources

bioRxiv2025

Bone marrow mesenchymal stromal cells mediate cellular inflammation in HFpEF

During the genesis of heart failure, the myocardium recruits an abundance of bone marrow-derived leukocytes, primarily monocytes, with various disease-promoting functions. Increased hematopoiesis fuels these unfavorable changes in cardiac leukocyte origin, number and phenotype. Here we examine hematopoietic niche cells, which regulate blood progenitor proliferation and systemic monocyte supply, in obese, hypertensive mice that develop heart failure with preserved ejection fraction (HFpEF). Single cell transcriptomics revealed that in HFpEF, stromal bone marrow niche cells expand and respond strongly to IFN{gamma}. Deleting the IFN{gamma} receptor in stromal cells of Prrx1CreERT2;Ifngr1fl/fl mice reduced hematopoietic progenitor proliferation and systemic monocytes in both the steady state and HFpEF and also increased the canonical hematopoietic maintenance factor CXCL12, resulting in reduced fibrosis and improved diastolic function. CD8+ T cells in adipose tissue were a major source of IFN{gamma} in mice with HFpEF; their depletion restored CXCL12 expression and lowered monocyte numbers. ScRNA-seq in mice with ischemic heart disease uncovered a diverging marrow response. These data indicate that in HFpEF, adipose tissue, bone marrow and adaptive and innate immune cells conspire to expand harmful macrophage subsets in the heart.

immunology↗

bioRxiv2024

Therapeutic Spp1 silencing in TREM2+ cardiac macrophages suppresses atrial fibrillation

Atrial fibrillation (AFib) and the risk of its lethal complications are propelled by fibrosis, which induces electrical heterogeneity and gives rise to reentry circuits. Atrial TREM2+ macrophages secrete osteopontin (encoded by Spp1), a matricellular signaling protein that engenders fibrosis and AFib. Here we show that silencing Spp1 in TREM2+ cardiac macrophages with an antibody-siRNA conjugate reduces atrial fibrosis and suppresses AFib in mice, thus offering a new immunotherapy for the most common arrhythmia.

immunology↗

bioRxiv2024

Tumor-localized interleukin-2 and interleukin-12 combine with radiation therapy to safely potentiate regression of advanced malignant melanoma in pet dogs

The clinical use of interleukin-2 and -12 cytokines against cancer is limited by their narrow therapeutic windows due to on-target, off-tumor activation of immune cells when delivered systemically. Engineering IL-2 and IL-12 to bind to extracellular matrix collagen allows these cytokines to be retained within tumors after intralesional injection, overcoming these clinical safety challenges. While this approach has potentiated responses in syngeneic mouse tumors without toxicity, the complex tumor-immune interactions in human cancers are difficult to recapitulate in mouse models of cancer. This has driven an increased role for comparative oncology clinical trials in companion (pet) dogs with spontaneous cancers that feature analogous tumor and immune biology to human cancers. Here, we report the results from a dose-escalation clinical trial of intratumoral collagen-binding IL-2 and IL-12 cytokines in pet dogs with malignant melanoma, observing encouraging local and regional responses to therapy that may suggest human clinical benefit with this approach.

cancer biology↗

bioRxiv2022

Reprogramming brain immunosurveillance with engineered cytokines

Immune surveillance of the brain is regulated by resident non-neuronal cells and the blood-brain barrier.1 Dys-regulation of immunosurveillance is a hallmark feature of several diseases2-5 including brain tumors6 that interact with and rely heavily on immune cells,7 suggesting that disrupting the neuroimmunology of tumors could slow their progression. Yet few tools are available to control brain immunology in vivo with local precision, and fewer yet are used for therapeutic intervention. 2 Here, we propose engineered cytokines as a neuroimmune-modulation platform. We demonstrate that the residence time of cytokines in the brain can be tuned by binding them to the extracellular matrix or synthetic scaffolds. We then show that the aluminum hydroxide adjuvant (alum) is retained in the brain >2 weeks. Tethering of inflammatory cytokines such as interleukins (IL) 2 and 12 to alum yields extended neuroinflammation and brain immunosurveillance after intracranial administration, while avoiding systemic toxicity. In mouse models of both immunologically hot and cold brain tumors, the intracranial deposition of alum-tethered cytokines causes significant delay in tumor progression. RNA profiling reveals that engineered cytokines engage both innate and adaptive immunity in the brain. These findings suggest that engineered cytokines can reprogram brain immunosurveillance, informing the development of future therapies for neuroimmune diseases.

bioengineering↗