Selected Grantee Publications
Prostatic Escherichia coli Infection Drives CCR2-Dependent Recruitment of Fibrocytes and Collagen Production
Scharpf et al., Disease Models & Mechanisms. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11789281
In men, lower urinary tract dysfunction (LUTD) is commonly linked to prostatic collagen accumulation through inflammation-mediated mechanisms. Researchers used 8- to 10-week-old male reporter mice, exposed to either sterile phosphate buffered saline (PBS) or Escherichia coli, to identify that circulating Lyz2+S100a4+Gli1+ myeloid-derived cells are recruited to the prostate to drive inflammation and collagen synthesis. Researchers also used 8- to 10-week-old male Ccr2‑/ - null and Ccr2+/- control mice, exposed to either sterile PBS or E. coli, to determine if Ccr2 is necessary for the fibrotic response to prostatic uropathogen infection. Results demonstrated that CCR2+ cells mediate the collagen abundance and fibrotic response to prostate inflammation. This study elucidates the cell types underlying prostate fibrosis and can be utilized to develop targeted therapies. Supported by ORIP (T32OD010957), NCI, NIDDK, and NIEHS.
Matrikine Stimulation of Equine Synovial Fibroblasts and Chondrocytes Results in an In Vitro Osteoarthritis Phenotype
Gagliardi et al., Journal of Orthopaedic Research. 2025.
https://pubmed.ncbi.nlm.nih.gov/39486895
Advancements in therapy development for osteoarthritis (OA) currently are limited due to a lack of physiologically relevant in vitro models. This study aimed to understand the effect of matrikine stimulation, using human recombinant fibronectin fragment containing domains 7–10 (FN7–10), on equine synovial fibroblasts and chondrocytes. Inflammatory cytokines, chemokines, and matrix degradation genes in equine synovial fibroblasts and chondrocytes were significantly altered in response to FN7–10 stimulation; marked upregulation was observed in interleukin-6 (IL-6), IL-4, IL-10, matrix metalloproteinase 1 (MMP1), MMP3, MMP13, CCL2/MCP1, and CXCL6/GCP-2 gene expression. Only IL-6 protein production was significantly increased in media isolated from cells stimulated with FN7–10. These results support the potential use of equine synovial fibroblasts and chondrocytes—employing FN7–10—as representative in vitro models to study OA. Supported by ORIP (T32OD011130) and NIAMS.
The Effect of Common Paralytic Agents Used for Fluorescence Imaging on Redox Tone and ATP Levels in Caenorhabditis elegans
Morton et al., PLOS One. 2024.
https://pubmed.ncbi.nlm.nih.gov/38669260
Caenorhabditis elegans is a highly valuable model organism in biological research. However, these worms must be paralyzed for most imaging applications, and the effect that common chemical anesthetics may have on the parameters measured—especially biochemical measurements such as cellular energetics and redox tone—is poorly understood. In this study, the authors used two reporters—QUEEN-2m for relative ATP levels and reduction-oxidation–sensitive green fluorescent protein for redox tone—to assess the impact of commonly used chemical paralytics. The results show that all chemical anesthetics at doses required for full paralysis alter redox tone and/or ATP levels, and anesthetic use alters the detected outcome of rotenone exposure on relative ATP levels and redox tone. Therefore, it is important to tailor the use of anesthetics to different endpoints and experimental questions and to develop less disruptive paralytic methods for optimal imaging of dynamic in vivo reporters. Supported by ORIP (P40OD010440, R44OD024963) and NIEHS.
Loss of Lymphatic IKKα Disrupts Lung Immune Homeostasis, Drives BALT Formation, and Protects Against Influenza
Cully et al., Immunohorizons. 2024.
https://pubmed.ncbi.nlm.nih.gov/39007717/
Tertiary lymphoid structures (TLS) have context-specific roles, and more work is needed to understand how they function in separate diseases to drive or reduce pathology. Researchers showed previously that lymph node formation is ablated in mice constitutively lacking IκB kinase alpha (IKKα) in lymphatic endothelial cells (LECs). In this study, they demonstrated that loss of IKKα in lymphatic endothelial cells leads to the formation of bronchus-associated lymphoid tissue in the lung. Additionally, they showed that male and female mice challenged with influenza A virus (IAV) exhibited markedly improved survival rates and reduced weight loss, compared with littermate controls. They concluded that ablating IKKα in this tissue reduces the susceptibility of the mice to IAV infection through a decrease in proinflammatory stimuli. This work provides a new model to explore the mechanisms of TLS formation and the immunoregulatory function of lung lymphatics. Supported by ORIP (T35OD010919), NHLBI, NIAID, and NIAMS.
Naturally Occurring Osteochondrosis Latens Lesions Identified by Quantitative and Morphological 10.5 T MRI in Pigs
Armstrong et al., Journal of Orthopaedic Research. 2023.
https://pubmed.ncbi.nlm.nih.gov/35716161/
Juvenile osteochondritis dissecans (JOCD) is a pediatric orthopedic disorder that is associated with pain and gait deficits. JOCD lesions form in the knee, elbow, and ankle joints and can progress to early-onset osteoarthritis. In this study, researchers used a noninvasive magnetic resonance imaging (MRI) method to identify naturally occurring lesions in intact knee and elbow joints of juvenile pigs. This work can be applied to noninvasive identification and monitoring of early JOCD lesions and determination of risk factors that contribute to their progression in children. Supported by ORIP (K01OD021293, T32OD010993), NIAMS, and NIBIB.
Gigapixel Imaging With a Novel Multi-Camera Array Microscope
Thomson et al., eLife. 2022.
https://www.doi.org/10.7554/eLife.74988
The dynamics of living organisms are organized across many spatial scales. The investigators created assembled a scalable multi-camera array microscope (MCAM) that enables comprehensive high-resolution, large field-of-view recording from multiple spatial scales simultaneously, ranging from structures that approach the cellular scale to large-group behavioral dynamics. By collecting data from up to 96 cameras, they computationally generated gigapixel-scale images and movies with a field of view over hundreds of square centimeters at an optical resolution of 18 µm. This system allows the team to observe the behavior and fine anatomical features of numerous freely moving model organisms on multiple spatial scales (e.g., larval zebrafish, fruit flies, slime mold). Overall, by removing the bottlenecks imposed by single-camera image acquisition systems, the MCAM provides a powerful platform for investigating detailed biological features and behavioral processes of small model organisms. Supported by ORIP (R44OD024879), NIEHS, NCI, and NIBIB.
Fluorescence-Based Sorting of Caenorhabditis elegans via Acoustofluidics
Zhang et al., Lab on a Chip. 2020.
The authors present an integrated acoustofluidic chip capable of identifying worms of interest based on expression of a fluorescent protein in a continuous flow and then separate them in a high-throughput manner. Utilizing planar fiber optics, their acoustofluidic device requires no temporary immobilization of worms for interrogation/detection, thereby improving the throughput. The device can sort worms of different developmental stages (L3 and L4 stage worms) at high throughput and accuracy. In their acoustofluidic chip, the time to complete the detection and sorting of one worm is only 50 ms, which outperforms nearly all existing microfluidics-based worm sorting devices. Supported by ORIP (R43OD024963), NIEHS, and NIDDK.