Posted 06 October 2025 - 05:00 PM
In Advanced Science, a team of researchers has explained how partial cellular reprogramming through the OSKM factors restores nerve repair ability to older animals.
Stress as a signal
This paper focuses on Schwann cells, glial cells that are often responsible for maintaining the protective sheaths of myelin around neuronal axons and help peripheral nerves to regenerate [1]. However, as these cells age, these abilities diminish, leading to reduced regeneration after injuries [2] even while the neurons themselves have the same amounts of regenerative factors [3].
The researchers chose to investigate this aging in the context of stress granules (SGs), which occur when ribosomes bound to mRNA (polysomes) become unbound, leaving the mRNA free to bind to other proteins [4]. SGs often prevent cellular senescence by sequestering core senescence-related proteins [5]. Under normal circumstances, SGs form under stress conditions and then are disassembled when the stress is alleviated; however, with aging, cells fail both to assemble [6] and disassemble [7] SGs. Treatments to reduce SGs in axons themselves have been found to aid in regeneration [8].
As partial cellular reprogramming through OSKM has been found to assist in nerve repair [9], the researchers decided to take a closer look at its effects on Schwann cells and their responses to nerve injury.
Older repair cells become stuck
The researchers’ first experiment involved a crush injury to the sciatic nerves of 3-month-old (young) and 24-month-old (aged) rats. As expected, the young rats recovered much more completely and quickly than the aged rats; the aged rats’ local muscles began to deteriorate while the younger rats’ did not, they did not recover ankle flexion nearly as quickly, and their nerves healed far more slowly. Senescence markers increased in both groups, but they increased particularly strongly in the aged group, and even more in Schwann cells compared to neurons. These included both markers of DNA damage and increases in p16 and p21.
A single-cell analysis of gene expression in Schwann cells provided some insight as to why. These cells’ gene expression was highly perturbed by nerve injury; notably more than many other types of cells. Schwann cells were found to dedifferentiate into repair-related states three days after the injury, while two weeks afterwards, they redifferentiated into myelin-producing cells. In aged animals, however, many of the cells failed to redifferentiate; these cells, identified by their expresion of Runx2, became stuck in an intermediate state and were unable to remyelinate neurons.
Reprogramming unsticks cells and reduces senescence
The researchers then looked into partial reprogramming as a potential method of solving this problem. Mice were engineered to produce the OSKM reprogramming factors when doxycycline was administered, and these mice were then aged for 20 months and compared to a young control group. Inducing OSKM expression for two weeks after a sciatic nerve injury had a moderate effect, somewhat lengthening axons compared to untreated aged mice, but inducing it for four weeks made the older mice’s axons even longer and their regeneration much more like that of the young mice. As expected, the OSKM-induced groups had fewer Schwann cells stuck at the intermediate state represented by Runx2.
Also as expected, the reprogrammed Schwann cells had a significant decrease in inflammatory, pro-senescence factors and a significant increase in pro-regeneration factors. These changes came alongside an increased homeostasis of SGs; the reprogrammed cells were found to be much more effective in both creating and dismantling SGs than their unreprogrammed counterparts. Much of this effect was found to be due to eIF2, a protein signaling pathway that governs the regulation of SGs through G3bp1, which governs the production of Runx2. The increase in SG dismantling was also found to be improved by an increase in autophagy, the maintenance process by which cells consume their own organelles.
This research clearly shows one way that epigenetic reprogramming can be used to improve cellular functionality and regeneration. Translating this reprogramming into a therapy for human use, however, is particularly difficult, and there is no way yet known to precisely reprogram cells within a human being. The researchers suggest that it may be possible to target the Runx2-positive population of Schwann cells. It may also be possible to introduce iPSC-generated or other Schwann cells to better repair damaged nerves in older people in order to restore function and motion.
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Literature
[1] Bosch-Queralt, M., Fledrich, R., & Stassart, R. M. (2023). Schwann cell functions in peripheral nerve development and repair. Neurobiol Dis, 176(105952), 10-1016.
[2] Painter, M. W., Lutz, A. B., Cheng, Y. C., Latremoliere, A., Duong, K., Miller, C. M., … & Woolf, C. J. (2014). Diminished Schwann cell repair responses underlie age-associated impaired axonal regeneration. Neuron, 83(2), 331-343.
[3] Chen, W. A., Luo, T. D., Barnwell, J. C., Smith, T. L., & Li, Z. (2017). Age-dependent schwann cell phenotype regulation following peripheral nerve injury. The Journal of Hand Surgery (Asian-Pacific Volume), 22(04), 464-471.
[4] Ma, Y., & Farny, N. G. (2023). Connecting the dots: Neuronal senescence, stress granules, and neurodegeneration. Gene, 871, 147437.
[5] Omer, A., Patel, D., Lian, X. J., Sadek, J., Di Marco, S., Pause, A., … & Gallouzi, I. E. (2018). Stress granules counteract senescence by sequestration of PAI‐1. EMBO reports, 19(5), e44722.
[6] Lindström, M., Chen, L., Jiang, S., Zhang, D., Gao, Y., Zheng, J., … & Liu, B. (2022). Lsm7 phase-separated condensates trigger stress granule formation. Nature Communications, 13(1), 3701.
[7] Wu, H., Wang, L. C., Sow, B. M., Leow, D., Zhu, J., Gallo, K. M., … & Li, R. (2024). TDP43 aggregation at ER-exit sites impairs ER-to-Golgi transport. Nature communications, 15(1), 9026.
[8] van Erp, S., van Berkel, A. A., Feenstra, E. M., Sahoo, P. K., Wagstaff, L. J., Twiss, J. L., … & Eva, R. (2021). Age-related loss of axonal regeneration is reflected by the level of local translation. Experimental Neurology, 339, 113594.
[9] Tamanini, S., Comi, G. P., & Corti, S. (2018). In vivo transient and partial cell reprogramming to pluripotency as a therapeutic tool for neurodegenerative diseases. Molecular Neurobiology, 55(8), 6850-6862.
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