Brain neurons rejuvenate through cellular reprogramming

Research led by the University of Barcelona describes how neurons in the brains of mice can be rejuvenated through a cycle of controlled cellular reprogramming that helps restore some of the altered neurological properties and functions.

The work may open new perspectives for studying neurodegenerative diseases in patients. Thanks to an innovative approach, he examines the process of cellular rejuvenation of neurons and emphasizes the role of so-called Yamanaka Factorskey proteins that reverse aging, which are still poorly understood in the nervous system.

Research published in the journal Cell Stem cellunder the guidance of experts Daniel del Toro and Albert Giralt from the Faculty of Medicine and Health Sciences, the Institute of Neurosciences (UBneuro) and the Center for the Production and Testing of Advanced Therapies (CREATIO) UB, IDIBAPS and the Neurodegenerative Diseases Unit of the Network Center for Biomedical Research (CIBERNED) and Rüdiger Klein from Max Planck Institute for Biological Intelligence (Germany).

The work, whose first co-author is Sofia Saballa (UB-IDIBAPS-CIBERNED), also featured prominently by expert Manuel Serrano from the Barcelona IRB.

Rejuvenation of cerebral cortex neurons using Yamanaka factors

In 2012, Japanese scientist Shinya Yamanaka and British scientist John Gurdon received the Nobel Prize in Medicine for their research into reprogramming differentiated cells and returning them to a state typical of pluripotent cells. Those known as Yamanaka Factors – in particular, Oct4, Sox2, Klf4 and c-Myc – are transcription factors present throughout the scientific literature on cellular reprogramming.

While much of the international research has focused on anti-aging factors and regeneration of peripheral tissues (skin, muscle, liver and heart), new work is now delving into the effects they can cause in the central nervous system.

Specifically, the team studied the effects of controlled expression of Yamanaka factors in mouse brains during cycles of cellular reprogramming at different stages of neuronal development.

Daniel del Toro, principal investigator of the Ramón y Cajal program at the UB Faculty of Biomedicine, emphasizes that “when Yamanaka factors are introduced during development, more neurons are generated and the brain becomes more voluminous (it can reach double size). This leads to improved motor and social functioning in adulthood.”

“These results,” the expert continues, “are explained by the fact that we have made all brain cells capable of expressing these factors, including stem cells.” “It was very surprising to find that if we very precisely control the expression of these factors, we can also control the process of cell proliferation and produce brains with a larger cortex without losing proper structure and function,” he adds.

Improved behavior

The researcher admits that “we were also surprised to see that from a behavioral perspective there were no negative effects, and the mice even showed improved motor behavior and social interaction.”

For his part, Professor Albert Giralt clarified that in the case of adult mice, “the expression of Yamanaka factors in adult neurons causes these cells to rejuvenate and exhibit protection against neurodegenerative diseases such as Alzheimer’s disease.”

“In this case, we induced the expression of Yamanaka factors only in mature neurons. Because these cells do not divide, their number does not increase, but we have identified many markers indicating the process of neuronal rejuvenation. In these rejuvenated neurons, we find that the number of synaptic connections increases, the altered metabolism is stabilized, and the epigenetic profile of the cell is normalized,” details Giralt. “This whole set of changes has a very positive effect on their functionality as neurons,” says the expert.

Cellular reprogramming to combat neurodegenerative diseases

Understanding the aging process at the cellular scale opens new horizons in the fight against disease through cellular reprogramming. However, this process also carries the risk of causing the growth of aberrant cell populations, that is, tumors.

Experts clarify that “in our research and through precise control in specific neural populations, we have ensured that these factors are not only safe, but also improve synaptic plasticity of neurons, as well as higher order cognitive functions, such as the ability to socialize and form new ones.” memories. In addition, they emphasize that “since beneficial effects have also been identified when factors occur at very early stages of brain development, we believe it would be interesting to study their consequences in neurodevelopmental disorders.”

Functions of Yamanaka factors

So how do these factors affect the nervous system? All indications are that Yamanaka factors operate at at least three molecular levels. Firstly, they have epigenetic effects and this will affect gene transcription (DNA methylation process, histones, etc.). It will also compromise metabolic pathways and mitochondrial function (production and regulation of cellular energy). Finally, they can affect many genes and signaling pathways involved in synaptic plasticity.

Work published in the journal Cell Stem cellexpands knowledge of the functions of the Yamanaka factors described so far. These factors are known to improve regeneration after damage to retinal ganglion cells (David A. Sinclair, Harvard University, 2020) and also induce epigenetic changes in dentate gyrus neurons of the mouse hippocampus (Jesus Avila, CBMSO-CSIC-UAM, and Manuel Serrano , IRB Barcelona, ​​2020).

The researchers conclude that based on the new neuronal and brain findings, “we want to encourage future research to determine which other nervous system diseases may benefit from cell reprogramming technology, delving into the underlying molecular mechanisms to develop new therapeutic strategies.” and finally bring the results closer to clinical practice in treating patients.”

Help Article:

Shen, Yi-Ru; Zaballa, Sofia, etc.. Expanding the neocortex and protecting against neurodegeneration by transient reprogramming in vivo. Cell Stem cellOctober 2024 DOI:10.1016/j.stem.2024.09.013

Fountain: UB