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Expression of coxsackievirus and adenovirus receptor separates hematopoietic and cardiac progenitor cells in fetal liver kinase 1-expressing mesoderm.

ABSTRACT: In developing embryos or in vitro differentiation cultures using pluripotent stem cells (PSCs), such as embryonic stem cells and induced pluripotent stem cells, fetal liver kinase 1 (Flk1)-expressing mesodermal cells are thought to be a heterogeneous population that includes hematopoietic progenitors, endothelial progenitors, and cardiac progenitors. However, information on cell surface markers for separating these progenitors in Flk1? cells is currently limited. In the present study, we show that distinct types of progenitor cells in Flk1? cells could be separated according to the expression of coxsackievirus and adenovirus receptor (CAR, also known as CXADR), a tight junction component molecule. We found that mouse and human PSC- and mouse embryo-derived Flk1? cells could be subdivided into Flk1?CAR? cells and Flk1?CAR? cells. The progenitor cells with cardiac potential were almost entirely restricted to Flk1?CAR? cells, and Flk1?CAR? cells efficiently differentiated into hematopoietic cells. Endothelial differentiation potential was observed in both populations. Furthermore, from the expression of CAR, Flk1, and platelet-derived growth factor receptor-? (PDGFR?), Flk1? cells could be separated into three populations (Flk1?PDGFR?? CAR? cells, Flk1?PDGFR??CAR? cells, and Flk1?PDGFR??CAR? cells). Flk1?PDGFR?? cells and Flk1?PDGFR?? cells have been reported as cardiac and hematopoietic progenitor cells, respectively. We identified a novel population (Flk1?PDGFR?? CAR? cells) with the potential to differentiate into not only hematopoietic cells and endothelial cells but also cardiomyocytes. Our findings indicate that CAR would be a novel and prominent marker for separating PSC- and embryo-derived Flk1? mesodermal cells with distinct differentiation potentials.

SUBMITTER: Tashiro K

PROVIDER: S-EPMC4414217 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Expression of coxsackievirus and adenovirus receptor separates hematopoietic and cardiac progenitor cells in fetal liver kinase 1-expressing mesoderm.

Tashiro Katsuhisa K Hirata Nobue N Okada Atsumasa A Yamaguchi Tomoko T Takayama Kazuo K Mizuguchi Hiroyuki H Kawabata Kenji K

Stem cells translational medicine 20150311 5

In developing embryos or in vitro differentiation cultures using pluripotent stem cells (PSCs), such as embryonic stem cells and induced pluripotent stem cells, fetal liver kinase 1 (Flk1)-expressing mesodermal cells are thought to be a heterogeneous population that includes hematopoietic progenitors, endothelial progenitors, and cardiac progenitors. However, information on cell surface markers for separating these progenitors in Flk1⁺ cells is currently limited. In the present study, we show th ...[more]

PMID: 25762001

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Project description:UnlabelledThe coxsackievirus and adenovirus receptor (CAR) is a cell contact protein with an important role in virus uptake. Its extracellular immunoglobulin domains mediate the binding to coxsackievirus and adenovirus as well as homophilic and heterophilic interactions between cells. The cytoplasmic tail links CAR to the cytoskeleton and intracellular signaling cascades. In the heart, CAR is crucial for embryonic development, electrophysiology, and coxsackievirus B infection. Noncardiac functions are less well understood, in part due to the lack of suitable animal models. Here, we generated a transgenic mouse that rescued the otherwise embryonic-lethal CAR knockout (KO) phenotype by expressing chicken CAR exclusively in the heart. Using this rescue model, we addressed interspecies differences in coxsackievirus uptake and noncardiac functions of CAR. Survival of the noncardiac CAR KO (ncKO) mouse indicates an essential role for CAR in the developing heart but not in other tissues. In adult animals, cardiac activity was normal, suggesting that chicken CAR can replace the physiological functions of mouse CAR in the cardiomyocyte. However, chicken CAR did not mediate virus entry in vivo, so that hearts expressing chicken instead of mouse CAR were protected from infection and myocarditis. Comparison of sequence homology and modeling of the D1 domain indicate differences between mammalian and chicken CAR that relate to the sites important for virus binding but not those involved in homodimerization. Thus, CAR-directed anticoxsackievirus therapy with only minor adverse effects in noncardiac tissue could be further improved by selectively targeting the virus-host interaction while maintaining cardiac function.ImportanceCoxsackievirus B3 (CVB3) is one of the most common human pathogens causing myocarditis. Its receptor, the coxsackievirus and adenovirus receptor (CAR), not only mediates virus uptake but also relates to cytoskeletal organization and intracellular signaling. Animals without CAR die prenatally with major cardiac malformations. In the adult heart, CAR is important for virus entry and electrical conduction, but its nonmuscle functions are largely unknown. Here, we show that chicken CAR expression exclusively in the heart can rescue the otherwise embryonic-lethal CAR knockout phenotype but does not support CVB3 infection of adult cardiomyocytes. Our findings have implications for the evolution of virus-host versus physiological interactions involving CAR and could help to improve future coxsackievirus-directed therapies inhibiting virus replication while maintaining CAR's cellular functions.

Dataset Information

Expression of coxsackievirus and adenovirus receptor separates hematopoietic and cardiac progenitor cells in fetal liver kinase 1-expressing mesoderm.

Publications

Expression of coxsackievirus and adenovirus receptor separates hematopoietic and cardiac progenitor cells in fetal liver kinase 1-expressing mesoderm.

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