Dresden University of Technology

PHILADELPHIA, June 11, 2024 /PRNewswire/ -- As humans age, hematopoietic stem cells—the immature precursor cells that give rise to all blood and immune cells—accumulate mutations. Some of the mutations allow these stem cells to self-renew and expand more effectively than their non-mutated counterparts. This relatively poorly understood condition, known as clonal hematopoiesis of indeterminate potential (CHIP), is detectable in more than 10% of people older than 65 and is linked to increased risks of various inflammation-related diseases. "These mutations change the character of the progeny cells, making them more inflammatory," says Dr. George Hajishengallis of Penn Dental Medicine. "When a large fraction of your immune cells are derived from these mutant stem cells, it spells bad news for chronic inflammatory diseases." Now, a team led by Hajishengallis, together with collaborators at the Dresden University of Technology and the University of North Carolina at Chapel Hill (UNC), have uncovered mechanistic insights into CHIP. They also found that an FDA-approved drug for preventing organ transplant rejection, rapamycin, has the potential to block these mutant stem cells and treat CHIP-driven inflammatory bone loss diseases, such as periodontitis and arthritis. Their research is published in the journal Cell. "We found a compelling observational association between DNMT3A, a gene most commonly affected in CHIP, and the prevalence and severity of periodontitis in a cohort of 4,946 people aged 52 to 74," Hajishengallis says. "What's more, we corroborated these findings with our mouse model, demonstrating a strong causal relationship between DNMT3A mutations and increased susceptibility to inflammatory bone loss disorders. And most excitingly, we were able to show the efficacy of rapamycin in protecting mice from CHIP-exacerbated inflammatory bone loss, which paves the way for eventually treating such diseases in humans." Considering potential therapeutic strategies Hajishengallis says, "Screening for CHIP among the elderly population may identify individuals with increased risk for inflammatory comorbidities." These individuals may benefit from therapeutic interventions aiming to block the aberrant expansion of the CHIP-mutant hematopoietic stem cell clones and their adverse impact on chronic inflammatory comorbidities. Read more on the study >> CONTACT: Beth Adams, [email protected] SOURCE PENN DENTAL MEDICINE

在一项新的研究中，来自德国埃尔朗根-纽伦堡大学、德国神经退行性疾病中心、德国糖尿病研究中心、德累斯顿工业大学、美国索尔克生物研究所和奥地利科学技术研究所的研究人员证实大脑神经细胞中的某些 RNA 分子终生不会更新。相关研究结果发表在2024年4月5日的Science期刊上，论文标题为“Lifelong persistence of nuclear RNAs in the mouse brain”。RNA 通常是寿命很短的分子，会根据环境条件不断重建。这些作者希望通过这项新研究的成果，破译大脑复杂的衰老过程，并更好地了解相关的退行性疾病。人体内的大多数细胞都会定期更新，从而保持活力。但也有例外：心脏、胰腺和大脑中的细胞在整个生命周期中都不会更新，但仍要保持完全正常的工作状态。论文共同通讯作者、埃尔朗根-纽伦堡大学神经表观基因组学教授Tomohisa Toda 博士说，“衰老的神经元是阿尔茨海默病等神经退行性病变的重要风险因素。深入了解细胞衰老过程以及那些维护细胞基本功能的关键组件，对于开发有效的治疗方法至关重要。”在这项新颖的研究工作中，研究团队揭示了大脑衰老过程中的一个核心要素：首次证明了一部分负责保护遗传物质的核糖核酸分子具有与神经元同等的长寿属性。Toda博士对此感到惊讶：“与相对稳定的DNA不同，大多数RNA分子的寿命十分短暂且处于不断替换的状态，而此次发现的某些RNA分子却能伴随神经元终身存在。”为了确定 RNA 分子的寿命，Toda及其团队与奥地利科技研究所细胞生物学家Martin Hetzer教授的团队进行了合作。凭借在表观遗传学和神经生物学方面的深厚造诣，Toda博士阐述：“我们巧妙地运用荧光标记技术追踪了RNA分子在小鼠脑细胞中的存续状况，令人惊奇的是，我们甚至能在相当于人类七旬老人的两岁小鼠体内，识别出带有荧光标记的长寿命RNA（long-lived RNA, LL-RNA）。不仅在成熟的神经元中，还在大脑的成体神经干细胞中发现了此类LL-RNA。”图片来自Science, 2024, doi:10.1126/science.adf3481此外，他们还发现LL-RNA往往位于细胞核中，与染色质紧密相连，其中染色质是由DNA和蛋白组成的复合物，经浓缩后会形成染色体。这表明LL-RNA 在调节染色质方面发挥着关键作用。为了证实这一假设，这些研究人员在成年神经干细胞模型的体外实验中降低了LL-RNA的浓度，结果发现染色质的完整性受到了严重损害。Toda博士进一步阐释：“我们现在有足够的证据相信，LL-RNA在基因组稳定性长期维护以及神经细胞生存全程中均发挥了核心作用。未来的科研项目将深入探究LL-RNA长期稳定的生物物理机制。我们期待能更多地揭示LL-RNA在染色质调控中的生物功能细节，同时探索衰老过程对这些精细调控机制的影响。”参考资料：Sara Zocher et al. Lifelong persistence of nuclear RNAs in the mouse brain. Science, 2024, doi:10.1126/science.adf3481.Neuroscientists at FAU discover building blocks in nerve cells that last a life timehttps://www.fau.eu/2024/04/05/news/research/rna-that-doesnt-age/本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

A collaboration between research groups at the University of California, TU Dresden in Germany and Cedars-Sinai Guerin Children's in Los Angeles has identified a mechanism by which embryonic cells organize themselves to send signals to surrounding cells, telling them where to go and what to do. While these signaling centers have been known to science for a while, how individual cells turn into organizers has been something of a mystery. A collaboration between research groups at the University of California, TU Dresden in Germany and Cedars-Sinai Guerin Children's in Los Angeles has identified a mechanism by which embryonic cells organize themselves to send signals to surrounding cells, telling them where to go and what to do. While these signaling centers have been known to science for a while, how individual cells turn into organizers has been something of a mystery. Until now. In a paper published in the journal Nature Cell Biology, the researchers find that cells are literally pressed into becoming organizers. "We were able to usemicrodroplet techniquesto figure out how the buildup of mechanical pressure affects organ formation," said co-corresponding authorOtger Campàs, former associate professor of mechanical engineering at UC Santa Barbara, who is currently managing director, professor and chair of tissue dynamics at thePhysics of Life Excellence Cluster of TU Dresden. Peer pressure Finding out how cells decide to become organizers during the formation of organs remains a central challenge in the study of embryogenesis, and is key to understanding embryonic development. "By understanding how an embryo forms organs, we can start to ask questions about what goes wrong in children born with congenital malformations," said fellow co-authorOphir Klein, MD, executive director of Cedars-Sinai Guerin Children's, where he is also the David and Meredith Kaplan Distinguished Chair in Children's Health. Building on techniques previously developed by Campàs, in which minute droplets inserted between developing embryonic cells sense the forces exerted by cells on each other, and through observations of an embryonic incisor tooth, the researchers found that pressure influences a cell's fate -- they feel the squeeze and use this information to organize themselves. "It's like those toys that absorb water and grow in size," said Neha Pincha Shroff, a postdoctoral scholar in the School of Dentistry at UCSF, and co-lead author of the study. "Just imagine that happening in a confined space. What happens in the incisor knot is that the cells multiply in number in a fixed space and this causes a pressure to build up at the center, which then becomes a cluster of specialized cells." The researchers found that the cells feeling the stronger pressure stop growing and start sending signals to organize the other surrounding cells in the tooth. Embryos use several of these signaling centers to guide cells as they form tissues and organs. Cells around these centers receive stronger or weaker signals depending on their location, and they make decisions accordingly. Like building skyscrapers or bridges, sculpting our organs involves tight planning, a lot of coordination and the right structural mechanics. Failure in any of these processes can be catastrophic when it comes to building a bridge, and it can also be damaging for us when growing in the womb. "This work may lead to additional research into how birth defects are formed and can be prevented," Klein remarked. Seeing how pressure works in embryonic development opens up further research possibilities, according to Campàs. "It is really exciting that pressure has a role in establishing signaling centers," he said. "It will be interesting to see if or how mechanical pressure affects other important developmental processes." Investigators Pengfei Xu (co-first author), Sangwoo Kim, Elijah Shelton, Ben Gross, Yucen Liu, Carlos Gomez, Qianlin Ye, Tingsheng Yu Drennon, Jimmy Hu, and Jeremy Green also participated in the study.