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Red Blood Cell Ageing in Vivo and in Vitro: the Integrated Omics Perspective

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Red Blood Cell Ageing in Vivo and in Vitro: the Integrated Omics Perspective UNIVERSITA’ DEGLI STUDI DELLA TUSCIA DI VITERBO DIPARTIMENTO DI SCIENZE ECOLOGICHE E BIOLOGICHE DOTTORATO DI RICERCA IN GENETICA E BIOLOGIA CELLULARE XXV CICLO Red blood cell ageing in vivo and in vitro: the Integrated omics perspective Settore scientific disciplinare: BIO/11 Candidato Coordinatore del corso Tutor Angelo D’Alessandro Prof. Giorgio Prantera Prof. Lello Zolla “We are only what we know, and I wished to be so much more than I was, sorely.” David Mitchell I would like to dedicate this thesis to my friends and colleagues. I could not ever be able to even scratch the surface of red blood cell biology without the invaluable contribution and the team work of my friends and colleagues, Barbara Blasi, Federica Gevi, Gian Maria D’Amici, Maria Giulia Egidi, Valentina Longo, Cristina Marrocco, Cristiana Mirasole, Leonardo Murgiano Valeria Pallotta, Sara Rinalducci, Anna Maria Timperio, Valerio Zolla (strictly in alphabetical order!!!). I love you, nakamas! With you I shared my hopes and my despair, my will and desires. Wish you all the best! I would also like to dedicate this thesis to Dr. Grazzini and the Italian National Blood Centre, since they believed in me when I was but a M.Sc. graduate, full of hopes and void of the rest. They filled that void with the passion for red blood cells, and that is why I owe you so much. I would like to dedicate this thesis to my parents. In a country where social ladders have been abated, a worker and a housewife never stopped fueling my hopes and pointing straight towards the dream of a “three years old” boy, now closer to realization than ever before. I dedicate this to their sacrifices and their silent suffering, constantly by my side. I am grateful to destiny for allowing me to meet a handful of people that changed my life. My friends, Marco, Giansante and Alessandro. You taught me that happiness can be found in the smallest things, as Trilussa wrote: “C'è un'ape che si posa su un bottone di rosa: lo succhia e se ne va. Tutto sommato, la felicità è una piccola cosa” My “father in science”, Prof. Lello Zolla. I hope I repaid your bet on me. Together we traveled, we invested, we planned, we worked hard. Very hard. You guided and protected me. Looking up on you I found the example to follow. What I learned from you, paraphrasing Rabelais, could be summarized as follows: “Science sans “passion”, n’est que ruine de l’ âme!” Last but not least, I dedicate this thesis to the one who helped me the most, my soulmate. This is for you: “Souls cross ages like clouds cross skies, an' tho' a cloud's shape nor hue nor size don't stay the same, it's still a cloud an' so is a soul. Who can say where the cloud's blowed from or who the soul'll be 'morrow? … Our lives are not our own. We are bound to others, past and present, and by each crime and every kindness, we birth our future.” David Mitchell Chapter 1: Introduction Chapter 1: Introduction Contents 1.1 Introduction to Red Blood Cell storage: the clinical/biological question about storage quality and compromised safety and efficacy of long-stored erythrocyte concentrates 1.2 Introduction to the field of “Integrated Omics”: Proteomics, Metabolomics, Lipidomics and Interactomics and their application to Transfusion Medicine and Red Blood cell Biology relevant issues The contents of this chapter represent a critical and updated re-elaboration of the following publications of the candidate: 1. D'Alessandro A, Liumbruno G, Grazzini G, Zolla L. Red blood cell storage: the story so far. Blood Transfus. 2010;8(2):82-8. 2. Zolla L, D’Alessandro A. Proteomic Investigations on Stored Red Blood Cells. In Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood. 2010; Mozzarelli A. Editor; John Wiley and Sons Ltd The Atrium, Southern Gate Chichester, West Sussex, PO19 8SQ 3. Liumbruno G, D'Alessandro A, Grazzini G, Zolla L. Blood-related proteomics. J Proteomics. 2010;73(3):483-507. 4. D'Alessandro A, Zolla L. Proteomics for quality-control processes in transfusion medicine. Anal Bioanal Chem. 2010;398(1):111-24. 5. Liumbruno G, D'Alessandro A, Grazzini G, Zolla L. How has proteomics informed transfusion biology so far? Crit Rev Oncol Hematol. 2010;76(3):153-72. 6. D'Alessandro A, Zolla L. Pharmacoproteomics: a chess game on a protein field. Drug Discov Today. 2010;15(23-24):1015-23. 7. D'Alessandro A, Zolla L. The SODyssey: superoxide dismutases from biochemistry, through proteomics, to oxidative stress, aging and nutraceuticals. Expert Rev Proteomics. 2011;8(3):405-21. 8. Zolla L, D’Alessandro. Shaking hands with the future through Omics application in Transfusion Medicine and Clinical Biochemistry. Preface Blood Transfusion 2012; 10 Suppl 2:s1-3. 9. D’Alessandro A, Gevi F, Timperio AM, Giardina B, Zolla L. Clinical Metabolomics: the next stage of clinical biochemistry Blood Transfusion 2012; 10 Suppl 2:s19-24. 10. D’Alessandro A, Zolla L. Metabolomics and cancer drug discovery: let the cells do the talking Drug Discov Today 2012; 17(1-2):3-9. 11. Zolla L, D’Alessandro A. Preface to the Special Issue Integrated Omics. J Proteomics 2012; doi: 10.1016/j.jprot.2012.10.007 3 Chapter 1: Introduction 1. Introduction to Red Blood Cell storage: the clinical/biological question about storage quality and compromised safety and efficacy of long stored erythrocyte concentrates Overview of this section At the dawn of the RBC biopreservation-research era, the donor and the recipient were forced to lay side by side. A sequence of fundamental achievements, from storage solutions to plastic bags and additive solutions have lead to increase the shelf-life of stored RBCs. Cold liquid storage, enabling a 42 –day storage of RBCs, was early paralleled by long-term frozen storage, which potentially allows RBCs to be stored for more than three decades. Notwithstanding this, frozen storage has not hitherto found a broad diffusion due to its elevated costs for required facilities and trained personnel. Accumulating data over the years showed how the storage processes negatively affect the quality of RBCs, ultimately causing risks to the recipients. These risks are stressed on the critically ill patients. Strikingly, one entire unit out of four meeting International criteria is rapidly removed from the circulation of the recipient only after 24 hours, owing to the senescent/apoptotic-like process which RBCs undergo during storage. Therefore, notwithstanding its long history, red blood cell storage is still a “work in progress”. Indeed, recent clinical retrospective non randomized trials have stressed the likely harmful potential and the reduced safety and effectiveness of long-stored red blood cells. However, conclusive data from prospective randomized studies are still missing and, although smoke could be seen on the horizons, it is still impossible to draw an unbiased conclusion on the presence of a burning fire nearby. On the other hand, a growing body of molecular studies has been recently built which underlines the dramatic changes red blood cells undergo during prolonged storage. Although some are reversible (such as pH drop, 2,3-DPG and ATP consumption), other events such as fragmentation and aggregation occur, triggered by many factors, including oxidative damage. These changes irreversibly compromise the erythrocyte physiology and thus its functionality, survival and immunogenic/pro-inflammatory potential upon reinfusion to the recipients. In this chapter, we summarize the recent past of the RBC biopreservation research, by focusing on a few milestones and pointing out future perspectives. Moreover, RBC storage lesions will be briefly listed out. All these notions will contribute to depict a well-rounded portrait of the happenings at the molecular levels during RBC storage.In particular, reactive oxygen species seem to be the eligible trigger for these lesions and the main contributor to the final quality loss (both at the macroscopic and microscopic levels) of RBCs. Hereby we describe alternative storage protocols which have been proposed in order to overpass these hurdles, such as RBC anaerobic storage. For the foreseeable future, the “quality issue” should become a top priority in the RBC biopreservation field and early attempts to prevent storage lesions appear to be a preferable option.Definitive clinical evidence is awaited to resume these whole observations under a unique question: the need for a new storage protocol. Whether this will become a priority, alternative storage strategies could represent a clue for a not-yet definitely posed question. At the end of this thesis, upon evaluating currently allowed (either hypothermic and cryostorage) and recently proposed storage strategies (i.e. anaerobic storage), we will outline the necessity to wonder whether researchers should continue to pursue a longer storage or start focusing on a protocol to ensure a better one. In this view, we will also mention in this chapter the “antioxidant additive solution” perspective, which will be tested as well through Omics technologies within the framework of this PhD thesis project. Keywords: red blood cell; storage lesion; blood transfusion; adverse effect; oxidative stress; 4 Chapter 1: Introduction Red blood cell storage: the story so far Red blood cells (RBCs) are still the most widely transfused blood component worldwide and their story is intimately intertwined with the history of transfusion medicine and the changes in the collection and storage of blood (Hess, 2006; Zimrin and Hess, 2009). At present, the most widely used protocol for the storage of RBCs (for up to 42 days) is the collection of blood into anticoagulant solutions (typically citrate-dextrose-phosphate); red cell concentrates are prepared by the removal of plasma and, in some cases, also leukoreduction.
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