TBX18

XI'AN, China, Oct. 17, 2023 /PRNewswire/ -- Single-cell and spatially resolved omics have helped scientists take a closer look at tissue composition, structure, and function. This comprehensive understanding paves the way for them to uncover some intricate and previously unknown disease mechanisms. Three articles in the most recent special issue of the Journal of Pharmaceutical Analysis (JPA) discuss how single-cell and spatially resolved omics help unravel intercellular dynamics, aiding the development of novel therapeutic modalities. The first study focuses on microglia-astrocyte communication which may improve the therapeutic landscape of intracerebral hemorrhage (ICH). It is based on the notion that after a spinal cord injury or stroke, reactive astrocytes in the brain form a 'glial scar', that is lesser known in the context of ICH. To this end, the authors used spatial transcriptomics to investigate how microglial depletion (induced using PLX3397) affects astrocytic scar formation in the early and late stages of ICH. The article was available online in February 2023 and published in Volume 13, Issue 8 of JPA in August 2023. The researchers discovered that during early ICH, microglia-derived insulin-like growth factor 1 (IGF1) regulated protective astrocytic scar formation by activating the mechanistic target of rapamycin (mTOR) signaling pathway, which was further activated by the repopulating microglia. In chronic ICH, however, the scar had less protective and more neurotoxic effects. Interestingly, this effect could be partially reversed by delayed microglial depletion. The corresponding author Jianmin Zhang says, "Delayed microglial depletion may help with chronic ICH. Combined early-stage IGF1/osteopontin and late-stage PLX3397 treatment could be a promising therapeutic strategy for ICH." The second study attempted to investigate the testicular toxicity of triptolide, an active component of the traditional Chinese medicine Tripterygium wilfordii Hook. F., at the single cell level. Although triptolide is effective in the treatment of inflammatory diseases, its side effects, particularly testicular toxicity, limit its clinical use. The researchers used triptolide to treat mice, then isolated their testes and prepared single-cell suspensions. These were used to create a transcriptome map, which revealed that in treated mice, inflammatory response and reactive oxygen species signaling were upregulated, while germ cell and spermatid development were downregulated, indicative of triptolide-induced toxicity. "Our findings provide an invaluable resource for identifying the therapeutic targets of triptolide-induced male reproductive toxicity", explains corresponding author Dr. Chuanbin Yang. The third study elaborated on the single-cell and spatial analysis of epicardial cells in mouse heart tissue from embryonic day 9.5 to postnatal day 9. The team identified that the gene markers Msln, C3, Efemp1, and Upk3b were specific to postnatal (mature) epicardial tissue and were associated with increased extracellular matrix (ECM) signaling. Furthermore, while Wt1, Tbx18, and Upk3b were expressed at all stages, Msln, C3, and Efemp1 were expressed only in mature stages. "The findings of our research can enhance the current understanding of epicardial cells, contributing to the development of more effective cardiac regenerative therapy strategies. This, in turn, improves the prognosis of patients with myocardial infarction and propels advancements in the field of cardiac repair," comments author Dr. Ling Zhang. Together, these articles enlighten us with a deeper understanding of cellular mechanisms at the single-cell and spatial levels, offering hope for improved treatment strategies in the future. Reference Title of original paper: Temporal dynamics of microglia-astrocyte interaction in neuroprotective glial scar formation after intracerebral hemorrhage Journal: Journal of Pharmaceutical Analysis DOI: Media contact Mengjie Wang 367011@email4pr.com Xi'an, China +86-(0)29-88960092 View original content to download multimedia: SOURCE Journal of Pharmaceutical Analysis

Researchers have identified how biological pacemaker cells can 'fight back' against therapies to biologically correct abnormal heartbeat rates. The research also uncovered a new way to boost the effectiveness of RNA therapies by controlling this activity. Investigators from the Smidt Heart Institute at Cedars-Sinai have identified how biological pacemaker cells -- cells that control your heartbeat -- can "fight back" against therapies to biologically correct abnormal heartbeat rates. The research also uncovered a new way to boost the effectiveness of RNA therapies by controlling this "fighting back" activity. This novel concept, published today in the peer-reviewed journal Cell Reports Medicine, is an important step in the evolution and creation of biological pacemakers -- which aim to one day replace traditional, electronic pacemakers. "We are all born with a specialized group of heart cells that set the pace for our heartbeats," said Eugenio Cingolani, MD, senior author of the study and director of the Cardiogenetics Program in the Smidt Heart Institute at Cedars-Sinai. "But in some people, this natural heartbeat is too slow, leading to the need for an electronic pacemaker." While electronic pacemakers have saved many lives since they were invented in the 1950s, there are limitations and side effects, including battery life, device-related infections and system failure. They also come with risks, including infection, swelling, bleeding, blood clots, damage to neighboring blood vessels, and in some cases, a collapsed lung. "But the biggest problem is that the machines do not cure the problem," Cingolani said. "They only allow you to find a way around it. Our intention is to create a biological solution, cells that we can reprogram within the heart to naturally stabilize the heartbeat." In the latest research study, Cingolani and team harnessed the same modified messenger RNA (mRNA) technology used in creating the Pfizer and Moderna COVID-19 vaccines. MRNA carries information from genes to make proteins, the building blocks of life. An mRNA vaccine is essentially a code that, when it enters a cell, tells it to make a specific protein. In their latest research study, investigators injected laboratory mice with mRNA that was chemically modified to express a protein called TBX18. In doing so, they found that heart cells "fought back": They inhibited TBX18 protein expression by producing microRNAs, nature's own regulatory molecules that specifically fine-tune gene expression. As a result, the amount of TBX18 protein produced was insufficient to support the heartbeat. The team looked for a way to bypass the suppressive effect of the microRNAs. After identifying the precise microRNAs involved, the investigators used chemical antagonists to specifically suppress those microRNAs, increasing TBX18 protein expression, and stabilizing the heartbeat. "This concept that cells 'fight back' against modified RNA is of practical importance, as it suggests how one might improve the effectiveness of RNA therapy," said study author Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute and the Mark S. Siegel Family Foundation Distinguished Professor. "We now have a clearer picture of how to inhibit microRNAs, release the brake, and ultimately get better gene expression." Of equal significance, researchers found a similar reaction -- the cells' ability to fight back -- is at play in limiting the expression of VEGF-A, an alternative type of chemically modified messenger RNA that has been used to grow new blood vessels. As a next step, Cingolani, Marbán and team are planning additional studies to assess the long-term efficacy and safety, with a view to eventually apply the insights to improve the efficacy of mRNA therapy in clinical trials.