The Modulation of the Blood-Brain Barrier by Focused Ultrasound Stimulates Oligodendrogenesis

Objective

The current study aims to fill a gap in knowledge on the effects of focused ultrasound (FUS)-mediated blood-brain-barrier (BBB) modulation on the proliferation and development of oligodendrocyte progenitor cells (OPCs). Researchers established that FUS combined with intravenous microbubbles can modulate the BBB in a controlled, reversible, localized, and non-invasive manner to facilitate the delivery of intravenous therapeutics to the brain. Over a decade ago, we discovered that, even without intravenous therapeutics, FUS-BBB modulation stimulates elements of brain repair, including hippocampal neurogenesis.

Methods

In adult mice, FUS-BBB modulation was targeted unilaterally to the hippocampus and proliferation of OPCs was quantified at 1, 4, 7, and 10 days post-FUS. Mature oligodendrocytes were quantified at 30 days post-FUS. OPC proliferation was assessed at 7 days post-FUS, and mature oligodendrocytes at 30 days.

Results

The proliferation of hippocampal OPCs was increased by 6.8-fold and 2.3-fold between 1 and 4 days post-sonication, respectively, resulting in a 5.3-fold increase in mature oligodendrocytes one month later. To test the robustness of oligodendrogenesis following FUS-BBB modulation, the striatum was targeted as a second brain region with an independent experimental design. In line with hippocampal results, striatal FUS-BBB modulation promoted the generation of OPCs by 3.9-fold during the first week, leading to a 5.2-fold increase in oligodendrogenesis 30 days post-treatment.

Interpretation

We conclude that FUS-BBB modulation in the hippocampus and striatum promotes oligodendrogenesis by stimulating the proliferation of OPCs and being permissive to their maturation.

Highlights

• Beyond the potential for the delivery of therapeutics to the brain, the modulation of the BBB by FUS can stimulate regenerative effects, including oligodendrogenesis.

• FUS-BBB modulation induced a significant proliferation of OPCs which resulted in increases in oligodendrogenesis of 5.3-fold in the hippocampus and 6.7-fold in the striatum