Red blood cell metabolism in Rhesus macaques and humans: comparative biology of blood storage
Davide Stefanoni,
Hye Kyung H. Shin,
Jin Hyen Baek,
Devin P. Champagne,
Travis Nemkov,
Tiffany Thomas,
Richard O. Francis,
James C. Zimring,
Tatsuro Yoshida,
Julie A. Reisz,
Steven L. Spitalnik,
Paul W. Buehler,
Angelo D’Alessandro
Affiliations
Davide Stefanoni
Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO
Hye Kyung H. Shin
Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD
Jin Hyen Baek
Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD
Devin P. Champagne
Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO
Travis Nemkov
Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO
Tiffany Thomas
Department of Pathology & Cell Biology, Columbia University, New York, NY
Richard O. Francis
Department of Pathology & Cell Biology, Columbia University, New York, NY
James C. Zimring
BloodWorks Northwest, Seattle, WA
Tatsuro Yoshida
Hemanext Inc, Lexington, MA
Julie A. Reisz
Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO
Steven L. Spitalnik
Department of Pathology & Cell Biology, Columbia University, New York, NY
Paul W. Buehler
Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD
Angelo D’Alessandro
Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO;Department of Medicine, Division of Hematology, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO, USA
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 performed using fresh and stored RBC (sampled weekly until storage day 42) obtained from Rhesus macaques (n=20) and healthy human volunteers (n=21). These results were further validated with targeted quantification against stable isotope-labeled internal standards. Metabolomic analyses demonstrated inter-species differences in RBC metabolism independent of refrigerated storage. Although similar trends were observed throughout storage for several metabolic pathways, species- and sex-specific differences were also observed. The most notable differences were in glutathione and sulfur metabolites, purine and lipid oxidation metabolites, 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 suggest 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.
