Our data show that a subset of cells from the serosal mesothelium (SM;the gut equivalent of the proepicardium (PE)/epicardium) undergoes an epithelial/mesenchymal transition (EMT). These cells freely migrate to populate all organs of the alimentary canal and differentiate into a diverse set of cells including mural vasculogenic cells of the gut. Thus, SM differentiation mirrors specific aspects of PE development but significant differences in their developmental profiles also exist. While it is clear that SM has broad roles in development, its potential in and regulation of blood vessel formation and organogenesis is completely unknown. Additionally, we determined that isolated adult SM can be induced to differentiate into smooth muscle. This demonstrates that adult SM retains vasculogenic potential and suggests that the SM may serve as a naturally occurring source of progenitor cells for repair.
Our aims will examine three independent yet interactive concepts related to the potential of SM in development and repair.
Aim 1 will use heterotopic grafting to determine if SM and PE have interchangeable or inherently variable potential.
Aim 2 will use lineage and ablation models to determine how SM regulates blood vessel morphogenesis in the gut.
Aim 3 will use genetically-tagged SM transplants to determine its role in regulation of blood vessel repair after injury. Taken together these studies will determine how the broad yet still poorly understood potential of SM regulates vessel development and repair.

Public Health Relevance

Development of the major blood vessels of the gut is not understood. Our studies will determine the source of blood vessels in the embryonic gut and how the pattern of formation is regulated. These studies will form the background for future analysis of abnormal blood vessel formation in development and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083234-04
Application #
8298628
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Carrington, Jill L
Project Start
2009-08-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$332,548
Indirect Cost
$119,376
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Pfaltzgraff, Elise R; Bader, David M (2015) Heterogeneity in vascular smooth muscle cell embryonic origin in relation to adult structure, physiology, and disease. Dev Dyn 244:410-6
Pfaltzgraff, Elise R; Shelton, Elaine L; Galindo, Cristi L et al. (2014) Embryonic domains of the aorta derived from diverse origins exhibit distinct properties that converge into a common phenotype in the adult. J Mol Cell Cardiol 69:88-96
Winters, Nichelle I; Williams, Annabelle M; Bader, David M (2014) Resident progenitors, not exogenous migratory cells, generate the majority of visceral mesothelium in organogenesis. Dev Biol 391:125-32
Benesh, Emily C; Miller, Paul M; Pfaltzgraff, Elise R et al. (2013) Bves and NDRG4 regulate directional epicardial cell migration through autocrine extracellular matrix deposition. Mol Biol Cell 24:3496-510
Cross, Emily E; Thomason, Rebecca T; Martinez, Mitchell et al. (2011) Application of small organic molecules reveals cooperative TGFýý and BMP regulation of mesothelial cell behaviors. ACS Chem Biol 6:952-61