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  4. CRISPR-edited human ES-derived oligodendrocyte progenitor cells improve remyelination in rodents

CRISPR-edited human ES-derived oligodendrocyte progenitor cells improve remyelination in rodents

Nature Communications, 2024 · DOI: 10.1038/s41467-024-52444-w · Published: August 16, 2024

Regenerative MedicineNeurology

Simple Explanation

In Multiple Sclerosis (MS), damage to the myelin sheath around nerve fibers leads to neurodegeneration and disability. Remyelination, the repair of this sheath, is often inefficient. The study explores if transplanting genetically modified oligodendrocyte progenitor cells (OPCs) can improve remyelination. Researchers edited human embryonic stem cell-derived OPCs to be unresponsive to a repellent found in chronic MS lesions. These edited cells were then transplanted into rodent models of chronic lesions to observe their effect on remyelination. The study found that the edited human OPCs displayed enhanced migration and remyelination in the rodent models, regardless of the host's age or time since transplant. This suggests a potential therapeutic strategy for progressive MS by overcoming the inhibitory environment.

Study Duration
10 weeks post-transplantation
Participants
Rag2−/−mice, Shiverer (Shi/Shi) mice, 18-month-old Rag2−/−mice
Evidence Level
Not specified

Key Findings

  • 1
    Edited hOPCs showed enhanced migration into SEMA3A-loaded demyelinated lesions compared to control hOPCs.
  • 2
    Transplantation of NRP1−/− hOPCs resulted in more extensive remyelination in a mouse model of demyelination.
  • 3
    Transplanted hOPCs maintained their migratory capacity in both young and aged animals.

Research Summary

This study demonstrates that transplanting human oligodendrocyte progenitor cells (hOPCs), genetically modified to ignore inhibitory signals, improves remyelination in rodent models of multiple sclerosis (MS). The researchers edited hOPCs to be unresponsive to SEMA3A, a chemorepellent found in chronic MS lesions, and found that these edited cells showed enhanced migration and remyelination in demyelinated lesions. The study suggests that OPC transplantation, combined with genetic editing to overcome environmental inhibitors, could be a potential therapeutic strategy for MS, particularly for progressive forms of the disease.

Practical Implications

Therapeutic Strategy for MS

OPC transplantation combined with genetic editing can serve as a therapeutic strategy for MS.

Overcoming Inhibitory Signals

Genetically modified hOPCs can overcome negative environmental signals inhibiting remyelination.

Addressing Aged Endogenous OPCs

Transplanted stem cell-derived hOPCs can mitigate against the problem of aging endogenous OPCs.

Study Limitations

  • 1
    The study used one protocol for generating hOPCs with one ES cell line.
  • 2
    The study used one focal model of LPC-induced demyelination in the mouse.
  • 3
    VEGF also binds to NRP1, so the loss of NRP1 may also reduce this signalling.

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