Characterization of dormant intestinal stem cells () by a novel Optical Stem Cell Activity Reporter (OSCAR)
Final Report Abstract
Aging is linked to a decline in tissue maintenance, with adult stem cells playing a key role in repair and regeneration. As stem cell function declines with age, this could contribute to aging-related issues. Most adult stem cells remain dormant to protect against damage, but the exact process behind this dormancy is unclear. Over time, these dormant cells accumulate genetic, epigenetic, and metabolic damage, leading to organ dysfunction and diseases. Epigenetic changes in stem cells are a promising target for therapy, but are not fully understood. Previous studies showed that dormant stem cells exhibit low mRNA transcription, marked by inactive RNA polymerase II. We developed a fluorescent reporter, OSCAR, to track RNA polymerase II activity in living cells. Using this, we created a transgenic mouse line that reveals dormant stem cells in the intestine and other tissues. We aimed to use young and old OSCAR mice to explore how aging affects adult stem cell dormancy. We isolated OSCARhigh cells, which mark dormant stem cells, from the small intestine, a well-established stem cell niche. By characterizing these cells through RNA-Seq, and in vitro assays, we were able to determine whether aging leads to the depletion of dormant stem cells, and to identify the pathways and factors involved in healthy stem cell aging. We found that aging reduces the dormant stem cells and make them less able to regenerate the intestinal tissue due to loss of protein degradation homeostasis. This innovative tool provided a unique opportunity to test our hypothesis of dormant stem cell activation and exhaustion in the aging intestine. Understanding the underlying mechanisms of stem cell aging is crucial for developing therapies or preventive strategies to address aging-related dysfunctions and diseases, such as cancer, intestinal barrier loss, and decreased regenerative capacity.
Publications
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Establishment of a fluorescent reporter of RNA-polymerase II activity to identify dormant cells. Nature Communications, 12(1).
Freter, Rasmus; Falletta, Paola; Omrani, Omid; Rasa, Mahdi; Herbert, Katharine; Annunziata, Francesco; Minetti, Alberto; Krepelova, Anna; Adam, Lisa; Käppel, Sandra; Rüdiger, Tina; Wang, Zhao-Qi; Goding, Colin R. & Neri, Francesco
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Polyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis. Nature Cell Biology, 27(12), 2063-2077.
Minetti, Alberto; Omrani, Omid; Brenner, Christiane; Cansiz, Feyza; Imada, Shinya; Rösler, Jonas; Khawaled, Saleh; Allies, Gabriele; Meckelmann, Sven W.; Gebert, Nadja; Heinze, Ivonne; Rahnis, Norman; Lu, Jing; Spengler, Katrin; Rasa, Mahdi; Cirri, Emilio; Heller, Regine; Yilmaz, Ömer; Tasdogan, Alpaslan ... & Ori, Alessandro
