Mapping cellular response to destabilized transthyretin reveals cell- and amyloidogenic protein-specific signatures

Ghosh, Sabrina; Villacorta‐Martin, Carlos; Lindstrom-Vautrin, Jonathan; Kenney, Devin; Golden, Carly S.; Edwards, Camille V; Sanchorawala, Vaishali; Connors, Lawreen H.; Giadone, Richard M.; Murphy, George J.

doi:10.1080/13506129.2023.2224494

Cited by 2 publications

(4 citation statements)

References 43 publications

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“…Our group previously examined transcriptomic changes occurring in AC16 human ventricular cardiomyocyte cells exposed to a cardiomyopathy-associated κAL LC as described above from the Boston University Amyloidosis Center and amyloidogenic transthyretin (TTR) proteins [37]. Here, we performed a post-hoc functional gene set enrichment analysis (fgsea) to evaluate hallmark pathways enriched upon exposure of AC16 cells to a cardiomyopathy-associated κAL LC.…”

Section: Resultsmentioning

confidence: 99%

“…Gene expression and pathway analyses were performed using data from Ghosh et al 2022. [37] Functional predictions were made using the Enrichr gene set enrichment analysis web server [43–45] cross-referenced with the Gene Ontology Biological Process database [http://geneontology.org/]. The current version of the Broad Institute Connectivity Map [CMap] [46] was used to query the gene expression signature derived from bulk RNA sequencing on AC16 ventricular cardiomyocytes exposed to the cardiomyopathy-associated κAL LC.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we characterized neuronal SH-SY5Y and cardiac AC16 cells to an amyloidogenic, cardiomyopathy-associated kappa 1 LC (cardiomyopathy-associated κAL LC) as compared to amyloidogenic transthyretin (TTR) via RNA sequencing (RNAseq). [37] In doing so, we demonstrated that AC16 cells exposed to cardiomyopathy-associated κAL LC displayed a significantly higher number of differentially expressed genes than AC16 cells exposed to non-AL amyloidogenic proteins with no significant overlap in differentially regulated genes between study groups. [37] Herein, we used human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to validate the gene expression changes of clinically relevant genes in cardiac dysfunction-related pathways that are differentially activated upon exposure to a cardiomyopathy-associated κAL LC.…”

Section: Introductionmentioning

confidence: 95%

“…[37] In doing so, we demonstrated that AC16 cells exposed to cardiomyopathy-associated κAL LC displayed a significantly higher number of differentially expressed genes than AC16 cells exposed to non-AL amyloidogenic proteins with no significant overlap in differentially regulated genes between study groups. [37] Herein, we used human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to validate the gene expression changes of clinically relevant genes in cardiac dysfunction-related pathways that are differentially activated upon exposure to a cardiomyopathy-associated κAL LC. We then used this data to guide subsequent interrogation of our clinical dataset for measurable parameters that reflect gene expression changes observed in these cardiac dysfunction-related pathways.…”

Section: Introductionmentioning

confidence: 99%

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Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition

Edwards,

Ferri,

Villegas-Galaviz

et al. 2024

Preprint

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Background: Cardiac dysfunction in AL amyloidosis is thought to be partly related to the direct impact of AL LCs on cardiomyocyte function, with the degree of dysfunction at diagnosis as a major determinant of clinical outcomes. Nonetheless, mechanisms underlying LC-induced myocardial toxicity are not well understood. We identified gene expression changes correlating with human cardiac cells exposed to a cardiomyopathy-associated κAL LC. We then sought to confirm these findings in a clinical dataset by focusing on clinical parameters associated with the pathways dysregulated at the gene expression level. Upon exposure to a cardiomyopathy-associated κAL LC, cardiac cells exhibited gene expression changes related to myocardial contractile function and inflammation, leading us to hypothesize that there could be clinically detectable changes in GLS on echocardiogram and serum inflammatory markers in patients. Thus, we identified 29 patients with normal IVSd but abnormal cardiac biomarkers suggestive of LC-induced cardiac dysfunction. These patients display early cardiac biomarker staging, abnormal GLS, and significantly reduced serum inflammatory markers compared to patients with clinically evident amyloid fibril deposition. Collectively, our findings highlight early molecular and functional signatures of cardiac AL amyloidosis, with potential impact for developing improved patient biomarkers and novel therapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition

Edwards,

Ferri,

Villegas-Galaviz

et al. 2024

Preprint

Self Cite

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A longevity‐specific bank of induced pluripotent stem cells from centenarians and their offspring

Dowrey,

Cranston,

Skvir

et al. 2024

Aging Cell

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Centenarians provide a unique lens through which to study longevity, healthy aging, and resiliency. Moreover, models of human aging and resilience to disease that allow for the testing of potential interventions are virtually non‐existent. We obtained and characterized over 96 centenarian and offspring peripheral blood samples including those connected to functional independence data highlighting resistance to disability and cognitive impairment. Targeted methylation arrays were used in molecular aging clocks to compare and contrast differences between biological and chronological age in these specialized subjects. Isolated peripheral blood mononuclear cells (PBMCs) from 20 of these subjects were then successfully reprogrammed into high‐quality induced pluripotent stem cell (iPSC) lines which were functionally characterized for pluripotency, genomic stability, and the ability to undergo directed differentiation. The result of this work is a one‐of‐a‐kind resource for studies of human longevity and resilience that can fuel the discovery and validation of novel therapeutics for aging‐related disease.

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Mapping cellular response to destabilized transthyretin reveals cell- and amyloidogenic protein-specific signatures

Cited by 2 publications

References 43 publications

Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition

Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition

A longevity‐specific bank of induced pluripotent stem cells from centenarians and their offspring

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