In a recent study, researchers investigated aging- and disease-associated changes in gene expression related to epithelial-mesenchymal transition. Inducing the Yamanaka factors in mice allowed them to rejuvenate cells and tissues and reverse some of these aging-associated changes [1].
Rejuvenating cellular identity
Aging-related epigenetic changes result in decreased capacity to maintain cellular identity [2], and some studies suggest aging-related changes in cellular states [3].
Such changes to the cell state can be a target for rejuvenation strategies. Probably the most famous rejuvenation strategy is the use of the Yamanaka factors, OCT4, SOX2, KLF4, and c-MYC (OSKM), which can rejuvenate fully differentiated aged cells into pluripotent stem cells; however, there is much to be understood regarding the mechanisms driving this rejuvenation.
The authors of this study focus specifically on the process of mesenchymal-epithelial transition (MET), which initiates the rejuvenation of fibroblasts into a pluripotent state by OSKM.
Drifting into old age
The authors analyzed gene expression in human tissue biopsies to identify aging-related trends. They noted some trends that are common among tissues and already known to be associated with aging, such as the aging-related increase in inflammation.
One specific observation, common across the tissues, captured the researchers’ attention: upregulation of pathways related to epithelial-mesenchymal transition (EMT). Given the common nature of this process across aging tissues, they named it ‘‘mesenchymal drift’’ (MD). They defined this as a process during which “cells undergo a partial or complete transition, leading to a compromised original cellular identity while acquiring new or intensifying existing mesenchymal traits, including altered extracellular matrix (ECM) production, cellular junction, tissue mechanical stiffening, and cytokine production.” They suggest that mesenchymal drift contributes to age-related organ dysfunction and might contribute to age-related diseases.
To investigate the latter, they analyzed available data from human biopsies obtained in various studies. They observed an increased expression, to a varying degree, of mesenchymal drift-associated genes in the disease-affected tissues taken from patients with lung diseases, liver diseases, chronic kidney diseases, cardiomyopathies, Alzheimer’s disease, osteoarthritis, and inflammatory bowel diseases as well as aged skin and endothelial cells from calcified atherosclerotic cores.
Prognostic marker
Because of the observed associations between multiple aging-associated diseases and mesenchymal drift, the researchers investigated its role as a predictor of clinical outcomes. They focused on idiopathic pulmonary fibrosis (IPF) in order to establish a proof of concept.
They divided IPF patients into low, middle, and high mesenchymal drift gene expression groups. The median survival of those groups was inversely correlated with the magnitude of mesenchymal drift. This suggests that mesenchymal drift genes can be used as prognostic markers and therapeutic targets.
Rejuvenating potential
Since the data obtained so far only establishes associations between the two observations, the researchers investigated the causality between mesenchymal drift and aging. They asked if biological age, as measured by epigenetic clocks, would be changed if they modulate the regulator of mesenchymal drift.
They re-analyzed publicly available data from breast cancer cell experiments that repressed ZEB1, a key EMT transcription factor that suppresses epithelial markers. Two epigenetic clocks (Horvath’s and PhenoAge) showed that repressing ZEB1 resulted in reduced biological age, suggesting that targeting mesenchymal drift has rejuvenating potential.
With this in mind, the researchers analyzed plasma proteins for potential drivers of mesenchymal drift across organs. They used UK Biobank data to identify mortality-associated plasma proteins. that have a stronger association with mortality were enriched in EMT pathways. They suggest that these findings show a significant association between mesenchymal drift regulators, aging, and increased mortality and that these plasma proteins are possible factors in driving mesenchymal drift across organs.
Rejuvenating without pluripotency
These researchers also aimed to mitigate mesenchymal drift using the Yamanaka factors, which are famous for their rejuvenating effects. Previous research has found that differentiated cells dedifferentiate by going through MET during the Yamanaka factor-driven rejuvenation process. [4] To learn more about the transition between the mesenchymal and epithelial states in aged cells, the researchers measured gene expression in human fibroblasts from a 96-year-old donor at different time points following OSKM induction.
Among different paths taken by cells, they identified a “partially reprogrammed” trajectory that shows some rejuvenation features. This trajectory was characterized by downregulation of mesenchymal genes in the first days following OSKM induction, while reprogramming-associated epithelial genes “were only beginning to be upregulated toward the pluripotency state.” Such a response suggests a critical window during early partial reprogramming that plays an essential role in the dampening of mesenchymal drift through partial MET.
Experiments in cell cultures with a non-functional OCT4 ene, which are unable to be reprogrammed to pluripotent stem cells, showed that those cells are still able to suppress the mesenchymal drift gene program following the expression of the three other Yamanaka factors. Those results suggest that mitigating mesenchymal drift is a potential mechanism behind rejuvenation, independent of inducting pluripotency.
Partial reprogramming’s impact on tissues and cells
Promising results obtained in the cell cultures led to further research in mice. First, in naturally aged mice, long-term (over 7 months) OSKM induction led to significantly decreased mesenchymal drift gene expression in the kidney and liver, and the trend toward decrease was also observed in most other organs. Short-term (around 1 month) OSKM induction at an advanced age significantly reduced mesenchymal drift in the spleen and showed a trend towards a decrease in the liver. Similar results (downregulation of mesenchymal drift in the bone marrow compartment and a similar trend in the skin and spleen) were seen in progeroid mice treated with a virus expressing OSK for two and a half months.
A cellular analysis followed the tissue-level analysis. The researchers used the available data from different studies regarding the mouse intestine and pancreas gene expression following a few days of OSKM induction. In the intestine, most cell types showed mesenchymal drift gene expression reduction, which the researchers linked to improved intestinal regenerative capacity. However, in the pancreas, they observed increased mesenchymal drift gene expression in most cell types; however, some subpopulations showed a decrease, suggesting cell-type-specific responses to OSKM induction that call for optimization of the Yamanaka factors induction duration and cell-type-specific targeting for optimal effects in further therapies.
The researchers concluded that their results show “that the partially reprogrammed state exhibited a notable decrease in the expression of mesenchymal drift genes through partial MET.” While those results are promising, this research was conducted on cell cultures and animal models and needs further validation in human trials.
Literature
[1] Lu, J. Y., Tu, W. B., Li, R., Weng, M., Sanketi, B. D., Yuan, B., Reddy, P., Rodriguez Esteban, C., & Izpisua Belmonte, J. C. (2025). Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming. Cell, S0092-8674(25)00853-0. Advance online publication.
[2] Hernando-Herraez, I., Evano, B., Stubbs, T., Commere, P. H., Jan Bonder, M., Clark, S., Andrews, S., Tajbakhsh, S., & Reik, W. (2019). Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells. Nature communications, 10(1), 4361.
[3] Izgi, H., Han, D., Isildak, U., Huang, S., Kocabiyik, E., Khaitovich, P., Somel, M., & Dönertaş, H. M. (2022). Inter-tissue convergence of gene expression during ageing suggests age-related loss of tissue and cellular identity. eLife, 11, e68048.
[4] Waryah, C., Cursons, J., Foroutan, M., Pflueger, C., Wang, E., Molania, R., Woodward, E., Sorolla, A., Wallis, C., Moses, C., Glas, I., Magalhães, L., Thompson, E. W., Fearnley, L. G., Chaffer, C. L., Davis, M., Papenfuss, A. T., Redfern, A., Lister, R., Esteller, M., … Blancafort, P. (2023). Synthetic Epigenetic Reprogramming of Mesenchymal to Epithelial States Using the CRISPR/dCas9 Platform in Triple Negative Breast Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10(22), e2301802.
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