Zebrafish exhibit a robust ability to regenerate their hearts following injury, and the immunesystem plays a key role in this process. We previously showed that delaying macrophage recruitmentby clodronate liposome (CL) treatment compromises neutrophil resolution and heart regeneration,even when the infiltrating macrophage number was restored within the first-week post injury (Lai etal., 2017). Here, we examined the molecular mechanisms underlying the cardiac repair of regenerativePBS-control hearts vs. non-regenerative CL-treated hearts. Bulk transcriptomic analyses revealed thatCL-treated hearts exhibited disrupted inflammatory resolution and energy metabolism during cardiacrepair. Temporal single-cell profiling of inflammatory cells in regenerative vs. non-regenerativeconditions further identified heterogenous macrophages and neutrophils with distinct infiltrationdynamics, gene expression, and cellular crosstalk. Among them, two residential macrophagesubpopulations were enriched in regenerative hearts and barely recovered in non-regenerative hearts.Early CL treatment at 8 days or even 1 month before cryoinjury led to the depletion of residentmacrophages without affecting the circulating macrophage recruitment to the injured area. Strikingly,these resident macrophage-deficient zebrafish still exhibited compromised neovascularization and scarresolution. Our results characterized the inflammatory cells of the zebrafish injured hearts andidentified key resident macrophage subpopulations prerequisite for successful heart regeneration.
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