Transcription factor-mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells.

Cell-based therapies for myelin disorders, such as multiple sclerosis and leukodystrophies, require technologies to generate functional oligodendrocyte progenitor cells. Here we describe direct conversion of mouse embryonic and lung fibroblasts to induced oligodendrocyte progenitor cells (iOPCs) using sets of either eight or three defined transcription factors. iOPCs exhibit a bipolar morphology and global gene expression profile consistent with bona fide OPCs. They can be expanded in vitro for at least five passages while retaining the ability to differentiate into multiprocessed oligodendrocytes. When transplanted to hypomyelinated mice, iOPCs are capable of ensheathing host axons and generating compact myelin. Lineage conversion of somatic cells to expandable iOPCs provides a strategy to study the molecular control of oligodendrocyte lineage identity and may facilitate neurological disease modeling and autologous remyelinating therapies.

Functional trade-offs in white matter axonal scaling.

The brains of large mammals have lower rates of metabolism than those of small mammals, but the functional consequences of this scaling are not well understood. An attractive target for analysis is axons, whose size, speed and energy consumption are straightforwardly related. Here we show that from shrews to whales, the composition of white matter shifts from compact, slow-conducting, and energetically expensive unmyelinated axons to large, fast-conducting, and energetically inexpensive myelinated axons. The fastest axons have conduction times of 1-5 ms across the neocortex and <1 ms from the eye to the brain, suggesting that in select sets of communicating fibers, large brains reduce transmission delays and metabolic firing costs at the expense of increased volume. Delays and potential imprecision in cross-brain conduction times are especially great in unmyelinated axons, which may transmit information via firing rate rather than precise spike timing. In neocortex, axon size distributions can account for the scaling of per-volume metabolic rate and suggest a maximum supportable firing rate, averaged across all axons, of 7 +/- 2 Hz. Axon size distributions also account for the scaling of white matter volume with respect to brain size. The heterogeneous white matter composition found in large brains thus reflects a metabolically constrained trade-off that reduces both volume and conduction time.

Speed limits in the cerebellum: constraints from myelinated and unmyelinated parallel fibers.

Cerebellar parallel fibers are among the thinnest known vertebrate axons and represent an extreme anatomical adaptation. Until now a systematic examination of their properties across species has not been carried out. We used transmission electron microscopy and light microscopy to compare parallel fibers in mammals of different brain sizes. From mouse to macaque, the average unmyelinated parallel fiber diameter was 0.2-0.3 microm, consistent with the idea that they are evolutionarily selected for compactness. Average unmyelinated parallel fiber diameter scaled up slightly with brain size, and across species the estimated total conduction time is 5-10 ms. However, these conduction times can vary by milliseconds, and unmyelinated PFs consume large amounts of energy per action potential. These functional disadvantages are overcome in myelinated parallel fibers, which we found in the deep regions nearest the Purkinje cell layer in marmoset, cat and macaque. These axons were 0.4-1.1 microm wide, have expected conduction times of 0.5-1.0 ms, and may convey fast feedforward inhibition via basket cells to Purkinje cells.