Saddouk et al. report that, in established pulmonary hypertension, endothelial production of platelet-derived growth factor B is required for survival of pathological distal arteriole smooth muscle cells via the autophagy initiator Beclin1, thereby sustaining hemodynamic abnormalities. The cover image of the murine lung shows enhanced staining for proapoptotic marker activated BAX (red) in pulmonary arteriole smooth muscle cells (green) with deletion of Beclin1. Image credit: Fatima Z. Saddouk and Junichi Saito.
BACKGROUND. Identifying patients with acute kidney injury (AKI) who are at higher risk of chronic kidney disease (CKD) progression at time of AKI diagnosis remains a major challenge in clinical practice. METHODS. Kidney transcriptome sequencing was applied to identify the top up-regulated genes in mice with AKI. The product of the top-ranked gene was identified in the tubular cells and urine both in mouse and human AKI. Data from two cohorts of patients with a prehospitalization estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73m2 who survived for at least 90 days after AKI were used to derive and validate multivariable prediction models. AKI to CKD progression was defined as a persistent eGFR < 60 ml/min/1.73m2 and with a minimum 25% reduction from baseline eGFR 90 days after AKI in patients with prehospitalization eGFR ≥ 60 ml/min/1.73m2. AKI to advanced CKD was defined by a sustained reduction of eGFR < 30 ml/min/1.73m2 90 days after AKI in those with prehospitalization eGFR 45–60 ml/min/1.73m2. RESULTS. Kidney cytokeratin 20 (CK20) was up-regulated in injured proximal tubular cells and detectable in urine within 7 days after AKI. High concentrations of urinary CK20 (uCK20) were independently associated with the severity of histological AKI and the risk of AKI to CKD or advanced CKD progression. In Test set, the AUC of uCK20 for predicting AKI to CKD or advanced CKD was 0.80, outperformed currently used biomarkers for detecting kidney tubular injury. Addition of uCK20 to an established clinical model improved the ability for predicting AKI-CKD progression with an AUC of 0.90, and largely improved the risk reclassification. CONCLUSION. This finding highlighted uCK20 as a useful predictor for AKI to CKD progression, and may provide a tool to early identify patients at high risk of CKD following AKI. FUNDING. The National Natural Science Foundation of China (Key Program).
Rui Ma, Han Ouyang, Shihong Meng, Jun Liu, Jianwei Tian, Nan Jia, Youhua Liu, Xin Xu, Xiaobing Yang, Fan Fan Hou
Tumor evolution is driven by genetic variation; however, it is the tumor microenvironment (TME) that provides the selective pressure contributing to evolution in cancer. Despite high histopathological heterogeneity within glioblastoma (GBM), the most aggressive brain tumor, the interactions between the genetically distinct GBM cells and the surrounding TME are not fully understood. To address this, we analyzed matched primary and recurrent GBM archival tumor tissues with imaging-based techniques aimed to simultaneously evaluate tumor tissues for presence of hypoxic, angiogenic, and inflammatory niches, extracellular matrix organization, TERT promoter mutational status, and several oncogenic amplifications on the same slide and location. We found that the relationships between genetic and TME diversity are different in primary and matched recurrent tumors. Interestingly, the texture of the extracellular matrix (ECM), identified by label-free reflectance imaging, was predictive of single-cell genetic traits present in the tissue. Moreover, reflectance of ECM revealed structured organization of the perivascular niche in recurrent GBM, enriched in immunosuppressive macrophages. Single-cell spatial transcriptomics further confirmed the presence of the niche-specific macrophage populations and identified interactions between endothelial cells, perivascular fibroblasts, and immunosuppressive macrophages. Our results underscore the importance of GBM tissue organization in tumor evolution and highlight novel genetic and spatial dependencies.
Ugoma Onubogu, Chandler D. Gatenbee, Sandhya Prabhakaran, Kelsey Wolfe, Benjamin Oakes, Roberto Salatino, Rachael Vaubel, Oszkar Szentirmai, Alexander R. A. Anderson, Michalina Janiszewska
Prenatal exposure to viral pathogens has been known to cause the development of neuropsychiatric disorders in adulthood. Furthermore, COVID-19 has been associated with a variety of neurological manifestations, raising the question of whether in utero SARS-CoV-2 exposure can affect neurodevelopment, resulting in long-lasting behavioral and cognitive deficits. Using a human ACE-2-knock-in mouse model, we have previously shown that prenatal exposure to SARS-CoV-2 at later stages of development leads to fetal brain infection and gliosis in the hippocampus and cortex. In this study, we aimed to determine if infection of the fetal brain results in long-term neuroanatomical alterations of the cortex and hippocampus, as well as any cognitive deficits in adulthood. Here, we show that infected mice developed slower and weighed less in adulthood. We also found altered hippocampal and amygdala volume and aberrant newborn neuron morphology in the hippocampus of adult mice infected in utero. Furthermore, we observed sex-dependent alterations in anxiety-like behavior and locomotion, as well as hippocampal-dependent spatial memory. Taken together, our study revealed long-lasting neurological and cognitive changes as a result of prenatal SARS-CoV-2 infection, identifying a window for early intervention and highlighting the importance of immunization and antiviral intervention in pregnant women.
Courtney L. McMahon, Erin M. Hurley, Aranis Muniz Perez, Manuel Estrada, Daniel J. Lodge, Jenny Hsieh
We present a transcriptomic analysis that provides a better understanding of regulatory mechanisms within the healthy and injured periosteum. The focus of this work is on characterizing early events controlling bone healing during formation of periosteal callus on day 3 post fracture. Building upon our previous findings showing that induced Notch1 signaling in osteoprogenitors leads to better healing, we compared samples in which Notch 1 intracellular domain is overexpressed by periosteal stem/progenitor cells with control intact and fractured periosteum. Molecular mechanisms and changes in skeletal stem/progenitor cells (SSPCs) and other cell populations within the callus, including hematopoietic lineages were determined. Notably, Notch ligands were differentially expressed in endothelial and mesenchymal populations, with Dll4 restricted to endothelial cells, whereas Jag1 was expressed by mesenchymal populations. Targeted deletion of Dll4 in endothelial cells using Cdh5CreER resulted in negative effects on early fracture healing, while deletion in SSPCs using α-smooth muscle actin-CreER did not impact bone healing. Translating these observations into clinically relevant model of bone healing revealed the beneficial effects of delivering Notch ligands alongside osteogenic inducer, BMP2. These findings provide insights into the regulatory mechanisms within the healthy and injured periosteum, paving the way for novel translational approaches to bone healing.
Sanja Novak, Hitoshi Tanigawa, Vijender Singh, Sierra H. Root, Tannin A. Schmidt, Kurt D. Hankenson, Ivo Kalajzic
Dendritic cell inhibitory receptor (DCIR) is a C-type lectin receptor selectively expressed on myeloid cells, including monocytes, macrophage, dendritic cells, and neutrophils. Its role in immune regulation has been implicated in murine models and human genome-wide association studies (GWAS), suggesting defective DCIR function associates with increased susceptibility to autoimmune diseases such as rheumatoid arthritis, lupus and Sjogren’s syndrome. However, little is known about the mechanisms underlying DCIR activation to dampen inflammation. Here, we developed anti-DCIR agonistic antibodies that promote phosphorylation on DCIR’s immune receptor tyrosine-based inhibitory motifs (ITIM) and recruitment of SH2 containing protein tyrosine phosphatase-2 (SHP2) for reducing inflammation. We also explored the inflammation resolution by depleting DCIR+ cells with antibodies. Utilizing a human DCIR knock-in mouse model, we validated the anti-inflammatory properties of the agonistic anti-DCIR antibody in experimental peritonitis and colitis. These findings provide critical evidence for targeting DCIR to develop transformative therapies for inflammatory diseases.
Liang Chen, Suresh Patil, Jeffrey Barbon, James Waire, F. Stephen Laroux, Donna McCarthy, Mishra Pratibha, Suju Zhong, Feng Dong, Karin Orsi, Gunarso Nguyen, Yingli Yang, Nancy Crosbie, Eric Dominguez, Arun Deora, Geertruida Veldman, Susan V. Westmoreland, Liang Jin, Timothy Radstake, Kevin White, Hsi-Ju Wei