Dipti Tripathi

All Publications

• Multiscale profiling of tyrosine kinase inhibitor cardiotoxicity reveals mechanosensitive ion channel PIEZO1 as cardioprotective. Science translational medicine Manhas, A., Liu, Y., Noishiki, C., Wu, D., Tripathi, D., Mirza, S., Thomas, D., Liu, L., Guha, A., Nguyen, P. K., Chen, I. Y., Chitalia, V., Cheng, P., Sayed, D., Telli, M. L., Sallam, K., Wu, J. C., Sayed, N. 2025; 17 (829): eadv9403

  Abstract

  Tyrosine kinase inhibitors (TKIs) have improved cancer outcomes but are limited by cardiovascular toxicity, most notably hypertension and heart failure. The underlying mechanisms remain poorly understood, hindering the development of protective strategies. Here, we investigated the role of endothelial mechanotransduction in mediating vascular and cardiac injury caused by the vascular endothelial growth factor receptor-targeting TKI sunitinib. Using patient-specific induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) and a mouse model of TKI-induced hypertension, we identified down-regulation of piezo-type mechanosensitive ion channel component 1 (PIEZO1), a mechanically activated ion channel, as a driver of endothelial dysfunction. Restoring PIEZO1 expression, either pharmacologically with Yoda1, a selective agonist, or through inducible overexpression in iPSC-ECs, reversed sunitinib-induced endothelial dysfunction and mitigated its hypertensive effects, providing both mechanistic and genetic validation of PIEZO1's protective role against vascular toxicity. In mice, cotreatment with sunitinib and Yoda1 prevented the long-term cardiac dysfunction observed after sunitinib exposure and normalized elevations in circulating cardiac stress biomarkers. Single-nucleus multiomic profiling of mouse hearts revealed that sunitinib exposure activated chromatin remodeling and fibrogenic programs, which were reversed with PIEZO1 activation. Human engineered cardiac organoids further demonstrated that sunitinib impaired cardiomyocyte function only in the presence of endothelial cells, confirming a role for disrupted endothelial-cardiomyocyte cross-talk in TKI cardiotoxicity. Together, these findings identify endothelial PIEZO1 as a mediator of TKI-induced hypertension and cardiac dysfunction and highlight PIEZO1 activation as a potential therapeutic strategy for protecting cardiovascular health during cancer therapy.

  View details for DOI 10.1126/scitranslmed.adv9403

  View details for PubMedID 41406242

• Generation of an induced pluripotent stem cell line from a patient with Varicose veins. Stem cell research Noishiki, C., Manhas, A., Adkar, S. S., Tripathi, D., Wu, D., Sadat, S., Liu, L., Sallam, K., Leeper, N. J., Fukaya, E., Sayed, N. 2025; 89: 103850

  Abstract

  Chronic venous disease is among the most common vascular diseases globally. Varicose veins (VV), characterized by permanent dilation, elongation, and tortuosity of superficial veins, is a manifestation of chronic venous disease. Here, we generated an induced pluripotent stem cell (iPSC) line from PBMCs obtained from a patient with VV. The iPSC line exhibited typical morphology, maintained undifferentiated hPSC state markers, demonstrated a normal karyotype, and successfully differentiated into all three germ layers. This iPSC line provides a valuable platform to model VV pathogenesis and investigate the molecular mechanisms underlying venous dysfunction.

  View details for DOI 10.1016/j.scr.2025.103850

  View details for PubMedID 41075513

• Generation of an induced pluripotent stem cell line from a malignant melanoma patient who developed the immune checkpoint inhibitor-related myasthenia gravis, myositis, and myocarditis overlap syndrome. Stem cell research Huynh, D. T., Noishiki, C., Lai, J., Yarahmadi, P., Le, T., Tripathi, D., Tacco, I. R., Manhas, A., Sallam, K., Chen, I. Y., Sayed, N., Nguyen, P. K. 2025; 87: 103797

  Abstract

  Immune checkpoint inhibitors (ICI) are a pivotal class of immuno-oncology therapeutics that have improved survival rates for patients with cancer. Their widespread usage, however, is limited due to the development of serious and potentially deadly ICI-related side effects. To develop novel diagnostic and therapeutic strategies to identify and treat patients at risk, we need a better understanding of the underlying mechanisms mediating these potentially deadly side effects. To reach this goal, we have generated and validated induced pluripotent stem cells from the peripheral blood mononuclear cells of a melanoma patient who developed ICI-related myasthenia gravis, myositis, and myocarditis overlap syndrome.

  View details for DOI 10.1016/j.scr.2025.103797

  View details for PubMedID 40795579

• Exploration of Underlying Mechanisms of Vascular Ehlers-Danlos Syndrome in Patients' iPSCs-Derived Endothelial Cells Liu, L., Wu, D., Bharucha, N., Turbes, N., Noishiki, C., Manhas, A., Tripathi, D., Adkar, S., Lee, J., Fukaya, E., Leeper, N., Karakikes, I., Sayed, N. LIPPINCOTT WILLIAMS & WILKINS. 2025

  View details for DOI 10.1161/res.137.suppl_1.Thu041

  View details for Web of Science ID 001597428500003

• Plasma Proteomics of the Fontan Circulation Reveal Signatures of Oxidative Stress and Cell Death. Circulation. Heart failure Lecointe, J., Gan, S., Tripathi, D., Ichimura, S., Clouthier, K. L., Kushwaha, A., Mercer-Rosa, L., Reddy, S. 2025: e012136

  Abstract

  Single ventricle congenital heart disease like hypoplastic left heart syndrome with a Fontan circulation constitutes, the largest group of children hospitalized with circulation failure, experiencing an in-hospital mortality rate of 20% to 50%. We investigated the mechanisms leading to Fontan failure to identify novel therapeutic targets.Blood was collected from patients with hypoplastic left heart syndrome post-Fontan and controls (n=6/group). Plasma microvesicles were isolated, and proteomics assessed using data-independent acquisition mass spectroscopy. Dysregulated proteins with a fold change >1.5 or ≤1.5, P<0.05, were evaluated using DAVID and Ingenuity pathway analysis. Correlation of highly dysregulated proteins was assessed with New York Heart Association class, right ventricular fractional area change, oxygen saturation, and hemoglobin.The age of Fontan patients versus controls was 16.0±2.1 versus 15.3±2.2. Three of six Fontan patients were in New York Heart Association class II, and 3 of 6 were in New York Heart Association III/IV; 4 of 6 had Fontan-associated liver disease. Overall, 72 proteins were upregulated, and 187 proteins were downregulated in Fontan failure. Proteins upregulated in Fontan failure predicted cell death pathways (Solute carrier family 2, Angiotensinogen, CD14) and mitochondrial reactive oxygen species signaling (ATP5F1A, S100A8); downregulated proteins predicted impaired cell survival (tyrosine-protein kinase, endothelial growth factors) and mitochondrial antioxidant enzymes (GPX1, PRDX5) Increasing expression of the following proteins was associated with worsening New York Heart Association class, ventricular function and cyanosis: complement system (C1QA, r=0.91), mitochondrial reactive oxygen species generation (HSPD1, r=0.81; ATP5F1A, r=0.75), and cytoskeletal proteins (ANK1, r=0.63; ACTN1, r=0.76).Proteins from circulating microvesicles from patients with hypoplastic left heart syndrome post-Fontan are mostly from the liver. While this pilot study is limited by its sample size and may not represent the broader Fontan population, the proteomic changes were associated with worsening heart failure and cyanosis, suggesting their potential utility as biomarkers.

  View details for DOI 10.1161/CIRCHEARTFAILURE.124.012136

  View details for PubMedID 40235440

• Generation of induced pluripotent stem cell line from a patient with long COVID. Stem cell research Wu, D., Manhas, A., Noishiki, C., Tripathi, D., Liu, L., Turbes, N., Thomas, D., Sallam, K., Lee, J. T., Sayed, N. 2025; 83: 103652

  Abstract

  Long COVID, or post-acute sequelae of SARS-CoV-2 infection, leads to vascular dysfunction, which contributes to the chronic multi-organ damage often seen in affected patients. Long COVID, a global health concern is associated with increased thrombotic risk, also known as COVID-19-associated coagulopathy (CAC). Here, we derived an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells (PBMCs) of a long COVID patient. This iPSC line showed normal morphology, maintained pluripotency, had a stable karyotype, and demonstrated the ability to differentiate into the three germ layers (ectoderm, endoderm, and mesoderm). This line provides a valuable tool for modeling long COVID and exploring mechanisms underlying multi-organ dysfunction.

  View details for DOI 10.1016/j.scr.2025.103652

  View details for PubMedID 39823918

• CCL2-mediated endothelial injury drives cardiac dysfunction in long COVID. Nature cardiovascular research Thomas, D., Noishiki, C., Gaddam, S., Wu, D., Manhas, A., Liu, Y., Tripathi, D., Kathale, N., Adkar, S. S., Garhyan, J., Liu, C., Xu, B., Ross, E. G., Dalman, R. L., Wang, K. C., Oro, A. E., Sallam, K., Lee, J. T., Wu, J. C., Sayed, N. 2024; 3 (10): 1249-1265

  Abstract

  Evidence linking the endothelium to cardiac injury in long coronavirus disease (COVID) is well documented, but the underlying mechanisms remain unknown. Here we show that cytokines released by endothelial cells (ECs) contribute to long-COVID-associated cardiac dysfunction. Using thrombotic vascular tissues from patients with long COVID and induced pluripotent stem cell-derived ECs (iPSC-ECs), we modeled endotheliitis and observed similar dysfunction and cytokine upregulation, notably CCL2. Cardiac organoids comprising iPSC-ECs and iPSC-derived cardiomyocytes showed cardiac dysfunction after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, driven by CCL2. Profiling of chromatin accessibility and gene expression at a single-cell resolution linked CCL2 to 'phenotype switching' and cardiac dysfunction, validated by high-throughput proteomics. Disease modeling of cardiac organoids and exposure of human ACE2 transgenic mice to SARS-CoV-2 spike proteins revealed that CCL2-induced oxidative stress promoted post-translational modification of cardiac proteins, leading to cardiac dysfunction. These findings suggest that EC-released cytokines contribute to cardiac dysfunction in long COVID, highlighting the importance of early vascular health monitoring in patients with long COVID.

  View details for DOI 10.1038/s44161-024-00543-8

  View details for PubMedID 39402206

  View details for PubMedCentralID 7899720

• Cardiovascular Toxicity in Cancer Therapy: Protecting the Heart while Combating Cancer. Current cardiology reports Manhas, A., Tripathi, D., Thomas, D., Sayed, N. 2024

  Abstract

  This review explores the cardiovascular toxicity associated with cancer therapies, emphasizing the significance of the growing field of cardio-oncology. It aims to elucidate the mechanisms of cardiotoxicity due to radiotherapy, chemotherapy, and targeted therapies, and to discuss the advancements in human induced pluripotent stem cell technology (hiPSC) for predictive disease modeling.Recent studies have identified several chemotherapeutic agents, including anthracyclines and kinase inhibitors, that significantly increase cardiovascular risks. Advances in hiPSC technology have enabled the differentiation of these cells into cardiovascular lineages, facilitating more accurate modeling of drug-induced cardiotoxicity. Moreover, integrating hiPSCs into clinical trials holds promise for personalized cardiotoxicity assessments, potentially enhancing patient-specific therapeutic strategies. Cardio-oncology bridges oncology and cardiology to mitigate the cardiovascular side-effects of cancer treatments. Despite advancements in predictive models using hiPSCs, challenges persist in accurately replicating adult heart tissue and ensuring reproducibility. Ongoing research is essential for developing personalized therapies that balance effective cancer treatment with minimal cardiovascular harm.

  View details for DOI 10.1007/s11886-024-02099-2

  View details for PubMedID 39042344

  View details for PubMedCentralID 4829054

• Generation of two iPSC lines from dilated cardiomyopathy patients with pathogenic variants in the SCN5A gene. Stem cell research Dexheimer, R., Manhas, A., Wu, D., Tripathi, D., Yu Chan, S., Li, J., Yu, R., Sayed, N., Wu, J. C., Sallam, K. 2024; 80: 103498

  Abstract

  Dilated cardiomyopathy (DCM) is a disorder of cardiac ventricular dilation and contractile dysfunction that often progresses to heart failure. Multiple genes have been associated with DCM, including SCN5A which has been linked to 2 % of all DCM cases. Peripheral mononuclear blood cells from DCM patients with SCN5A variants (c.2440C>T and c.665G>A) were utilized to generate two human induced pluripotent stem cell (iPSC) lines. Both lines exhibited typical iPSC morphology, expressed pluripotency markers, normal karyotypes, and trilineage differentiation capabilities. These lines offer valuable resources for investigating the mechanism of SCN5A-associated DCM, facilitating studies of ion channel protein involvement in the disease.

  View details for DOI 10.1016/j.scr.2024.103498

  View details for PubMedID 39067410

• Generation of two iPSC lines from vascular Ehlers-Danlos Syndrome (vEDS) patients carrying a missense mutation in COL3A1 gene. Stem cell research Manhas, A., Tripathi, D., Noishiki, C., Wu, D., Liu, L., Sallam, K., Lee, J. T., Fukaya, E., Sayed, N. 2024; 79: 103485

  Abstract

  Vascular Ehlers-Danlos Syndrome (vEDS) is an inherited connective tissue disorder caused by COL3A1 gene, mutations that encodes type III collagen, a crucial component of blood vessels. vEDS can be life-threatening as these patients can have severe internal bleeding due to arterial rupture. Here, we generated induced pluripotent stem cell (iPSC) lines from two vEDS patients carrying a missense mutation in the COL3A1 (c.226A > G, p.Asn76Asp) gene. These lines exhibited typical iPSC characteristics including morphology, expression of pluripotency markers, and could differentiate to all three germ layer. These iPSC lines can serve as valuable tools for elucidating the pathophysiology underlying vEDS.

  View details for DOI 10.1016/j.scr.2024.103485

  View details for PubMedID 38944978

• Generation of induced pluripotent stem cell line from a patient suffering from arterial calcification due to deficiency of CD73 (ACDC). Stem cell research Tripathi, D., Manhas, A., Noishiki, C., Wu, D., Adkar, S., Sallam, K., Fukaya, E., Leeper, N. J., Sayed, N. 2023; 75: 103285

  Abstract

  Arterial calcification due to deficiency of CD73 (ACDC) is an adult onset, rare genetic vascular disorder signified by calcium deposition in lower extremity arteries and joints of hands and feet. Mutations in NT5E gene has been shown to be responsible for the inactivation of enzyme CD73 causing calcium buildup. Here, we report a iPSC line generated from a patient showing signs of ACDC and carrying a missense mutation in NT5E (c.1126AG,p.T376A) gene. This iPSC line shows normal morphology, pluripotency, karyotype, and capability to differentiate into three germ layers, making it useful for disease modeling and investigating pathological mechanisms of ACDC.

  View details for DOI 10.1016/j.scr.2023.103285

  View details for PubMedID 38199067

• iPSC model of congenital heart disease predicts disease outcome. Cell stem cell Tripathi, D., Reddy, S. 2022; 29 (5): 659-660

  Abstract

  In this issue of Cell Stem Cell, Xu etal. demonstrate that induced pluripotent stem cell-derived cardiomyocytes from patients with hypoplastic left heart syndrome exhibit mitochondrial dysfunction and can be used for disease modeling. In addition, they show the potential to predict future heart failure and develop therapies.

  View details for DOI 10.1016/j.stem.2022.04.010

  View details for PubMedID 35523134