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Haematologica 2020 Volume 105(8):2174-2186
Blood Transfusion
Red blood cell metabolism in Rhesus macaques and humans: comparative biology of blood storage
Davide Stefanoni,1 Hye Kyung H. Shin,2 Jin Hyen Baek,2 Devin P. Champagne,1 Travis Nemkov,1 Tiffany Thomas,3 Richard O. Francis,3 James C. Zimring,4 Tatsuro Yoshida,5 Julie A. Reisz,1 Steven L. Spitalnik,3 Paul W. Buehler2 and Angelo D’Alessandro1,6
1Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO; 2Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD; 3Department of Pathology & Cell Biology, Columbia University, New York, NY; 4BloodWorks Northwest, Seattle, WA; 5Hemanext Inc, Lexington, MA and 6Department of Medicine, Division of Hematology, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO, USA
ABSTRACT
Macaques are emerging as a critical animal model in transfusion medicine, because of their evolutionary similarity to humans and perceived utility in discovery and translational science. However, little is known about the metabolism of Rhesus macaque red blood cells (RBC) and how this compares to human RBC metabolism under standard blood banking conditions. Metabolomic and lipidomic analyses, and tracing experiments with [1,2,3-13C3]glucose, were per- formed using fresh and stored RBC (sampled weekly until storage day 42) obtained from Rhesus macaques (n=20) and healthy human volun- teers (n=21). These results were further validated with targeted quantifi- cation against stable isotope-labeled internal standards. Metabolomic analyses demonstrated inter-species differences in RBC metabolism inde- pendent of refrigerated storage. Although similar trends were observed throughout storage for several metabolic pathways, species- and sex-spe- cific differences were also observed. The most notable differences were in glutathione and sulfur metabolites, purine and lipid oxidation metabo- lites, acylcarnitines, fatty acyl composition of several classes of lipids (including phosphatidylserines), glyoxylate pathway intermediates, and arginine and carboxylic acid metabolites. Species-specific dietary and environmental compounds were also detected. Overall, the results sug- gest an increased basal and refrigerator-storage-induced propensity for oxidant stress and lipid remodeling in Rhesus macaque RBC cells, as compared to human red cells. The overlap between Rhesus macaque and human RBC metabolic phenotypes suggests the potential utility of a translational model for simple RBC transfusions, although inter-species storage-dependent differences need to be considered when modeling complex disease states, such as transfusion in trauma/hemorrhagic shock models.
Introduction
Rhesus macaques (Macaca mulatta, hereafter RM) are one of the most thoroughly studied non-human primates, in part because of their broad geographic distribution, reaching from Afghanistan and India, and across to China. In addition, RM evolu- tionarily diverged from human ancestors ~25 million years ago (by comparison, rodents and human ancestors diverged ~70 million years ago). Indeed, macaques share an average sequence identity of ~93% with Homo sapiens1 and preclinical mod- els often rely on macaques to investigate mechanisms and test interventions in the context of leading causes of human disease, including trauma/hemorrhagic shock,2 human immunodeficiency virus,3 cancer, and cardiovascular disease.4 For example,
Correspondence:
ANGELO D’ALESSANDRO
angelo.dalessandro@ucdenver.edu
PAUL W. BUEHLER,
Paul.Buehler@fda.hhs.gov
Received: June 19, 2019. Accepted: October 10, 2019. Pre-published: November 7, 2019.
doi:10.3324/haematol.2019.229930
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/8/2174
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