Multiple myeloma gammopathies

Light chain amyloidosis induced inflammatory changes in cardiomyocytes and adipose-derived mesenchymal stromal cells

Abstract

Light chain (AL) amyloidosis is a progressive, degenerative disease characterized by the misfolding and amyloid deposition of immunoglobulin light chain (LC). The amyloid deposits lead to organ failure and death. Our laboratory is specifically interested in cardiac involvement of AL amyloidosis. We have previously shown that the fibrillar aggregates of LC proteins can be cytotoxic and arrest the growth of human RFP-AC16 cardiomyocytes in vitro. We showed that adipose-derived mesenchymal stromal cells (AMSC) can rescue the cardiomyocytes from the fibril-induced growth arrest through contact-dependent mechanisms. In this study, we examined the transcriptome changes of human cardiomyocytes and AMSC in the presence of AL amyloid fibrils. The presence of fibrils causes a ‘priming’ immune response in AMSC associated with interferon associated genes. Exposure to AL fibrils induced changes in the pathways associated with immune response and extracellular matrix components in cardiomyocytes. We also observed upregulation of innate immune-associated transcripts (chemokines, cytokines, and complement), suggesting that amyloid fibrils initiate an innate immune response on these cells, possibly due to phenotypic transformation. This study corroborates and expands our previous studies and identifies potential new immunologic mechanisms of action for fibril toxicity on human cardiomyocytes and AMSC rescue effect on cardiomyocytes.

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Fig. 1: AMSC cultured with Wil fibrils shows an immune-based priming response.
Fig. 2: Principal component analysis of RFP-AC16 cultures shows differential clustering separation from COCX with AMSC with and without Wil fibrils.
Fig. 3: RFP-AC16 cultured with Wil Fibrils shows upregulation of immune-related genes.
Fig. 4: Addition of AMSC for AC16 COCX Wil show differential changes in immune and metabolic pathways.

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Acknowledgements

We thank the staff of the Medical Genome Facility Expression Core for carrying out the RNAseq analysis and the staff of the Flow Cytometry Core for their assistance. We also thank Michael Bergman, Shawna Cooper, Christopher Parks, and Christopher Paradise for their contributions to this project. TLJ is a graduate student at Mayo Clinic Graduate School of Biomedical Sciences. This work is submitted in partial fulfillment of the requirement for the PhD program. This study was supported in part by NIH R01 GM 128253, the Mayo Foundation, and the generous support of amyloidosis patients and their families.

Author information

TLJ, MRA and YL designed experiments, analyzed results, and wrote the manuscript. TLJ, KM, PM, CJD, LBM, KRR, AW, conducted experiments AvW analyzed data and wrote the manuscript JSW analyzed data and wrote the manuscript

Correspondence to Yi Lin or Marina Ramirez-Alvarado.

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Jordan, T.L., Maar, K., Redhage, K.R. et al. Light chain amyloidosis induced inflammatory changes in cardiomyocytes and adipose-derived mesenchymal stromal cells. Leukemia (2019). https://doi.org/10.1038/s41375-019-0640-4

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