Single-Cell Temporal Atlas of Myeloid Cells in the Live Haemorrhagic Brain
Kawamura, Y.; Johnson, C.; DeLong, J.; de Lima Camillo, L. P.; Takahashi, M.; Beatty, H. E.; Herbert, R.; Cord, B. J.; Matouk, C.; Askenase, M.; Sansing, L. H.
Show abstract
CNS-resident microglia and recruited myeloid cells populate the haematoma in intracerebral haemorrhage (ICH), but the contribution of these cell populations to injury and repair has been controversial. To better characterise myeloid cell changes over time, we employed single-cell RNA sequencing to generate a unique paired dataset of live haematoma and peripheral blood samples from 10 ICH patients. This work presents a temporal atlas of ICH myeloid populations and identifies population-specific in-situ transcriptional drivers. In addition to distinct populations of activated microglia and TNF-low microglia, we found a unique and highly activated population of CD14+ monocytes in the haematoma. Perturbation analysis comparing haematoma-associated monocytes to shared populations in blood and haematomas identified TNF signalling as the primary driver of their activation. Employing a custom temporal trajectory analysis based on the embeddings of a single-cell foundation model, we found that this TNF response in monocytes was transient, peaking early after haemorrhage and decreasing over the ensuing 48 hours. Our analysis further identified a transient population of highly activated microglia as the likely source of TNF during the acute stage of ICH. Acute TNF signalling in CD14+ monocytes associated with better adjusted outcomes both in our and external cohorts. Overall, our results suggest that acute TNF signalling between transient populations of activated microglia and unique haematoma-associated monocytes could potentially be beneficial in recovery after ICH. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/630187v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@10495d8org.highwire.dtl.DTLVardef@9be62org.highwire.dtl.DTLVardef@1b22148org.highwire.dtl.DTLVardef@1a73a56_HPS_FORMAT_FIGEXP M_FIG C_FIG One sentence summaryWe present a single-cell temporal atlas of myeloid cells in intracerebral haemorrhage and identify TNF signalling as a driver of haematoma dynamics.
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