Lactate-sensing fibroblasts in stroke

Millions of people suffer from stroke every year, and stroke is the main cause of disabilities among adults. One of the best preventive strategies in stroke is exercise, but no consensus has been reached regarding the optimal exercise regime. We have previously shown that a lactate receptor, HCAR1, is present and active on fibroblasts in the meninges, especially in the pia mater (Lauritzen et al., 2014; Morland et al., 2017). We further showed that activation of these receptors, by high-intensity interval exercise, or lactate injections, induce increased density of capillaries in the brain (Morland et al., 2017). In the present project we use a mouse model for ischemic stroke, to examine the potential role of lactate, through activation of HCAR1, in the treatment of stroke. We have recently published the HCAR1 is also present in the choroid plexus, the structure that produces the cerebrospinal fluid, as well as along the neuroepithelial lining of the third ventricle (Hadzic et al., 2020). We are currently studying whether HCAR1 is involved in the preventive effects of exercise or lactate in stroke (Geiseler et al., A in prep) or in the treatment after stroke (Geiseler et al., B in prep). Finally, we investigate whether high HCAR1 regulates neurogenesis. We found that HCAR1 induced neurogenesis in the subventricular zone but not in the hippocampus (Lambertus et al., 2020). We have further studies whether high or low-to-medium intensity exercise is the optimal regime to maintain neurogenesis in the two main neurogenic niches (Lambertus et al., in prep).

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Millions of people suffer from stroke every year, and stroke is the main cause of disabilities among adults. One of the best preventive strategies in stroke is exercise, but no consensus has been reached regarding the optimal exercise regime. We have recently shown that a lactate receptor, HCAR1, is present and active in the brain. In a follow-up (submitted as a letter to Nature), we demonstrate high levels of HCAR1 on fibroblasts in the meninges, especially in the pia mater. We further show that activation of these receptors, by lactate injections or high-intensity interval exercise, induces angiogenesis through a VEGF-dependent mechanism in the brain of wild type mice but not in HCAR1 knock-out mice. Growth factors like VEGF, FGF2 and IGF-1, all of which can be released from fibroblasts, are important regulators of recovery after ischemia. In particular, the combined action of these growth factors regulates the migration of neuronal stem cells into the ischemic area and their proliferation into functional neurons to rescue brain function. We therefore hypothesize that lactate-sensing fibroblasts of the meninges represent a novel therapeutic and preventive target in stroke, and that this may underlay the beneficial effects of exercise. New evidence suggests that fibroblasts themselves can migrate into the brain parenchyma and differentiate into functional neurons. If lactate released from the ischemic area can initiate HCAR1-dependent neurogenesis, this is a likely protective mechanism in stroke. Through the same mechanisms, activation of HCAR1 by circulating lactate may underlie the beneficial effects of exercise in stroke. The present project will investigate the potential lactate-dependent reprogramming of fibroblasts to neurons, their HCAR-dependent release of growth factors, and the impact of these mechanisms in cerebral stroke.