Biology subjects

McCarty, J. H.

Publications and source records attributed to McCarty, J. H..

3 recordsLinked to original sources

bioRxiv2026

The Endothelial Cell-Expressed Prion Protein Prnd/Doppel Promotes Neovascularization and Long-term Recovery after Ischemic Stroke

Ischemic stroke remains a leading cause of mortality and long-term disability, yet therapeutic options for promoting recovery remain severely limited. Here, we investigate the role of Prnd/Doppel, a prion family member, in stroke pathophysiology and recovery. Using middle cerebral artery occlusion (MCAO) in mice genetically null for Prnd (KO), inducibly overexpressing Prnd in endothelial cells (ECs), or wild-type (WT) controls, we assessed outcomes through infarct volume measurements, behavioral analysis, and immunohistochemical evaluation of vascular integrity and inflammation. While acute infarct volumes at 24 hours were comparable between WT and KO mice, striking differences emerged during recovery: KO mice exhibited significantly impaired functional outcomes at both 14 and 30 days post-MCAO, accompanied by disorganized cerebrovascular architecture, increased brain atrophy, and elevated CD68-positive inflammatory infiltration by day 30. Conversely, endothelial-specific Prnd overexpression, though not affecting acute outcomes, markedly enhanced tight junction protein expression at day 7, promoted angiogenesis, and improved long-term neuronal survival in the ischemic territory. These findings establish Prnd as a critical mediator of post-stroke vascular remodeling and functional recovery, distinguishing it from acute neuroprotective mechanisms. Our results identify Prnd as a promising therapeutic target for enhancing organized neovascularization and promoting sustained functional recovery following ischemic stroke, with potential applications to other neurological disorders characterized by cerebrovascular dysfunction.

neuroscience↗

bioRxiv2024

In Situ Single-Cell Spatial Profiling of Matrisome Gene Expression in Glioblastoma

The human brain contains a rich milieu of extracellular matrix (ECM) components that are often dysregulated in pathologies including the malignant cancer glioblastoma (GBM). Here, we have used in situ single-cell spatial transcriptomic platforms to map the expression patterns of nearly 400 ECM genes in normal brain and GBM samples. Our analysis identifies at least four different GBM cell populations with unique ECM expression profiles that show spatial enrichment in distinct intratumor regions. Spatial mapping also demonstrates largely non-overlapping expression signatures of various ECM components in GBM stromal cell types, particularly in vascular endothelial cells and reactive microglia/macrophages. Comparisons of GBM (IDH1 wild type) versus lower-grade II and III astrocytoma samples (IDH1 R132H) identifies differential expression of key ECM components, including elevated levels of select ECM glycoproteins (IGFBP2 and MGP) and ECM-affiliated proteins (ANXA1 and ANXA2). In addition, we detect spatially enriched expression of COL8A1 (collagen), LUM (proteoglycan), and POSTN (ECM glycoprotein) in perivascular stromal cells in GBM but not in lower grade tumors. Computational analysis of putative ligand-receptor interactions reveals novel ECM communication networks between cancer cells and stromal components, particularly in regions of GBM microvascular proliferation and pseudopalisading necrosis. In summary, this comprehensive spatial map provides new insights into microenvironmental control of GBM initiation and progression and identifies potential therapeutic targets in the ECM.

cancer biology↗

bioRxiv2022

HepaCAM Suppresses Glioblastoma Stem Cell Invasion in the Brain

Glioblastoma (GBM) is a malignant brain cancer that contains sub-populations of highly invasive tumor cells that drive progression and recurrence after surgery and radiochemotherapy. The exact mechanisms that enable GBM cells to disperse from the main tumor mass and navigate throughout the brain microenvironment remain largely unknown. As a result, there is a lack of effective strategies to block cancer cell invasive growth in primary and recurrent GBM. Here we report that hepatocyte cell adhesion molecule (hepaCAM), which is normally expressed in perivascular astrocytes, plays central roles in controlling the invasive growth features of GBM cells. Genetically targeting HEPACAM induces a transition from GBM cell proliferation/self-renewal to invasion. Increased invasion is due, in part, to an activation of focal adhesion signaling pathways and enhanced GBM cell adhesion to the extracellular matrix (ECM) in the brain microenvironment. Transcriptional profiling of GBM cells reveals various HEPACAM-regulated genes with links to polarity and invasion. Collectively, these data show that hepaCAM balances ECM adhesion and signaling pathways to control cancer cell proliferation versus invasion in the brain parenchyma. Targeting select components of the hepaCAM pathway may be an effective way to block tumor progression and recurrence in patients with GBM.

cancer biology↗