Ghotbi et al. demonstrate that transcription factor KROX20 marks a stem cell population in the hair follicle whose lineages contribute to the interfollicular epidermis. In the cover image, the green spheres within the upper hair follicle region represent KROX20-positive stem cells that migrate up to maintain proper epidermal homeostasis. Image credit: Elnaz Ghotbi, generated using ChatGPT.
Talc pleurodesis is highly effective for preventing recurrence of pneumothorax and pleural effusion, but can be complicated by dissemination, acute lung injury, lead exposure, and foreign body-induced chronic inflammation and pain. Our objective is to develop a safe, biodegradable, contaminant-free particle for pleurodesis. We used mouse models of pneumothorax and malignant pleural effusion to compare the efficacy and safety of pleurodesis with talc and hydroxyapatite microspheres (HAM). Intrapleural instillation of microspheres induced pleural adhesions, fibrosis and symphysis as effectively as talc, and resulted in more durable protection from experimental pneumothorax. HAM and talc both induced an osteoclastogenic, inflammatory and fibrotic response in pleural lavage cells. Intrapleural HAM was resorbed by osteoclast action over 3 months, whereas talc was not cleared. Deletion of the osteoclast effector, CTSK, diminished pleural adhesion formation and fibrosis by talc and HAM, and inhibition of osteoclastogenesis with anti-RANKL antibody delayed HAM clearance. We found no difference in activity level, feeding behavior or lung compliance between particles, but talc induced more persistent pleural inflammation. We conclude that HAM resulted in an osteoclastogenic and fibrogenic pleural response that induced pleurodesis that was more durable than talc with a superior safety profile due in part to osteoclast-mediated particle clearance.
Yusuke Tanaka, Yuki Takahashi, Yuma Shindo, Lori B. Pitstick, Steven L. Teitelbaum, Wei Zou, Xiangning Wang, Jason Woods, Kathryn A. Wikenheiser-Brokamp, Francis X. McCormack
BK virus nephropathy is a severe, graft-threatening complication of kidney transplantation that requires an effective T cell response. It typically emerges in the kidney medulla. Elevated osmolyte concentrations that dynamically respond to loop diuretic therapy characterize this environment. BK-viremia development in kidney graft recipients negatively correlated with loop diuretic therapy. The association remained significant in multivariable and propensity score matched analyses. Kidney function was better preserved and CD8+ T cell abundance higher in loop diuretic-exposed allografts. CD8+ T cell densities in healthy human and murine kidney medulla were lower than in cortex and increased upon loop diuretic therapy in mice. As a potential underlying mechanism, kidney medullary NaCl and urea concentrations decreased primary human CD8+ T cell numbers in vitro by induction of cell death and limitation of proliferation, respectively. Both osmolytes downregulated interferon-related gene expression. NaCl induced p53-dependent apoptosis and upregulated Na+-transporter SLC38A2, which promoted caspase 3 activation. Both decreased T cell response and cytokine secretion in response to viral peptide and allogenic tubular epithelial cell killing, components of anti-BKV response in the kidney allograft. Our results propose osmolyte-mediated mitigation of CD8+ T cell function as a what we believe to be novel mechanism that impairs immune response to BK virus, therapeutic potential of which is testable.
Peyman Falahat, Adrian Goldspink, Lucia Oehler, Jessica Schmitz, Julia Miranda, Islem Gammoudi, Jan Hinrich Bräsen, Niklas Klümper, Olena Babyak, Christian Kurts, Herrmann Haller, Marieta Toma, Sibylle von Vietinghoff
BACKGROUND. Emerging evidence indicates a reduced incidence of multiple cancers in users of Glucagon-like peptide-1 receptor agonists (GLP-1RAs), drugs widely used for glycemic control and weight reduction that modulate several key regulators of metabolism. We sought to examine their association with non-small cell lung cancer (NSCLC) outcomes in overweight and obese patients and gain mechanistic insights from mouse models. METHODS. Two clinical cohorts of overweight and obese NSCLC patients—one undergoing surgical resection (n=1,177, 71 GLP-1RA users) and another receiving immune checkpoint inhibitors (ICIs; n=300, 10 GLP-1RA users), were propensity score matched for relevant covariates and analyzed for clinical outcomes. RESULTS. GLP-1RA use was associated with increased recurrence-free survival in overweight and obese patients (HR=0.41 [95%CI=0.16-1.04], p=0.026) after lobectomy. GLP-1RA treatment reduced tumor burden in obese but not normal-weight mice and altered the frequency and phenotypes of leukocyte populations and gene expression patterns in obese tumors, crucial to cancer progression and anti-tumor immunity. Concurrent GLP-1RA and immunotherapy was associated with improved overall (0.41 [0.16-1.01], 0.027) and progression-free survival (HR=0.31, [0.10-0.94], 0.019) for patients with advanced NSCLC. CONCLUSIONS. In our cohort, GLP-1RAs enhanced lung cancer-specific clinical outcomes and augment immunotherapy efficacy. Preclinical evidence suggested this effect to be obesity-restricted and mediated by immune modulation of the tumor microenvironment. FUNDING. This work was supported by a generous donation from Mr. George Duke to SY; W81XWH-21-1-0377, (GM147497), and RSG-22-071-01-TBE to VRS; 1R01 CA255515-01A1 to SY and JB; and NIH/NCI Cancer Center Support Grants P30CA013696 and P30CA016056.
Akhil Goud Pachimatla, Bailey Fitzgerald, Joyce Ogidigo, Meera Bhatia, Randall J. Smith Jr., Kalyan Ratnakaram, Sukumar Kalvapudi, Yeshwanth Vedire, Deschana Washington, Robert Vethanayagam rr, Hua-Hsin Hsiao, Spencer Rosario, Viraj R. Sanghvi, Joseph Barbi, Sai Yendamuri
Adipose inflammation plays a key role in obesity-induced metabolic abnormalities. Epigenetic regulation, including DNA methylation, is a molecular link between environmental factors and complex diseases. Here we found that high fat diet (HFD) feeding induced a dynamic change of DNA methylome in mouse white adipose tissue (WAT) analyzed by reduced representative bisulfite sequencing. Interestingly, DNA methylation at the promoter of estrogen receptor α (Esr1) was significantly increased by HFD, concomitant with a down-regulation of Esr1 expression. HFD feeding in mice increased the expression of DNA methyltransferase 1 (Dnmt1) and Dnmt3a, and binding of DNMT1 and DNMT3a to Esr1 promoter in WAT. Mice with adipocyte-specific Dnmt1 deficiency displayed increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity upon HFD challenge; while mice with adipocyte-specific Dnmt3a deficiency showed a mild metabolic phenotype. Using a modified CRISPR/RNA-guided system to specifically target DNA methylation at the Esr1 promoter in WAT, we found that reducing DNA methylation at Esr1 promoter increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity in HFD-challenged mice. Our study demonstrated that DNA methylation at Esr1 promoter played an important role in regulating adipose inflammation, which may contribute to obesity-induced insulin resistance.
Rui Wu, Fenfen Li, Shirong Wang, Jia Jing, Xin Cui, Yifei Huang, Xucheng Zhang, Jose A. Carrillo, Zufeng Ding, Jiuzhou Song, Liqing Yu, Huidong Shi, Bingzhong Xue, Hang Shi
The cellular etiology of seizures in CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), remains elusive. Given that Cln2R207X/R207X mice display fatal spontaneous seizures and an early loss of several cortical GABAergic interneuron populations, we hypothesized that these two events might be causally related. To study the cell-autonomous effects of interneuron-specific TPP1 deficiency, we first generated a transgenic mouse expressing loxP-flanked lysosomal membrane-tethered TPP1 (TPP1LAMP1) on the Cln2R207X/R207X genetic background, and then crossed TPP1LAMP1 mice with Vgat-Cre mice. These Vgat-Cre; TPP1LAMP1 mice accumulated storage in cortical and striatal interneurons. Vgat-Cre; TPP1LAMP1 mice also died more readily after pentylenetetrazole-induced seizures, indicating that interneuron-specific TPP1 deficiency renders these mice more susceptible to seizure-induced mortality. We also selectively activated interneurons using Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) in Vgat-Cre; Cln2R207X/R207X mice. Electroencephalogram monitoring revealed that DREADD-mediated activation of interneurons markedly accelerated the onset of spontaneous seizures and seizure-associated death in Vgat-Cre; Cln2R207X/R207X mice, suggesting that modulating interneuron activity can exacerbate epileptiform abnormalities. Taken together, these results provide new mechanistic insights into the underlying etiology of seizures and premature death that characterize CLN2 disease.
Keigo Takahashi, Nicholas R. Rensing, Elizabeth M. Eultgen, Letitia L. Williams, Sophie H. Wang, Hemanth R. Nelvagal, Steven Q. Le, Marie S. Roberts, Balraj Doray, Edward B. Han, Patricia I. Dickson, Michael Wong, Mark S. Sands, Jonathan D. Cooper