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Rewiring Neuronal Glycerolipid Metabolism Determines the Extent of Axon Regeneration.

ABSTRACT: How adult neurons coordinate lipid metabolism to regenerate axons remains elusive. We found that depleting neuronal lipin1, a key enzyme controlling the balanced synthesis of glycerolipids through the glycerol phosphate pathway, enhanced axon regeneration after optic nerve injury. Axotomy elevated lipin1 in retinal ganglion cells, which contributed to regeneration failure in the CNS by favorably producing triglyceride (TG) storage lipids rather than phospholipid (PL) membrane lipids in neurons. Regrowth induced by lipin1 depletion required TG hydrolysis and PL synthesis. Decreasing TG synthesis by deleting neuronal diglyceride acyltransferases (DGATs) and enhancing PL synthesis through the Kennedy pathway promoted axon regeneration. In addition, peripheral neurons adopted this mechanism for their spontaneous axon regeneration. Our study reveals a critical role of lipin1 and DGATs as intrinsic regulators of glycerolipid metabolism in neurons and indicates that directing neuronal lipid synthesis away from TG synthesis and toward PL synthesis may promote axon regeneration.

SUBMITTER: Yang C

PROVIDER: S-EPMC6975164 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Rewiring Neuronal Glycerolipid Metabolism Determines the Extent of Axon Regeneration.

Yang Chao C Wang Xu X Wang Jianying J Wang Xuejie X Chen Weitao W Lu Na N Siniossoglou Symeon S Yao Zhongping Z Liu Kai K

Neuron 20191127 2

How adult neurons coordinate lipid metabolism to regenerate axons remains elusive. We found that depleting neuronal lipin1, a key enzyme controlling the balanced synthesis of glycerolipids through the glycerol phosphate pathway, enhanced axon regeneration after optic nerve injury. Axotomy elevated lipin1 in retinal ganglion cells, which contributed to regeneration failure in the CNS by favorably producing triglyceride (TG) storage lipids rather than phospholipid (PL) membrane lipids in neurons. ...[more]

PMID: 31786011

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Project description:In the last decades, mesenchymal stem cells (MSCs) have become the cornerstone of cellular therapy due to their unique characteristics. Specifically human placenta-derived mesenchymal stem cells (hPMSCs) are highlighted for their unique features, including ease to isolate, non-invasive techniques for large scale cell production, significant immunomodulatory capacity, and a high ability to migrate to injuries. Researchers are exploring innovative techniques to overcome the low regenerative capacity of Central Nervous System (CNS) neurons, with one promising avenue being the development of tailored mesenchymal stem cell therapies capable of promoting neural repair and recovery. In this context, we have evaluated hPMSCs as candidates for CNS lesion regeneration using a skillful co-culture model system. Indeed, we have demonstrated the hPMSCs ability to stimulate damaged rat-retina neurons regeneration by promoting axon growth and restoring neuronal activity both under normoxia and hypoxia conditions. With our model we have obtained neuronal regeneration values of 10%-14% and axonal length per neuron rates of 19-26, μm/neuron. To assess whether the regenerative capabilities of hPMSCs are contact-dependent effects or it is mediated through paracrine mechanisms, we carried out transwell co-culture and conditioned medium experiments confirming the role of secreted factors in axonal regeneration. It was found that hPMSCs produce brain derived, neurotrophic factor (BDNF), nerve-growth factor (NGF) and Neurotrophin-3 (NT-3), involved in the process of neuronal regeneration and restoration of the physiological activity of neurons. In effect, we confirmed the success of our treatment using the patch clamp technique to study ionic currents in individual isolated living cells demonstrating that in our model the regenerated neurons are electrophysiologically active, firing action potentials. The outcomes of our neuronal regeneration studies, combined with the axon-regenerating capabilities exhibited by mesenchymal stem cells derived from the placenta, present a hopeful outlook for the potential therapeutic application of hPMSCs in the treatment of neurological disorders.

Dataset Information

Rewiring Neuronal Glycerolipid Metabolism Determines the Extent of Axon Regeneration.

Publications

Rewiring Neuronal Glycerolipid Metabolism Determines the Extent of Axon Regeneration.

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