Mesenchymal-to-Epithelial Transition as a Barrier to Cellular Rejuvenation?

A vast body of research has linked altered epigenetic patterning with aging and the associated loss of cell identity (Izgi et al.); however, partial cellular reprogramming through the expression of transcription factors such as OCT4, SOX2, KLF4, and MYC (OSKM) (Takahashi and Yamanaka) can "rejuvenate" cells in vitro and in vivo, in part by resetting their aged epigenetic profile to a younger state (Zhang et al.). Of note, reprogramming of somatic cells such as fibroblasts into induced pluripotent stem cells (iPSCs) requires cellular differentiation from a mesenchymal state to an epithelial state (Li et al. and Samavarchi-Tehrani et al.); however, whether reprogramming requires this shift in cellular state or whether this shift represents a detrimental byproduct remains an open question. Furthermore, we remained unsure whether this mesenchymal-to-epithelial transition represents a barrier to the effective rejuvenation of aged cells. This question drove the development of a study from the lab of Juan Carlos Izpisua Belmonte (Alto Labs/Salk), whose new Cell paper now reports on the existence of a "mesenchymal drift" at the cellular and tissue levels associated with normal human aging and disease development and reports how partial reprogramming significantly mitigates this seemingly detrimental process in vitro and in vivo (Lu et al.).

Exploring the links between histone modifications and transcriptomes in single cells from tissues during healthy and pathological aging could serve as a valuable complement to this exciting research. Could Paired-Tag technology from Epigenome Technologies, which generates joint epigenetic and transcriptomic profiles at single-cell resolution and detects histone modifications and RNA transcripts in individual nuclei with efficiency comparable to single-nucleus RNA-seq/ChIP-seq assays, support ongoing research in this hugely exciting and ever more relevant field of research?

A Mesenchymal Drift Characterizes Normal Aging and Diseased States in Humans

The authors set out to identify molecular signatures of aging by analyzing gene expression data from a wide range of human tissues. In addition to pan-tissue hallmarks and tissue-specific functional decline, they observed the upregulation of pathways related to the epithelial-to-mesenchymal transition across most tissues. This prevalent phenomenon - "mesenchymal drift" – involved the partial/complete transition of cells (which compromises cell identity) and the acquisition/intensification of mesenchymal traits (which contribute to dysfunction with increased age). Fascinatingly, the team then revealed a link between mesenchymal drift and human diseases (especially those linked to aging) through their analysis of vast in vivo biopsy datasets; of note, this study chose not to focus on cancer, considering previous extensive explorations (Brabletz et al.).

This exciting study also highlighted the expression of mesenchymal drift genes as prognostic markers and potential therapeutic targets and revealed the potential for mesenchymal drift-targeted epigenetic rejuvenation; additionally, the analysis of a UK Biobank dataset (Goeminne et al.) associated higher mortality with plasma proteins associated with epithelial-mesenchymal transition pathways. Overall, these findings linked mesenchymal drift to aging and increased mortality and suggest that circulating factors may help propagate this effect across multiple organs. The authors suggest that aging tissues affected by mesenchymal drift may behave like dysfunctional endocrine organs, releasing drift-associated signals and driving aging- and aging-associated phenotypes; if proven true, this mechanism could represent an important target for the development of anti-aging interventions.

As partial reprogramming can induce epigenetic rejuvenation in aged cells (Ocampo et al. and Browder et al.), the authors next explored whether this process also mitigated mesenchymal drift by evaluating the transcriptomes of human fibroblasts derived from an aged donor at different time points after OSKM induction. In this case, partially reprogrammed cells rapidly downregulated mesenchymal genes before upregulating epithelial and pluripotency genes. Interestingly, a subsequent single-cell transcriptomic comparison of reprogramming in young and aged cells revealed that OSKM effectively dampened the mesenchymal program in aged cells, as part of a partial mesenchymal-to-epithelial transition effect unassociated with iPSC generation.

While these in vitro experiments provided fascinating results, the authors chose to drive on and explore the potential for partial reprogramming to mitigate mesenchymal drift in vivo using an OSKM-inducible mouse model. Partial reprogramming by long-term systemic OSKM induction in naturally aging mice significantly decreased mesenchymal drift gene expression in the kidney and liver (with lesser effects in other organs), coinciding with a decrease in epigenetic age. Meanwhile, shorter-term OSKM induction in an advanced-age mouse induced a significant decrease in mesenchymal drift in the spleen (and a trend in the liver), which associated with a less obvious change in epigenetic age. Finally, long-term OSK induction in progeroid mice led to reduced mesenchymal drift in the bone marrow and decreasing trends in the skin and spleen. These data highlighted the ability of partial reprogramming (associated with epigenetic rejuvenation) to reduce mesenchymal drift via a partial mesenchymal-to-epithelial transition, reverse aging signatures in vitro, and improve health and tissue function in vivo.

The Future of Mesenchymal Drift and Anti-aging Research

This large-scale meta-analysis of human sequencing data revealed the mechanistic basis for the beneficial effects of partial reprogramming on aging; indeed, the discovery of a "mesenchymal drift" across multiple organs could serve as a launching pad for the development of novel, effective interventions that support healthy human aging. The authors do, however, note the need for future studies to determine whether mesenchymal drift precedes disease onset and contributes causally; as such, they hypothesize that repeated cycles of injury and repair over a lifespan may induce mesenchymal drift in human tissues (Youssef & Nieto).

More importantly, the team underscored the need for additional epigenomic analyses to clarify the mechanisms underlying the mitigation of mesenchymal drift associated with partial reprogramming. The implementation of Paired-Tag technology from Epigenome Technologies, which generates joint epigenetic and transcriptomic profiles at single-cell resolution and detects histone modifications and RNA transcripts in individual nuclei with efficiency comparable to single-nucleus RNA-seq/ChIP-seq assays, has the potential to provide deeper insight into such research aims. What more could the simultaneous single-cell analysis of histone modification and transcriptomic profiles tell us about mesenchymal drift and the reversal of the aging process through partial reprogramming?