Editors' ChoiceNeurological Disease

Accelerating the production of insulating brain cells

See allHide authors and affiliations

Science Translational Medicine  12 Jul 2017:
Vol. 9, Issue 398, eaan8203
DOI: 10.1126/scitranslmed.aan8203

Abstract

A 3D hydrogel enables rapid and scalable production of oligodendrocyte progenitor cells for transplantation to treat demyelination diseases.

Many neural connections in the central nervous system are insulated by oligodendrocytes, which wrap concentric layers of a fatty cell membrane called myelin around axons to enhance electric transmission. Oligodendrocytes also provide nutritional support to long neural fibers that may be inadequately supported by their cell bodies. Oligodendrocyte loss resulting from a broad array of diseases, ranging from pediatric leukodystrophies to multiple sclerosis to white matter stroke, leads to demyelination and impaired neurological function. No cure currently exists for these diseases, but transplanting oligodendrocyte progenitor cells (OPCs) into demyelinated brain and spinal cord tissues is a promising potential therapeutic strategy because transplanted OPCs can mature into oligodendrocytes and restore myelin formation in vivo. Although advances in stem cell research have enabled the generation of OPCs from human pluripotent stem cells, rapid and scalable production of high-quality OPCs remains a major challenge.

In a new study, Rodrigues et al. developed a three-dimensional (3D) culture system for scalable generation of transplantation-quality OPCs from human pluripotent stem cells (hPSCs). Using a synthetic, thermoresponsive hydrogel scaffold that is liquid at 4°C but gels at 37°C, the authors exposed gel-embedded hPSCs to a temporal sequence of chemical signals to promote OPC differentiation in vitro. Pairing fine-tuned modulating factors, such as growth factors and morphogens, with the 3D biomaterial enhanced early OPC differentiation. The researchers also demonstrated that the 3D culture system enables maturation of OPCs to late-stage fully differentiated oligodendrocytes, which can be used for disease modeling and drug screening.

To test whether OPCs generated in the 3D gel can be used for cell therapy, the researchers harvested cells by reducing the temperature to 4°C, liquefying the gel. OPC differentiation efficiencies approached 90%, allowing them to skip cell purification, which is laborious and can decrease cell viability. They implanted the harvested cells into the mouse brain via stereotaxic injection, and, over the course of 6 months, the injected OPCs proliferated and migrated throughout the corpus callosum and cortex. A small percentage of these cells expressed the molecular markers of myelin-producing oligodendrocytes, demonstrating full maturation and integration of the implanted cells. Importantly, the researchers did not observe any cancerous cell overgrowth.

This study demonstrates that a scalable 3D culture system can rapidly produce transplantation-quality OPCs from hPSCs and that the implanted OPCs can robustly migrate, proliferate, and form myelin-producing oligodendrocytes in vivo. Together with encouraging initial clinical results from OPC transplantation in spinal cord injury, further development of this 3D culture technology may enable effective treatment of demyelination diseases in the future.

Highlighted Article

View Abstract

Navigate This Article