Yamanka factors reprogram cells into fluorinpotent embryonic stem cells,
they cause the cells to reset their cellular identity (thereby the cells forget their functions and the organs they were destined for) using only 4 programming factors
(Oct4, Sox2, Klf4 and c-Myc (OSKM)) Exposure to reprogramming factors for a sufficient time makes it possible to reverse the cell's age without erasing its identity.
This is the basis for partial cell reprogramming.
In a study published in Nature, scientists report its effect on neurogenesis, the creation of new neurons.
Increased neuroblast production;
Long gone are the days when a common misconception was that older brains do not produce new neurons.
Since then, scientists have found that certain areas of the brain, such as the hippocampus and the subventricular zone (SVZ),
contain neurogenic niches that give rise to new neurons even in adulthood.
However, this process slows considerably with age.
In their study, the researchers used the classic Yamanaka OSKM cocktail.
Many researchers have been concerned with how to increase the efficiency of reprogramming and lower the risks of tumors,
tumors mainly associated with c-Myc, but this was not the case in this study.
First, the scientists went for whole-body reprogramming by creating genetically engineered mice that express OSKM when treated with a molecular trigger:
in this case, doxycycline.
Using single-cell RNA sequencing, the researchers found that with age, the proportion of neuroblasts, the immediate precursors of neurons, among the descendants of neural stem cells (NSCs), decreases, indicating impaired neurogenesis.
The treatment reversed this trend, returning the proportion of neuroblasts to youthful levels.
Next, the researchers used an even more sophisticated mouse model in which OSKM expression was spatially restricted to the SVZ only.
Interestingly, this restriction allowed them to increase the expression time of OSKM to what would be lethal in a whole-body model and worked safely.
The effect on the NSCs and neuroblasts was even more impressive than in whole body reprogramming.
Reprogrammed neuron metrics
To avoid niche-wide effects, the researchers also conducted experiments with NSCs cultured in vitro.
Just like a living organism, NSCs harvested from old mice produced a lower proportion of neuroblasts than those harvested from younger mice.
Treatment of NSCs with OSKM increased the proportion of neuroblasts in their progeny,
suggesting a "getting things back to normal" regenerative-like effect.
However, it is neurons, not neuroblast precursors, that we are ultimately interested in.
Did the treatment result in more neurons being born? Apparently, yes.
In mice, SVZ-derived neuroblasts migrate to the olfactory region, where they become mature neurons (this shows how important the sense of smell is to these animals).
With age, this process slows down dramatically.
OSKM treatment increased the number of neurons born in the olfactory bulb, although not to juvenile levels.
Using single-cell transcription and immunostaining validation, we find that partial whole-body reprogramming in aged mice partially reverses the age-related defect in neuroblastic proportion in the SVZ neurogenic niche.
This "rejuvenation" effect can be reproduced by targeting the SVZ itself for partial reprogramming, indicating an intrinsic phenomenon.
Furthermore, partial reprogramming of old NSCs in cell culture autonomously enhances their differentiation into neural progenitors.
The study in question reveals the effect of partial reprogramming in old brains by systematically testing its effect on several different cell types.
The full study:
