Brain Peri-Hematomal Area, a Strategic Interface for Blood Clearance: A Human Neuropathological and Transcriptomic Study

Background: Enhancing the blood clearance process is a promising therapeutic strategy for intracerebral hemorrhage (ICH). We aimed to investigate the kinetic of this process after ICH in human brain tissue through the monocyte-macrophage scavenger receptor (CD163)/HO-1 (hemoxygenase-1) pathway. Methods: We led a cross-sectional post-mortem study including 22 consecutive ICH cases (2005-2019) from the Lille Neurobank. Cases were grouped according to the time of death: <= 72 hours, 4 to 7 days, 8 to 15 days, 16 to 90 days, and >90 days after ICH onset. Paraffin-embedded tissue was extracted from 4 strategic areas, including hematoma core and peri-hematomal area to perform histological investigations. Additionally, we extracted RNA from the peri-hematomal area of 6 cases to perform transcriptomic analysis. Results: We included 19 ICH cases (median age: 79 [71-89] years; median delay ICH-death: 13 [5-41] days). The peri-hematomal area concentrated most of reactive microglia, CD163/HO-1 and iron deposits as compared with other brain areas. We found a surge in the blood clearance process from day 8 to day 15 after ICH onset. Transcriptomic analysis showed that HO-1 was the most upregulated gene (2.81 +/- 0.39, adjusted P=1.11x10(-10)) and CD163 the sixth (1.49 +/- 0.29, adjusted P=1.68x10(-)(5)). We also identified several upregulated genes that exert a beneficial role in terminating inflammation and enhancing tissue repair. Conclusions: We provide histological and transcriptomic-based evidence in humans for the key role of peri-hematomal area in endogenous blood clearance process through the CD163/HO-1 pathway, especially from day 8 after ICH and favored by an anti-inflammatory environment. Our findings contribute to identify innovative therapeutic strategies for ICH.