Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

Sa, Silin; Gu, Mingxia; Chappell, James; Shao, Ning‐Yi; Ameen, Mohamed; Elliott, Kathryn A T; Li, Dan; Grubert, Fabian; Li, Caiyun G.; Taylor, Shalina; Cao, Aiqin; Ma, Yu; Fong, Ryan; Nguyen, Long V.; Wu, Joseph C.; Snyder, M; Rabinovitch, Marlene

doi:10.1164/rccm.201606-1200oc

Cited by 78 publications

(78 citation statements)

References 39 publications

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“…Since increased vulnerability to apoptosis is a feature of PAH PAEC 8 , we assessed the functional impact of HERV-K dUTPase on PAEC survival following serum withdrawal by the Caspase 3/7 assay. HERV-K dUTPase enhanced PAEC apoptosis following serum withdrawal (Figure 5A), as did co-culture with HERV-K dUTPase-treated monocytes (Supplemental Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

“…PAH patient and donor control PAEC 8 and PA smooth muscle cells (SMC) 9 were harvested as described previously. In some experiments, we used commercially available PAEC.…”

Section: Methodsmentioning

confidence: 99%

“…PASMC were cultured in smooth muscle cell media supplemented with 5% FBS, SMC growth supplement and gentamicin/amphotericin-B and used at passage 4–10. Induced pluripotent stem cells derived from fibroblasts and differentiated EC were generated by previously published protocols 8,10 .…”

Section: Methodsmentioning

confidence: 99%

“…PBMC were analyzed by single mass cytometry (CyTOF). PAEC were also assessed for apoptosis judged by heightened caspase activity during serum withdrawal 8 for 16 hr, when HERV-K dUTPase was added. PASMC were assessed for proliferation (MTT cell proliferation assay) in response to HERV-K dUTPase for 48 hr.…”

Section: Methodsmentioning

confidence: 99%

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Upregulation of Human Endogenous Retrovirus-K Is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension

Saito¹,

Miyagawa²,

Chen³

et al. 2017

Circulation

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Background Immune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue and elevated cytokines have been related to PAH pathogenesis but without clear understanding of how these abnormalities are initiated, perpetuated and connected in the progression of disease. We therefore set out to identify specific target antigens in PAH lung immune complexes as a starting point toward resolving these issues to better inform future application of immunomodulatory therapies. Methods Lung immune complexes were isolated and PAH target antigens were identified by liquid chromatography tandem mass spectrometry (LCMS), confirmed by ELISA, and localized by confocal microscopy. One PAH antigen linked to immunity and inflammation was pursued and a link to PAH pathophysiology was investigated by next generation sequencing, functional studies in cultured monocytes and endothelial cells (EC) and hemodynamic and lung studies in a rat. Results SAM domain and HD1 domain-containing protein (SAMHD1), an innate immune factor that suppresses HIV replication was identified and confirmed as highly expressed in immune complexes from 16 hereditary and idiopathic PAH vs. 12 control lungs. Elevated SAMHD1 was localized to endothelial cells (EC), perivascular dendritic cells and macrophages and SAMHD1 antibodies were prevalent in tertiary lymphoid tissue. An unbiased screen using metagenomic sequencing related SAMHD1 to increased expression of human endogenous retrovirus K (HERV-K) in PAH vs. control lungs (n=4 each). HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) mRNAs were elevated in PAH vs. control lungs (n=10) and proteins were localized to macrophages. HERV-K dUTPase induced SAMHD1 and pro-inflammatory cytokines (e.g., IL6, IL1β and TNFα) in circulating monocytes and pulmonary arterial (PA) EC, and activated B cells. Vulnerability of PAEC to apoptosis was increased by HERV-K dUTPase in an IL6 independent manner. Furthermore, three weekly injections of HERV-K dUTPase induced hemodynamic and vascular changes of pulmonary hypertension in rats (n=8), and elevated IL6. Conclusions Our study reveals that upregulation of the endogenous retrovirus HERV-K could both initiate and sustain activation of the immune system and cause vascular changes associated with PAH.

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Section: Resultsmentioning

confidence: 99%

“…PAH patient and donor control PAEC 8 and PA smooth muscle cells (SMC) 9 were harvested as described previously. In some experiments, we used commercially available PAEC.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Upregulation of Human Endogenous Retrovirus-K Is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension

Saito¹,

Miyagawa²,

Chen³

et al. 2017

Circulation

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“…biology during disease progression and in response to treatment [50,51]. The use of induced pluripotent stem cell (iPSCs) to derive endothelial or smooth muscle cells from PAH patient could represent an alternative and a path to move PAH treatment into personalised medicine [52,53].…”

Section: How Could Precision Medicine Add To Current Pah/ph Management?mentioning

confidence: 99%

Precision medicine and personalising therapy in pulmonary hypertension: seeing the light from the dawn of a new era

et al. 2018

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Pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) include different cardiopulmonary disorders in which the interaction of multiple genes with environmental and behavioural factors modulates the onset and the progression of these severe conditions. Although the development of therapeutic agents that modulate abnormalities in three major pathobiological pathways for PAH has revolutionised our approach to the treatment of PAH, the long-term survival rate remains unsatisfactory. Accumulating evidence has underlined that clinical outcomes and responses to therapy in PAH are modified by multiple factors, including genetic variations, which will be different for each individual. Since precision medicine, also known as stratified medicine or personalised medicine, aims to better target intervention to the individual while maximising benefit and minimising harm, it has significant potential advantages. This article aims to assemble and discuss the different initiatives that are currently underway in the PH/PAH fields together with the opportunities and prospects for their use in the near future.

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Advanced In Vitro Lung Models for Drug and Toxicity Screening: The Promising Role of Induced Pluripotent Stem Cells

Moreira¹,

Müller

Costa³

et al. 2021

Advanced Biology

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Respiratory diseases are among the global leading causes of morbidity and mortality. Acute conditions arising from infection, such as pneumonia and tuberculosis, affect millions of people worldwide, the latter being the most common lethal infectious disease with 1.4 million annual deaths. [1] Upon infection, the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which caused a worldwide pandemic, leads to the clinical picture of the coronavirus disease-2019 (COVID-19) with possibly severe and life-threatening progression. Lung cancer is the most frequently diagnosed malignancy and the main cause of cancer-related death, [2] with markedly low survival rates especially when the diagnosis is performed at an advanced state of the disease. [3] Moreover, chronic respiratory diseases (CRDs), including chronic obstructive pulmonary disease (COPD), asthma, and interstitial lung disease (ILD), have consistently received less attention in comparison to other non-communicable diseases, continuing to exert a considerable socioeconomic impact. [4,5] Risk factors for the development of respiratory diseases include, for example, tobacco use and second-hand smoke, as well as exposure to air-pollutants, which has been accentuated with the widespread use of fossil fuels. [4] It is clear that a great number of these risks can be mitigated by lifestyle changes, promoted by anti-tobacco campaigns already in place at a global scale and by the use of renewable, clean energy sources, and two recent studies indicate that the age-standardized incidence and prevalence of CRDs has decreased from 1990 to 2017. [4,5] However, the risk of developing CRDs, particularly COPD, appears to increase steeply with age; [4,5] most strikingly, these diseases were the third leading cause of death in 2017 [4] and potentially in 2020. [6] In addition to microbial, environmental, and lifestyle-related factors, a large number of lung diseases have a genetic origin. [7] Cystic fibrosis (CF), for example, is an incurable hereditary disorder known to originate from different mutations in the gene coding for the CF transmembrane conductance regulator (CFTR), an ion transporter, resulting in severe alterations in pulmonary physiology that culminate in impaired lung function, respiratory distress and, ultimately, death. [8,9]

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Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

Cited by 78 publications

References 39 publications

Upregulation of Human Endogenous Retrovirus-K Is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension

Upregulation of Human Endogenous Retrovirus-K Is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension

Precision medicine and personalising therapy in pulmonary hypertension: seeing the light from the dawn of a new era

Advanced In Vitro Lung Models for Drug and Toxicity Screening: The Promising Role of Induced Pluripotent Stem Cells

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