Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia

Abstract

Neonatal cerebral hypoxia-ischemia (HI) is the leading cause of death and disability in newborns with the only current treatment option being hypothermia. An increased understanding of the pathways that facilitate tissue repair after HI can aid the development of better treatments. Here we have studied the role of lactate receptor HCAR1 (Hydroxycarboxylic acid receptor 1) in tissue repair after HI in mice. We show that HCAR1 knockout (KO) mice have reduced tissue regeneration compared with wildtype (WT) mice. Further, proliferation of neural progenitor cells and microglial activation were impaired after HI. Transcriptome analysis showed a strong transcriptional response to HI in the subventricular zone of WT mice involving about 7300 genes. In contrast, the HCAR1 KO mice showed a very modest response to HI, involving about 750 genes. Notably, fundamental processes involved in tissue repair such as cell cycle and innate immunity were dysregulated in HCAR1 KO. Taken together, our data suggest that HCAR1 is a key transcriptional regulator of the pathways that promote tissue regeneration after HI. Thus, HCAR1 could be a promising therapeutic target in the treatment of neonatal HI and other forms of brain ischemia.

Lactate Induces the Expressions of MCT1 and HCAR1 to Promote Tumor Growth and Progression in Glioblastoma

“…Lauritz et al. demonstrated, using the neurosphere assay, that brain cells lacking HCAR1 had reduced proliferation and repair abilities ( 51 ). Moreover, MCT1 is mainly used by oxidative cells for extracellular lactate intake, and MCT4 is mainly used to release accumulated lactate into the extracellular milieu, in many cases by hypoxic and/or highly glycolytic cells ( 52 – 54 ).…”

Lactate Metabolism Regulates Tumour Growth and Progression in Glioblastoma

“…Several authors showed that stimulation of HCAR1 leads to the activation of cell survival signalling promoting cell proliferation via the inhibition of apoptosis and stimulates the secretion of several angiogenic factors in a PI3K/Akt-CREB signalling pathway-dependent manner [44]. Interestingly, an essential part of the repair process after a neonatal brain injury is the generation of new cells by increase of proliferation and differentiation of stem cells, Lauritz H. K. et al, by neurosphere assays, demonstrated that the cells lacking HCAR1 had reduced proliferation ability [45].…”

Microglia dynamic response and phenotype heterogeneity in neural regeneration following hypoxic-ischemic brain injury

“…The hypoxic-ischemic injury activated microglia can also impact NPC proliferation through direct cell-cell interactions (169). A recent study used single-cell sequencing to construct myeloid cell composition map of the periinfarction area after ischemic stroke in rats, and further distinguished microglia state conducive to neural regeneration, the underlying mechanism of which can be attributed to SOX2 and its involvement in the regulation of Akt and CREB signaling pathways (170).Studies have shown that the knockout of the HCAR1 gene inhibits the activation of microglia, thereby weakening neurogenesis after hypoxic-ischemic brain injury (171). In vitro experiments showed that NSC cultured in a conditional medium with anti-inflammatory microglia subtypes exhibited better cell survival, stronger migration ability, and lower astrocyte differentiation ability (172).…”