Unraveling the complex pathophysiology of white matter hemorrhage in intracerebral stroke: A single-cell RNA sequencing approach

Abstract

Aim: This study aims to elucidate the cellular dynamics and pathophysiology of white matter hemorrhage (WMH) in intracerebral hemorrhage (ICH).

Methods: Using varying doses of collagenase IV, a consistent rat ICH model characterized by pronounced WMH was established. Verification was achieved through behavioral assays, hematoma volume, and histological evaluations. Single-cell suspensions from the hemorrhaged region of the ipsilateral striatum on day three post-ICH were profiled using single-cell RNA sequencing (scRNA-seq). Gene Ontology (GO) and gene set variation analysis (GSVA) further interpreted the differentially expressed genes (DEGs).

Results: Following WMH induction, there was a notable increase in the percentage of myeloid cells and oligodendrocyte precursor cells (OPCs), alongside a reduction in the percentage of neurons, microglia, and oligodendrocytes (OLGs). Post-ICH WMH showed homeostatic microglia transitioning into pro-, anti-inflammatory, and proliferative states, influencing lipid metabolic pathways. Myeloid cells amplified chemokine expression, linked with ferroptosis pathways. Macrophages exhibited M1 and M2 phenotypes, and post-WMH, macrophages displayed a predominance of M2 phenotypes, characterized by their anti-inflammatory properties. A surge in OPC proliferation aligned with enhanced ribosomal signaling, suggesting potential reparative responses post-WMH.

Conclusion: The study offers valuable insights into WMH's complex pathophysiology following ICH, highlighting the significance and utility of scRNA-seq in understanding the cellular dynamics and contributing to future cerebrovascular research.

Keywords: collagenase IV; heterogeneity; intracerebral hemorrhage; single-cell RNA sequencing; white matter hemorrhage; white matter injury.