DJ, Majka SM. ABCG2 pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling.

May 28, 2014; doi:10.1152/ajpcell.00057.2014.-Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by use of nonadherent cells, which are not ideal to model vascular cells in vivo. These studies addressed the hypothesis that pathological processes associated with PAH may be identified via a genetic signature common across multiple cell types. Expression array experiments were initially conducted to analyze cell types at different stages of vascular differentiation (mesenchymal stromal and endothelial) derived from PAH patient-specific induced pluripotent stem (iPS) cells. Molecular pathways that were altered in the PAH cell lines were then compared with those in fibroblasts from 21 patients, including those with idiopathic and heritable PAH. Wnt was identified as a target pathway and was validated in vitro using primary patient mesenchymal and endothelial cells. Taken together, our data suggest that the molecular lesions that cause PAH are present in all cell types evaluated, regardless of origin, and that stimulation of the Wnt signaling pathway was a common molecular defect in both heritable and idiopathic PAH. pulmonary arterial hypertension; gene array; induced pluripotent stem cell; mesenchymal stromal cell; endothelial cell; heritable pulmonary arterial hypertension; idiopathic pulmonary arterial hypertension; Wnt signaling PULMONARY ARTERIAL HYPERTENSION (PAH) is characterized by vascular remodeling, including endothelial cell (EC) dysfunction and occlusion or rarefaction of the peripheral pulmonary microvasculature. More recently, the contribution of multipotent mesenchymal stromal cells (MSC) to muscularization of microvessels has been described (13). The interactions between the lung microenvironment, vascular EC, and MSC during remodeling in PAH remain unclear. All forms of PAH have a high mortality rate, despite current therapeutic options.Deregulated bone morphogenetic protein (BMP) receptor type II (BMPR2) signaling is strongly associated with the development of PAH in both heritable (BMPR2 mut and Cav1 mut ) and idiopathic cases, although the molecular mechanisms through which BMPR2 derangement promotes PAH are unknown. Unfortunately, most rodent models of PAH do not precisely recapitulate the disease pathology; these models display less substantial pulmonary vascular remodeling in both proximal arteries and distal microvasculature, significantly slowing drug discovery efforts. Current in vitro models overexpressing mutant BMPR2 in cell types of interest are complicated by persistent retention of wild-type (WT) signaling. Moreover, human PAH tissue is limited in quantity, and specimens are typically obtained posttransplant or at autopsy, which limits conclusions about disease initiation and propagation. Previous global gene expression analyses using patient samples to identify risk factors for PAH have ...

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BackgroundVascular elasticity is crucial for maintaining hemodynamics. Molecular mechanisms involved in human elastogenesis are incompletely understood. We describe a syndrome of lethal arteriopathy associated with a novel, identical mutation in the fibulin 4 gene (FBLN4) in a unique cohort of infants from South India.MethodsClinical characteristics, cardiovascular findings, outcomes and molecular genetics of twenty-two infants from a distinct population subgroup, presenting with characteristic arterial dilatation and tortuosity during the period August 2004 to June 2011 were studied.ResultsPatients (11 males, 11 females) presented at median age of 1.5 months, belonging to unrelated families from identical ethno-geographical background; eight had a history of consanguinity. Cardiovascular features included aneurysmal dilatation, elongation, tortuosity and narrowing of the aorta, pulmonary artery and their branches. The phenotype included a variable combination of cutis laxa (52%), long philtrum-thin vermillion (90%), micrognathia (43%), hypertelorism (57%), prominent eyes (43%), sagging cheeks (43%), long slender digits (48%), and visible arterial pulsations (38%). Genetic studies revealed an identical c.608A > C (p. Asp203Ala) mutation in exon 7 of the FBLN4 gene in all 22 patients, homozygous in 21, and compound heterozygous in one patient with a p. Arg227Cys mutation in the same conserved cbEGF sequence. Homozygosity was lethal (17/21 died, median age 4 months). Isthmic hypoplasia (n = 9) correlated with early death (≤4 months).ConclusionsA lethal, genetic disorder characterized by severe deformation of elastic arteries, was linked to novel mutations in the FBLN4 gene. While describing a hitherto unreported syndrome in this population subgroup, this study emphasizes the critical role of fibulin-4 in human elastogenesis.

The majority of pulmonary arterial hypertension (PAH) is not associated with BMPR2 mutation, and major risk factors for idiopathic PAH are not known. The objective of this study was to identify a gene expression signature for IPAH. To accomplish this, we used Affymetrix arrays to probe expression levels in 86 patient samples, including 22 healthy controls, 20 IPAH patients, 20 heritable PAH patients (HPAH), and 24 BMPR2 mutation carriers that were as yet unaffected (UMC). Culturing the patient cells removes the signatures of drug effects and inflammation which have made interpretation of results from freshly isolated lymphocytes problematic. We found that gene expression signatures from IPAH patients clustered either with HPAH patients or in a single distinct group. There were no groups of genes changed in IPAH that were not also changed in HPAH. HPAH, IPAH, and UMC had common changes in metabolism, actin dynamics, adhesion, cytokines, metabolism, channels, differentiation, and transcription factors. Common to IPAH and HPAH but not UMC were an upregulation of vesicle trafficking, oxidative/nitrosative stress, and cell cycle genes. The transcription factor MSX1, which is known to regulate BMP signaling, was the most upregulated gene (4×) in IPAH patients. These results suggest that IPAH cases have a shared molecular origin, which is closely related to, but distinct from, HPAH. HPAH and IPAH share the majority of altered signaling pathways, suggesting that treatments developed to target the molecular etiology of HPAH will also be effective against IPAH.