Human Muse Cells Reconstruct Neuronal Circuitry in Subacute Lacunar Stroke Model

Area of Science:

• Stem Cell Biology
• Neuroscience
• Regenerative Medicine

Background:

• Multilineage-differentiating stress-enduring (muse) cells are endogenous, nontumorigenic stem cells with pluripotency.
• Muse cells can be harvested as SSEA-3+ cells from cultured bone marrow-mesenchymal stem cells.
• The precise mechanism of muse cell-mediated repair in neurological disease models is not fully understood.

Purpose of the Study:

• To investigate the mechanism of muse cell transplantation in a mouse model of lacunar infarction.
• To evaluate the differentiation, integration, and functional recovery potential of human bone marrow-derived muse cells after stroke.

Main Methods:

• Serum/xeno-free cultured human bone marrow-muse cells were transplanted into the perilesion brain of immunodeficient mice 2 weeks after induced lacunar infarction.
• Cell survival, differentiation, and neural connections were assessed using immunohistochemistry and dextran tracing.
• Functional recovery was evaluated using cylinder tests, and safety was assessed by monitoring for tumor formation and off-target cell distribution.

Main Results:

• Approximately 28% of transplanted muse cells remained in the host brain at 8 weeks post-transplantation.
• Muse cells differentiated into NeuN+, MAP2+, and GST-pi+ cells, indicative of neuronal and glial lineages.
• Dextran tracing confirmed connections between muse cells and host neurons, including extension along the pyramidal tract to the spinal cord.
• Muse cell transplantation led to significant functional recovery in stroke mice, which was reversible upon administration of human-specific diphtheria toxin.
• No tumor formation or off-target distribution of human cells was observed up to 10 months post-transplantation.

Conclusions:

• Muse cell transplantation in the delayed subacute phase after stroke promotes differentiation into neural cells.
• These cells facilitate neural reconstruction and improve functional outcomes in a lacunar stroke model.
• Muse cells demonstrate significant therapeutic potential for lacunar stroke with a favorable safety profile over a prolonged observation period.