Leukocyte dynamics after intracerebral hemorrhage in a living patient reveal rapid adaptations to tissue milieu

Abstract

Intracerebral hemorrhage (ICH) is a devastating form of stroke with a high mortality rate and few treatment options. Discovery of therapeutic interventions has been slow given the challenges associated with studying acute injury in the human brain. Inflammation induced by exposure of brain tissue to blood appears to be a major part of brain tissue injury. Here, we longitudinally profiled blood and cerebral hematoma effluent from a patient enrolled in the Minimally Invasive Surgery with Thrombolysis in Intracerebral Hemorrhage Evacuation trial, offering a rare window into the local and systemic immune responses to acute brain injury. Using single-cell RNA-Seq (scRNA-Seq), this is the first report to our knowledge that characterized the local cellular response during ICH in the brain of a living patient at single-cell resolution. Our analysis revealed shifts in the activation states of myeloid and T cells in the brain over time, suggesting that leukocyte responses are dynamically reshaped by the hematoma microenvironment. Interestingly, the patient had an asymptomatic rebleed that our transcriptional data indicated occurred prior to detection by CT scan. This case highlights the rapid immune dynamics in the brain after ICH and suggests that sensitive methods such as scRNA-Seq would enable greater understanding of complex intracerebral events.

T-Lymphocyte Interactions with the Neurovascular Unit: Implications in Intracerebral Hemorrhage

“…Flow cytometry revealed expression of TRAIL cognate receptor, DR5, was significantly upregulated on endothelial cells in the ICH brain; treatment with anti-DR5 monoclonal antibodies subsequently reduced endothelial cell death in experimental ICH [26]. Direct endothelial cell death caused by interaction with T cells is further supported in clinically derived data, wherein hematomal blood was sequenced and found enrichment of TNF-related apoptosis, which corresponds with the experimental findings [45].…”

“…Through per-gene analysis for association with volumetric parameters (ICH & PHE volumes) paired with weighted gene co-expression network construction (WGCNA), study authors report a positive correlation between ICH and PHE volumes with the transcriptome of peripheral T cells following ICH. T lymphocyte clustered WGCNA analysis detected 33 significant pathways positively associated with enlargement of relative PHE volumes; though most of these pathways were related to inflammatory processes, the calcium-induced T lymphocyte apoptosis pathway points to direct implications on endothelial and NVU impairment [44,45]. In our own work, single-cell sequencing of brain infiltrating T lymphocyte populations derived from an autologous blood injection mouse model, we observed an increase in apoptosis-related genes, Tnfsf10, Tnfrsf10b, and FasL at day 3 post-stroke [26].…”

Integrating endometrial proteomic and single cell transcriptomic pipelines reveals distinct menstrual cycle and endometriosis-associated molecular profiles

“…Seq-Well S 3 was performed as described previously. (Gierahn et al, 2017; Goods et al, 2021; Hughes et al, 2020) Briefly, at least 15,000 cells were loaded onto each array preloaded with barcoded mRNA capture beads (ChemGenes). Arrays were washed with protein-free RPMI media, then sealed with plasma-treated polycarbonate membranes.…”

Novel targets, treatments, and advanced models for intracerebral haemorrhage

“… 55 Whereas the numbers of circulating (CD4 + ) T- and natural killer (NK) cells are decreased, 55 there is a prominent invasion into the brain. 56 , 57 Immunosuppression after ICH has been investigated in rodent ICH models using cerebral injection of autologous blood 58 or collagenase, 59 revealing programmed death ligand 1 (PD-L1) and metoprolol as potential therapeutic options. However, haematoma location and size vary considerably in patients and may influence how the haematoma regulates immune responses after ICH.…”