OSAKA, JAPAN — Chronic inflammation of the middle ear can lead to various complications, impacting a person’s hearing and balance. One troubling consequence of this inflammation is the development of cholesteatomas, abnormal collections of cells in the ear that can cause bone erosion if left untreated.
These cholesteatomas can lead to distressing symptoms such as hearing loss, dizziness, facial paralysis, and even brain infections. However, researchers from Osaka University may have made a significant discovery that could pave the way for new treatments to help patients suffering from this condition.
Understanding Cholesteatomas
In a recent study published in Nature Communications, scientists from Osaka University uncovered the cause of cholesteatomas, providing a promising avenue for developing novel therapies. Cholesteatomas are composed of cysts or bumps in the ear, containing skin, collagen fibers, skin cells, fibroblasts, keratin, and dead tissue.
Schematic of osteoclastogenesis induced by cholesteatoma fibroblasts expressing activin A. Proinflammatory cytokines secreted from infiltrating macrophages induced activin A-expressing pathogenic fibroblasts; the activin A acted in conjunction with RANKL to promote ectopic osteoclastogenesis. Credit: Nature Comm
The exact mechanism behind the bone erosion caused by cholesteatomas has remained a mystery, with multiple theories proposed, including the activation of cells responsible for breaking down bone minerals and matrix, the presence of inflammatory markers and enzymes, and the accumulation and pressure from dead cells and tissues in the ear. Lead author Kotaro Shimizu emphasized the importance of understanding the true cause behind cholesteatomas, as they can reoccur even after surgical removal.
“A cholesteatoma can still return or happen again even after its surgical removal, so it is important to know what is actually causing it”
–Kotaro Shimizu, lead study author
To unravel this mystery, the researchers examined human cholesteatoma tissues surgically removed from patients. They utilized a cutting-edge process called single-cell RNA sequencing analysis to identify the cells responsible for triggering bone erosion, which they named osteoclastogenic fibroblasts. This study unveiled that these fibroblasts express a significant amount of activin A, a molecule that regulates various physiological functions in the body. The presence of activin A was found to initiate bone resorption, leading to the breakdown and absorption of bone minerals and matrix.
Subclustering and pseudotime analysis of human cholesteatoma fibroblasts. Cholesteatoma fibroblasts were associated with five subclusters labeled 1, 7, 8, 10, and 11 (right panel). The most differentiated cells (labeled red) were identical to cholesteatoma fibroblasts in subcluster 8 (middle panel). Cholesteatoma fibroblasts showed high levels of INHBA expression, and the area of high INHBA expression was identical to the area in cholesteatoma fibroblasts in subcluster 8 (left panel). Credit: Nature Comm
This groundbreaking research established a strong link between activin A and bone erosion in cholesteatoma. Senior author Masaru Ishii expressed excitement over the potential of targeting activin A as a viable treatment option for managing cholesteatomas.
“Our study showed that targeting activin A is a potential treatment in the management of cholesteatomas,” commented Ishii.
a Representative gating strategies used in cholesteatoma and skin samples. Live (calcein+ AAD−) CD45− cells. Scale bars: 5 mm. b UMAP plot of scRNA-seq data from 19,273 cells labeled by sample condition. Samples were obtained from three pairs of cholesteatoma and control skin samples labeled according to sample condition. c UMAP plot of scRNA-seq data labeled according to cell type identified in PanglaoDB. The main cell types were keratinocytes, fibroblasts, and endothelial cells. Credit: Nature Comm
Currently, complete surgical removal remains the only effective treatment for cholesteatomas in clinical settings. However, this newfound understanding of how cholesteatomas cause bone erosion offers hope for the development of innovative medical treatments. By targeting activin A, researchers envision a future where cholesteatoma management could become more efficient and successful.
Original article:
- Shimizu, K., Kikuta, J., Ohta, Y. et al. Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction. Nat Commun 14, 4417 (2023). https://doi.org/10.1038/s41467-023-40094-3
About Osaka University
Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan’s leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan’s most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Source: Nature Communications, Osaka University
