Extended Data Fig. 10: CCN1 from myelin degeneration-reactive LRAs orchestrates molecular and lipid metabolic reprogramming of local phagocytic microglia to mediate white matter repair after SCI.

Following SCI, LRAs in spared but reactive tissue regions exhibit molecularly distinct, neuroanatomically restricted reactivity states that evolve over time. Wallerian degeneration of severed axons extends white matter pathology into lesion-remote regions of the injured spinal cord. In response to local myelin breakdown, reactive white matter LRAs rapidly and persistently upregulate expression of the matricellular protein CCN1. Astrocyte-secreted CCN1 directs the molecular and lipid metabolic specification and function of local white matter degeneration-associated microglia (WDM), which acquire a repair-associated molecular profile and phagocytose myelin and axon debris. Specifically, astrocyte CCN1 can engage SDC4 receptors on microglia to aid the intracellular digestion of lipid-rich cellular debris via modulation of mechanisms that buffer excess debris-derived lipids – processes known to be essential for debris clearance and white matter repair. Accordingly, astrocyte CCN1 signaling to local microglia facilitates efficient white matter repair and aids neurological recovery. In the absence of astrocyte CCN1 (Ccn1-cKO), phagocytic microglia in degenerating white matter are dysfunctional and exhibit intracellular accumulation of undigested cellular debris and impaired buffering of excess lipids, characterized by disrupted lipid storage. Consequently, phagocytic microglia recruitment is amplified, resulting in chronically excessive and spatially aberrant white matter inflammation. This compensatory mechanism ultimately fails to effectuate debris clearance, culminating in attenuated white matter repair and impaired neurological recovery.