Lu LIU

All Publications

• Generation of two homozygous iPSC lines carrying variants of uncertain significance in LMNA associated with cardiomyopathy. Stem cell research Liu, L., Wu, D., Manhas, A., Noishiki, C., Tripathi, D., Sadat, S., Bharucha, N., Karakikes, I., Sallam, K., Sayed, N. 2026; 95: 104086

  Abstract

  Variants of uncertain significance (VUS) in the LMNA gene represent a major challenge in clinical genetics, as insufficient functional evidence limits their interpretation and clinical decision-making in laminopathies, including dilated cardiomyopathy (DCM). Here, we generated two isogenic induced pluripotent stem cell (iPSC) lines carrying homozygous LMNA variants, c.293A > G (p.Glu98Gly) and c.439G > A (p.Ala147Thr) by prime editing of a healthy donor iPSC line. Both variants are located within Coil 1B domain of lamin A. The edited iPSC lines retain normal morphology, pluripotency, genomic integrity, and trilineage differentiation capacity, providing a valuable platform for functional characterization and potential clinical reclassification of LMNA VUS.

  View details for DOI 10.1016/j.scr.2026.104086

  View details for PubMedID 42648117

• RUNX1-driven endothelial-to-mesenchymal transition contributes to remodelling in LMNA cardiomyopathy. European heart journal Wu, D., Tripathi, D., Manhas, A., Noishiki, C., Liu, L., Wu, C. A., Venkateshappa, R., Zhang, H., Ren, L., Thomas, D., Nalbandian, M., Limbu, L., DaValle, C. C., Rangan, E. S., Nallamshetty, S., Boyd, J. H., Malik, S. B., Woo, Y. J., Sayed, D., Sallam, K., Blau, H. M., Wu, J. C., Sayed, N. 2026

  Abstract

  LMNA-related dilated cardiomyopathy (LMNA-DCM) is a progressive genetic disorder characterized by conduction disease, malignant arrhythmias, myocardial fibrosis, and heart failure. Although LMNA mutations have traditionally been associated with cardiomyocyte-intrinsic defects, the mechanisms driving fibrotic remodelling remain incompletely understood.Spatial transcriptomics and integrated single-nuclei multiomics were performed on explanted human LMNA-DCM hearts to define endothelial transcriptional and epigenomic states associated with fibrosis. Patient-specific induced pluripotent stem cell-derived endothelial cells, engineered cardiac organoids, and the LMNAH222P/H222P mouse model were used to investigate RUNX1-mediated endothelial-to-mesenchymal transition (EndoMT). Genetic and pharmacological RUNX1 inhibition strategies were evaluated in vitro and in vivo.Endothelial populations exhibiting EndoMT-associated transcriptional and epigenomic signatures were identified in human LMNA-DCM hearts. LMNA induced pluripotent stem cell-derived endothelial cells demonstrated endothelial dysfunction, mesenchymal gene activation, and epigenetic activation of RUNX1 following loss of LMNA-mediated repression. Genetic RUNX1 deletion restored endothelial identity, reversed EndoMT-associated transcriptional programmes, and normalized chromatin accessibility at endothelial regulatory loci. In multicellular cardiac organoids, endothelial RUNX1 activation impaired endothelial-cardiomyocyte signalling and cardiomyocyte contractile function, whereas endothelial-specific RUNX1 deletion restored endothelial and myocardial function. Pharmacological RUNX1 inhibition with Ro24-7429 similarly improved endothelial and cardiomyocyte function in vitro and reduced myocardial fibrosis while preserving cardiac function in LMNAH222P/H222P mice, including after disease onset.RUNX1-driven EndoMT represents a central mechanism linking LMNA mutations to fibrotic remodelling in LMNA cardiomyopathy. These findings support endothelial transcriptional reprogramming and RUNX1 signalling as potential therapeutic targets in fibrotic cardiomyopathy.

  View details for DOI 10.1093/eurheartj/ehag619

  View details for PubMedID 42578927

• Generation of three induced pluripotent stem cell lines from an immune checkpoint inhibitor-induced myocarditis patient and controls. Stem cell research Sun, Y., Vitale, M. R., Hnatiuk, A. P., Wagner, N. S., Sun, S., Yang, X., Liu, L., Khatua, S., Sundar, H. A., Chou, H., Huang, Y. V., Waliany, S., Zhuge, Y., Witteles, R., Mercola, M., Wu, J. C., Zhu, H. 2026; 95: 104057

  Abstract

  Immune checkpoint inhibitor-associated myocarditis (ICIM) is an uncommon but potentially fatal inflammatory heart disease triggered by cancer immunotherapy, with up to 40% mortality. The underlying mechanisms are still elusive, partly due to the lack of appropriate human disease models. Here, we report the generation of three induced pluripotent stem cell (iPSC) lines derived from an ICIM patient, an ICI-treated patient without myocarditis, and a healthy donor. These lines exhibit typical pluripotent stem cell morphology, express pluripotency markers, maintain normal karyotypes, and differentiate into derivatives of the three germ layers, providing a valuable platform for mechanistic studies and therapeutic discovery.

  View details for DOI 10.1016/j.scr.2026.104057

  View details for PubMedID 42418861

• ZNF827 pleiotropic cardiovascular risk locus involves regulation by Nuclear Factor-1 transcription factors. Clinical science (London, England : 1979) Liu, Y., Liu, L., Esmael, A., Tezza, A., London, C., Fustier, M. A., Georges, A., Bouatia-Naji, N. 2026

  Abstract

  Spontaneous coronary artery dissection (SCAD) is a form of myocardial infarction that predominantly affects middle-aged women, caused by the spontaneous onset of an intramural hematoma leading to heart ischemia. SCAD genetic risk loci is ZNF827 locus on chromosome 4 was previously associated with the risk for coronary artery disease, systolic blood pressure and ascending aortic diameter variability, but the molecular processes driving these genetic associations are unknown. In this study, we demonstrated that these genetic associations were colocalized and could all be explained by the intronic common variant rs13128814, which overlapped epigenetic regulatory markers specifically active in vascular smooth muscle cells (SMCs) and fibroblasts. Using reporter assay experiments, we found that SCAD-risk allele (rs13128814-A) was associated to increased transcriptional activity in A7r5 SMCs. In silico predictions and reporter assays suggested Nuclear factor-1 (NF1) transcription factors to preferentially bind to SCAD risk allele. We found that SCAD genetic association colocalized with a ZNF827 eQTL association in artery tissues. Knockdown of ZNF827 in human iPSC-derived SMCs and fibroblasts identified a large number of dysregulated genes enriched in relevant pathways such as macroautophagy and insulin signaling. Our findings support NF1-dependent rs13128814 effect on the expression of ZNF827 as a potential molecular mechanism underpinning multiple cardiovascular traits genetic risk locus. ZNF827 may act as a broad regulator of gene expression in vascular SMCs and fibroblasts. Further investigation using multiple cell types organoids and in vivo models may clarify the implications of ZNF827 in arterial fragility observed in SCAD and other arterial diseases.

  View details for DOI 10.1042/CS20257956

  View details for PubMedID 41983892

• Generation of an induced pluripotent stem cell line from a patient with Loeys-Dietz syndrome. Stem cell research Liu, L., Manhas, A., Noishiki, C., Wu, D., Tripathi, D., Turbes, N., Sallam, K., Lee, J. T., Sayed, N. 2026; 94: 103981

  Abstract

  Loeys-Dietz syndrome (LDS) is a rare autosomal dominant connective tissue disorder caused by pathogenic variants in genes involved in the TGF-β signaling pathway. Here, we report the generation of a human induced pluripotent stem cell (iPSC) line derived from peripheral blood mononuclear cells (PBMCs) of an LDS patient carrying a heterozygous TGFBR1 mutation (c.679G > A, p.Glu227Lys). The iPSC line exhibits normal morphology, expresses pluripotency markers, maintains chromosomal integrity, and demonstrates trilineage differentiation capacity. This patient-specific iPSC line provides a valuable platform for modeling LDS pathogenesis and investigating vascular disease mechanisms.

  View details for DOI 10.1016/j.scr.2026.103981

  View details for PubMedID 41946258

• Harnessing iPSCs, 3D organoids, and multiomics to model rare vascular diseases: Emerging new approach methodologies. Vascular medicine (London, England) Liu, L., Wu, D., Tsao, P. S., Leeper, N. J., Sayed, N. 2026: 1358863X251394285

  Abstract

  Rare vascular diseases are a diverse group of life-threatening conditions defined by their low prevalence but profound impact on patient morbidity and quality of life. Diagnosing these disorders remains a significant clinical challenge due to their genetic heterogeneity, overlapping phenotypes, and limited patient populations. As such, the development of robust and human-relevant disease models is critical for elucidating pathogenic mechanisms and guiding therapeutic discovery. The advent of human induced pluripotent stem cell (iPSC) technology has opened new avenues for modeling rare vascular diseases by enabling the generation of patient-specific vascular cell types, including endothelial cells, smooth muscle cells, and fibroblasts, and the creation of both two-dimensional cultures and three-dimensional vascular organoids. Together with genome editing and next-generation multiomics, these platforms represent new approach methodologies (NAMs) that allow for detailed investigation of disease biology, facilitate the correction of pathogenic mutations, and enable high-throughput drug screening in a personalized context. In this review, we highlight the advancements in iPSC-derived vascular modeling, discuss the integration of gene editing and multiomics technologies, and explore their transformative potential for uncovering mechanisms and developing precision therapies for rare vascular diseases.

  View details for DOI 10.1177/1358863X251394285

  View details for PubMedID 41498403

• 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 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

• 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