Temporarily activating four cell reprogramming proteins reduced ischemic brain injury in old mice

Temporarily activating four cell reprogramming proteins reduced ischemic brain injury in old mice

On October 23, Aging Cell published a study in mice aged 12–18 months whose DNA contained an inducible set of genes encoding four proteins. The genes were activated in short cycles over four weeks, after which the mice underwent permanent occlusion of the middle cerebral artery. At 48 hours, the damaged area was 24,9% in mice carrying this system and 31,5% in controls.

Ischemic stroke begins when part of the brain loses its blood supply. These proteins had previously been studied in young brains. The authors tested how a predefined activation schedule would affect the response to acute ischemia in old mice.

The Yamanaka factors, or OSKM, are four proteins that can shift cells toward an earlier developmental state. One group of mice carried genes encoding these proteins in their DNA; their control littermates did not. Doxycycline, an antibiotic, served as the switch that activated the genes in this system. A cycle of three days of activation followed by four days without activation was repeated four times. The researchers chose short cycles because earlier experiments with continuous OSKM activation had caused teratomas and shortened lifespan in mice. In a model of continuous OSKM activation, the animals developed liver failure within four days, so the current experiment included a four-day break after each activation period.

After four weeks, the researchers permanently occluded the artery and compared the outcomes two days later. The OSKM group scored 2,68 points on the neurological function scale, compared with 1,41 in controls, and 2,75 points on the tightrope test, compared with 0,4 in controls. The beam-walking test showed no difference between the groups.

In the injured cortex of mice with OSKM, neuronal density and myelin were preserved. Myelin is the sheath around nerve fibers that speeds signal transmission. The researchers found more oligodendrocyte lineage cells and their precursors in the injured area; these cells produce and maintain myelin. Astrocytes, which support other cells in the brain, showed a weaker response.

Two days after occlusion, mice with cyclic OSKM activation had a smaller lesion, better preservation of neurons and myelin, and higher scores on the neurological function scale and tightrope test.