Dynamics of Microglia Activation in the Ischemic Brain: Implications for Myelin Repair and Functional Recovery

Abstract

Ischemic stroke is a neurological disorder representing a leading cause of death and permanent disability world-wide, for which effective regenerative treatments are missing. Oligodendrocyte degeneration and consequent myelin disruption are considered major contributing factors to stroke-associated neurological deficits. Therefore, fostering myelin reconstruction by oligodendrocyte precursor cells (OPCs) has emerged as a promising therapeutic approach to enhance functional recovery in stroke patients. A pivotal role in regulating remyelination is played by microglia, the resident immune cells of the brain. Early after stroke, microglial cells exert beneficial functions, promoting OPC recruitment toward the ischemic lesion and preserving myelin integrity. However, the protective features of microglia are lost during disease progression, contributing to remyelination failure. Unveiling the mechanisms driving the pro-remyelination properties of microglia may provide important opportunities for both reducing myelin damage and promoting its regeneration. Here, we summarize recent evidence describing microglia activation kinetics in experimental models of ischemic injury, focusing on the contribution of these innate immune cells to myelin damage and repair. Some molecular signals regulating the pro-regenerative functions of microglia after stroke have been highlighted to provide new possible therapeutic targets involved in the protective functions of these cells. Finally, we analyzed the impact of microglia-to-OPCs communication via extracellular vesicles on post-stroke remyelination and functional recovery. The results collected in this review underline the importance of supporting the pro-remyelination functions of microglial cells after stroke.

Longitudinal Changes in Iron and Myelination Within Ischemic Lesions Associate With Neurological Outcomes: A Pilot Study

“…30 Most cases of atherosclerosis and lacunar subtypes demonstrated lower magnetic susceptibility at the initial scan and negative Δmagnetic susceptibility and positive ΔR2* values, suggesting less extravasation compared with cardioembolic and dissection subtypes, as well as remyelination during the observation period. 31 Across the ischemic stroke subtypes, patients with ischemic lesions classified under the increased iron and demyelination groups, which are primarily the BAD subtype, tended to experience less improvement in neurological functions compared with those in the decreased iron and remyelination groups (Figure 4C). These findings highlight the disease course of the BAD subtype, characterized by less improvement in neurological outcomes due to increased iron content and demyelination, even during the subacute and chronic phases.…”

Role of microglia in stroke

“…Communication pathways between microglia and OPCs include extracellular vesicles that may promote remyelination and functional recovery after stroke, as recently reviewed (Raffaele & Fumagalli, 2022).…”

“…Following brain ischemia, microglia participate in remyelination (Pavic et al, 2021) by inducing OPC proliferation and preventing myelin damage (Raffaele et al, 2021). Communication pathways between microglia and OPCs include extracellular vesicles that may promote remyelination and functional recovery after stroke, as recently reviewed (Raffaele & Fumagalli, 2022).…”

The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery

“…Cerebral ischemic injury also leads to demyelination, also known as disruption of the myelin sheath, leading to oligodendrocyte (OL) damage [ 57 ] and myelin loss [ 58 ], resulting in functional deficits after stroke [ 59 ], such as long-term sensorimotor and cognitive impairment [ 60 ]. Myelin regeneration begins when oligodendrocyte precursor cells (OPCs) change from a quiescent state to a regenerative phenotype in response to injury around the lesion area [ 61 ].…”