Platelet and myeloid cell phenotypes in a rat model of Fabry disease. FASEB J 2021 Aug;35(8):e21818
Date
07/29/2021Pubmed ID
34320241Pubmed Central ID
PMC8341388DOI
10.1096/fj.202001727RRScopus ID
2-s2.0-85111530832 (requires institutional sign-in at Scopus site)Abstract
Fabry disease results from a deficiency of the lysosomal enzyme ⍺-Galactosidase-A (⍺-Gal A) and is estimated to occur in approximately 1:4100 live births. Characteristic of the disease is the accumulation of α-Gal-A substrates, primarily the glycosphingolipids (GSLs) globotriaosylceramide and globotriaosylsphingosine. Thrombotic events are a significant concern for Fabry patients, with strokes contributing to a significant decrease in overall lifespan. Currently, the mechanisms underlying the increased risk of thrombotic events experienced by Fabry patients are incompletely defined. Using a rat model of Fabry disease, we provide an improved understanding of the mechanisms linking GSL accumulation to thrombotic risk. We found that ⍺-Gal A-deficient rats accumulate myeloid-derived leukocytes at sites of GSL accumulation, including in the bone marrow and circulation, and that myeloid-derived leukocyte and megakaryocyte populations were prominent among cell types that accumulated GSLs. In the circulation, ⍺-Gal A-deficient rats had increases in cytokine-producing cell types and a corresponding elevation of pro-inflammatory cytokines. Lastly, circulating platelets from ⍺-Gal A-deficient rats accumulated a similar set of ⍺-Galactosidase-A substrates as was observed in megakaryocytes in the bone marrow, and exhibited increased platelet binding to fibrinogen in microfluidic and flow cytometric assays.
Author List
Kanack AJ, Aoki K, Tiemeyer M, Dahms NMAuthors
Kazuhiro Aoki PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinNancy M. Dahms PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBlood Platelets
Bone Marrow
CRISPR-Cas Systems
Fabry Disease
Female
Leukocytes
Male
Megakaryocytes
Myeloid Cells
Platelet Activation
Platelet Aggregation
Rats
alpha-Galactosidase
