Selected Grantee Publications
Increased Collective Migration Correlates With Germline Stem Cell Competition in a Basal Chordate
Fentress and De Tomaso et al., PLOS One. 2023.
https://pubmed.ncbi.nlm.nih.gov/37903140/
Cell competition is a process that compares the relative fitness of progenitor cells and results in healthier cells, contributing a higher proportion to the final tissue composition. Investigators are studying cell competition in a novel model organism, the colonial ascidian, Botryllus schlosseri. They demonstrated that winner germline stem cells show enhanced migratory ability to chemotactic cues ex vivo and that enhanced migration correlates with both expression of the Notch ligand, Jagged, and cluster size. The ability to study conserved aspects of cell migration makes Botryllus an excellent model for future studies on competition, chemotaxis, and collective cell migration. Supported by ORIP (R21OD030520) and NIGMS.
The Drosophila Chemokine-Like Orion Bridges Phosphatidylserine and Draper in Phagocytosis of Neurons
Ji et al., PNAS. 2023.
https://pubmed.ncbi.nlm.nih.gov/37276397/
Degenerating neurons can be cleared by phagocytosis triggered by “eat-me” signal phosphatidylserine (PS) and mediated by the engulfment receptor Draper (Drpr), yet the process is poorly understood. Investigators used several Drosophila models to study dendrite degeneration and demonstrated that the fly chemokine-like protein Orion binds to PS and mediates interactions between PS and Drpr to enable phagocytosis. This study identifies a link between immunomodulatory proteins and phagocytosis of neurons and reveals conserved mechanisms of clearing degenerating neurons. Supported by ORIP (R24OD031953, R21OD023824, S10OD018516) and NINDS.
A LGR5 Reporter Pig Model Closely Resembles Human Intestine for Improved Study of Stem Cells in Disease
Schaaf et al., The FASEB Journal. 2023.
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300223R
The constant epithelial regeneration in the intestine is the sole responsibility of intestinal epithelial stem cells (ISCs), which reside deep in the intestinal crypt structures. To effectively study ISCs, tools to identify this cell population are necessary. This study validates ISC isolation in a new porcine Leucine Rich Repeat Containing G Protein–Coupled Receptor 5 (LGR5) reporter line and demonstrates the use of these pigs as a novel colorectal cancer model. Overall, this novel porcine model provides critical advancement to the field of translational gastrointestinal research. Supported by ORIP (R21OD019738, K01OD019911), NCI, and NIDDK.
Probiotic Therapy During Vaccination Alters Antibody Response to Simian-Human Immunodeficiency Virus Infection But Not to Commensals
Wilson et al., AIDS Research and Human Retroviruses. 2023.
https://www.doi.org/10.1089/AID.2022.0123
Strategies to boost vaccine-induced mucosal humoral responses are critical to developing an HIV-1 vaccine, and probiotic supplementation could help boost antibody responses. Researchers analyzed antibody titers to explore this topic in rhesus macaques (sex not specified) infected with simian–human immunodeficiency virus (SHIV). They reported that probiotic treatment during vaccination led to delayed kinetics in the circulating HIV-specific IgA response after breakthrough SHIV infection. These findings highlight the potential of probiotic supplementation for reducing IgA-specific HIV antibodies in the plasma, which could help reduce HIV acquisition in vaccinated individuals. Supported by ORIP (P51OD011104, R21OD031435) and NIAID.
Ion Channel Function in Translational Bovine Gallbladder Cholangiocyte Organoids: Establishment and Characterization of a Novel Model System
Nagao and Ambrosini et al., Frontiers in Veterinary Science. 2023.
https://pubmed.ncbi.nlm.nih.gov/37303723/
The study of biliary physiology and pathophysiology has long been hindered by the lack of in vitro models that accurately reflect the complex functions of the biliary system. Recent advancements in 3D organoid technology may offer a promising solution to this issue. Bovine gallbladder models have recently gained attention in the investigation of human diseases due to their remarkable similarities in physiology and pathophysiology to the human gallbladder. In this study, the investigators successfully established and characterized bovine gallbladder cholangiocyte organoids (GCOs) that retain key characteristics of the gallbladder in vivo, including stem cell properties and proliferative capacity. Notably, their findings demonstrate that these organoids exhibit specific and functional cystic fibrosis transmembrane conductance regulator activity. These bovine GCOs represent a valuable tool for studying the physiology and pathophysiology of the gallbladder with human significance. Supported by ORIP (K01OD030515, R21OD031903).
In Vivo MRI Is Sensitive to Remyelination in a Nonhuman Primate Model of Multiple Sclerosis
Donadieu et al., eLife. 2023.
https://pubmed.ncbi.nlm.nih.gov/37083540/
Experimental autoimmune encephalomyelitis (EAE) in the common marmoset is a model for studying inflammatory demyelination in multiple sclerosis (MS). Researchers investigated the feasibility and sensitivity of magnetic resonance imaging (MRI) in characterizing remyelination, a crucial step to recover from MS. Investigators demonstrated that multisequence 7T MRI could detect spontaneous remyelination in marmoset EAE at high statistical sensitivity and specificity in vivo. This study suggests that in vivo MRI can be used for preclinical testing of therapeutic remyelinating agents for MS. Supported by ORIP (R21OD030163) and NINDS.
PGRN Deficiency Exacerbates, Whereas a Brain Penetrant PGRN Derivative Protects, GBA1 Mutation–Associated Pathologies and Diseases
Zhao et al., Proc Natl Acad Sci USA. 2023.
https://www.pnas.org/doi/10.1073/pnas.2210442120
Mutations in GBA1 are associated with Gaucher disease (GD) and are also genetic risks in developing Parkinson’s disease (PD). Investigators created a mouse model and demonstrated that progranulin (PGRN) deficiency in Gba1 mutant mice caused early onset and exacerbated GD phenotypes, leading to substantial increases in substrate accumulation and inflammation in visceral organs and the central nervous system. These in vivo and ex vivo data demonstrated that PGRN plays a crucial role in the initiation and progression. In addition, the mouse model provides a clinically relevant system for testing therapeutic approaches for GD and PD. Supported by ORIP (R21OD033660), NIAMS, and NINDS.