The VIMM, established in 2008 by Paul B. Fisher, M.Ph., Ph.D., the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by the VIMM members.     

Dissecting mechanisms that regulate the epithelial barrier in healthy gut and during mucosal inflammation.

 

 

 

 

Discovering the protective roles of a cytoskeletal motor in the gut

In healthy conditions, the epithelial layer of the gut creates a protective barrier, which prevents luminal bacteria and their toxins from entering the body. However in patients with IBD and other gastrointestinal diseases, the intestinal epithelial barrier becomes leaky due to disruption of adherens and tight junctions. Dr. Ivanov’s group previously described a novel mechanism that controls the assembly and functions of epithelial junctions in vitro . This mechanism involves the activity of a major cytoskeletal motor, non-muscle myosin IIA (NM IIA). Through fruitful collaboration with Dr. Robert Adelstein laboratory at the National Heart, Lung, and Blood Institute, they have now demonstrated for the first time that NM IIA is a critical regulator of the gut barrier in vivo . 

 

Dr. Ivanov’s group generated a mouse model with an intestinal epithelial-specific knockout of NM IIA heavy chain (NM IIA cKO) and examined the structure and function of the normal gut barrier, and the development of experimental colitis in these animals. Unchallenged NM IIA cKO mice showed increased intestinal permeability and altered expression/ localization of several AJ/TJ proteins. They did not develop spontaneous colitis, but demonstrated signs of a low-scale mucosal inflammation manifested by prolapses, lymphoid aggregates, increased cytokine expression, and neutrophil infiltration in the gut. The ability of NM IIA cKO mice to limit bacterial translocation throughout the leaky gut was related to a very high production of antibacterial IgA in their intestinal tissue. Interestingly, NM IIA cKO animals were much more susceptible to experimentally-induced colitis than wild type mice. They demonstrated significantly higher mortality, accelerated body weight loss, severe disruption of the gut barrier and exaggerated mucosal injury and inflammation. This study provides the first evidence that NM IIA plays important roles in establishing normal intestinal barrier, and protection from mucosal inflammation in vivo .

 

This study is an example of productive multilaboratory collaboration between Dr. Ivanov’s group and Dr. John Kuemmerle’s laboratories at VCU School of Medicine and Dr. Robert Adelstein’s laboratory at NIH. Dr. Nayden Naydenov, a Research Instructor at VCU is first author on this paper and performed the majority of the experimental work. This research was supported by National Institute of Health grants R01 DK083968, R01 DK084953 to Dr. Ivanov and by the Crohn's and Colitis Foundation of America research fellowship award 254881 to Dr. Naydenov. This study was published in Scientific Reports in 2016.

Figure Legend: Intestinal epithelial-specific knockout of NM IIA increases tissue injury and cell apoptosis during experimental colitis. NM IIA ^+/+ and NM IIA cKO mice were exposed to 3% dextran sulfate sodium (DSS) in drinking water, or water alone, for 7 days. (A) Intestinal permeability was determined by measuring transmucosal flux of FITC-dextran . (B,C) Hematoxylin & eosin staining was used to evaluate epithelial integrity and to calculate the tissue injury index. Changes in the tissue architecture are indicated by letters: e , epithelial erosion; i , leukocyte infiltration; s , submucosal edema. (D,E) Apoptotic cells were visualized using TUNEL assay (red). Nuclear counter-staining (blue) was used to visualize the position of individual cells. Data is presented as mean ± SE. *P< 0.01. Scale bar, 10 µm.

 

Publications:

Naydenov N. G., Feygin A., Wang L, Kuemmerle J. F., Harris G., Conti M. A., Adelstein R. S. and Ivanov A. I. Non-muscle myosin IIA regulates intestinal epithelial barrier in vivo and plays a protective role during experimental colitis. Sci. Reports 6: 24161, 2016. PMCID: PMC4827066

About the Investigators

Andrei I. Ivanov, PhD, is a Professor in the Department of Human and Molecular Genetics, Member of the VCU Institute of Molecular Medicine (VIMM), and Member of the VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine; Dr. Nayden G. Naydenov is a Research Instructor in the Department of Human and Molecular Genetics, VCU School of Medicine; Dr. Robert S. Adelstein, MD is Head of the Laboratory of Molecular Cardiology at NIH/NHLBI, Bethesda, MD; Dr. John F. Kuemmerle, MD is Professor and Head of the Division of Gastroenterology and Hepatology in the Department of Internal Medicine, VCU School of Medicine; Dr. Dongdong Wang is a Postdoctoral Associate in Dr. Ivanov’s lab; Alex Feygin is a Lab and Research Technician at VCU School of Medicine; Dr. Mary Anne Conti, PhD is a Scientific Staff working in Dr. Adelstein’s laboratory; Gianni Harris is a technician working at the University of Rochester Medical Center, Rochester, NY.