Reactive astrocytes were traditionally thought to induce both detrimental and beneficial effects for brain remodeling after stroke. Here, we propose a new concept whereby reactive astrocytes can surprisingly transfer mitochondria into adjacent neurons and endothelial cells to promote neurovascular remodeling in damaged brain. Our overall hypothesis is as follows. Damage associated molecular pattern (DAMP) signals upregulate CD38 in reactive astrocytes. In addition, accumulating endothelial progenitor cells (EPCs) secrete soluble CD31 that further amplify CD38 signaling. Altogether, this gliovascular crosstalk induces astrocytes to release of extracellular particles containing mitochondria. Mitochondria are then transferred into neurons and endothelium, thus enhancing neuroplasticity, BBB repair, angiogenesis and overall neurovascular recovery. Our pilot data are intriguing: (i) DAMPs or soluble CD31 upregulate CD38 in astrocytes, (ii) CD38 signaling causes astrocytes to release extracellular mitochondria, (iii) confocal microscopy reveals transfer of astrocytic mitochondria into neurons and endothelial cells, (iv) extracellular mitochondria enhance neural growth and angiogenesis, (v) suppression of astrocytic CD38 with siRNA inhibits neuronal plasticity after focal ischemia, and (vi) extracellular particles with functional mitochondria can e detected in CSF from human stroke patients. We will test 3 specific aims in this project.
In Aim 1, we will investigate mechanisms of extracellular mitochondria particle production in reactive astrocytes.
In Aim 2, we will dissect mechanisms of astrocytic mitochondria transfer for enhancing neurovascular remodeling. Finally in Aim 3, we will demonstrate that remodeling vascular signals promote mitochondria transfer from reactive astrocytes into neurons and endothelial cells after stroke in vivo. This study should define a novel mechanism of glial-EPCs crosstalk to enhance neurovascular remodeling and provide a new concept for mitochondrial transfer in the neurovascular unit.
Reactive astrocytes were traditionally thought to impede brain plasticity by producing a glial matrix scar after stroke. But emerging data now suggest that reactive astrocytes may also have beneficial actions. Here, we propose the new idea that when stimulated by remodeling vascular signals, astrocytes can transfer their mitochondria into adjacent neurons and endothelial cells to improve neural plasticity and vascular function during stroke recovery. Mitochondrial transfer between different cells in the recovering neurovascular unit may provide a new conceptual framework for promoting functional recovery after CNS injury.
| Chou, Sherry H-Y; Lan, Jing; Esposito, Elga et al. (2017) Extracellular Mitochondria in Cerebrospinal Fluid and Neurological Recovery After Subarachnoid Hemorrhage. Stroke 48:2231-2237 |
| Hayakawa, Kazuhide; Esposito, Elga; Wang, Xiaohua et al. (2016) Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535:551-5 |
| Hayakawa, Kazuhide; Wang, Xiaohua; Lo, Eng H (2016) CD200 increases alternatively activated macrophages through cAMP-response element binding protein - C/EBP-beta signaling. J Neurochem 136:900-6 |
