Suicide is the leading cause of non-natural death worldwide, and major depressive disorder (MDD) is the mood disorder with the highest prevalence among individuals with suicidal behaviour (SB). The role of inflammation and immunomodulation in mood disorders has raised interest in recent years, as inflammation biomarkers have been reported to be increased in mood disorder patients, suggesting a role of inflammation in their pathogenesis. The influence of inflammation on the haematopoietic production is well known; however, a comprehensive study of the haematopoietic production in patients with major depressive episodes (MDE) is lacking. We examined global haematopoietic parameters from complete blood counts (CBC) of patients with MDE, in search of prognostic patterns. MDE patients presented differences in several CBC parameters, differences that were clearly pronounced and/or significant in concurrence with suicide attempts (SA). Red and white blood cell lineage parameters were affected, suggesting general haematopoietic modulation or imbalance. We observed distinct haematological parameter changes in women versus men, with men presenting milder alterations than women. Interestingly, we found that the List of Threatening Experiences (LTE) score, but not the Childhood Trauma Questionnaire (CTQ), was associated with the haematopoietic alterations observed exclusively in women and, more importantly, served as a parameter to stratify female MDE patients based on concurrence or non-concurrence with SA. In conclusion, grades of haematopoietic modulation in MDE patients are associated with absence or presence of SA. Haematopoietic manifestations differ between men and women and, in the latter, are markedly influenced by late, and not early, traumatic events.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by enhanced platelet clearance and defective platelet production. Diagnosis by exclusion and trial-and-error treatment strategies is common practice, and despite the advancement in treatment options, many patients remain refractory. Although the existence of different pathophysiological entities is acknowledged, we are still far from stratifying and understanding ITP. To investigate, we sought to dissect the platelet proteome dynamics in so-called passive and active preclinical ITP mouse models, with which we propose to phenocopy respectively acute/newly diagnosed and persistent/chronic stages of ITP in humans. We obtained the platelet proteome at the thrombocytopenic stage and after platelet count recovery (reached naturally or by IVIg-treatment, depending on the model). Although most of the proteomic alterations were common to both ITP models, there were model-specific protein dynamics that accompanied and explained alterations in platelet aggregation responses, as measured in the passive ITP model. The expression dynamics observed in Syk may explain, extrapolated to humans and pending validation, the increased bleeding tendency of patients with ITP when treated with fostamatinib as third or later– as opposed to second line of treatment. We propose that the platelet proteome may give diagnostic and prognostic insights into ITP and that such studies should be pursued in humans.

The field of proteomics and its application to platelet biology, is rapidly and promisingly developing. Platelets (and megakaryocytes) are postulated as biosensors of health and disease, and their proteome poses as a tool to identify the specific health-disease hallmarks. Furthermore, the clinical management of certain pathologies where platelets are active players demands the development of alternative treatments, such is the case in patients where the balance thrombosis-bleeding is compromised, and a proteomics approach might aid at the identification of novel targets. Hereby, the mouse and human platelet proteomes and secretomes from public databases are compared, which shows that human and mouse platelets share a highly conserved proteome, considering identified proteins, and most importantly, their relative abundance. These supports, also interspecies wise, the use of the proteomics tool in the field, substantiated by a growing number of clinically relevant studies in humans or preclinical models. While the study of platelets through proteomics seems accessible and direct (i.e. noninvasive blood sampling, enucleated), there are some points of concern regarding the quality control of samples for such proteomics studies. Importantly, the quality of the generated data is improving over the years, which will allow cross-study comparisons. In parallel, the application of proteomics to the megakaryocyte compartment has a promising but long journey ahead. We foresee and encourage the application of platelet proteomics for diagnostic/prognostic purposes even beyond hematopoiesis and transfusion medicine, and as a tool that will procure the improvement of current therapies and the development of alternative treatment options.

SUMMARY: Modification by ubiquitination governs the half-lives of thousands of proteins that are fated for elimination by either the proteasome or autophagy pathways, depending on the intricate architectures of ubiquitin modification. This system mediates quality control for individual proteins, protein complexes, and organelles, as well as myriad purely regulatory functions. Here we provide a comprehensive survey of the ubiquitin-proteasome system (UPS), the scope of which is at present poorly defined. The UPS, with the inclusion of pathways involving ubiquitin-like modifiers, comprises in our estimate over 1400 distinct proteins in humans, a vast set of activities whose collective impact on the biology of the cell is pervasive. The UPS is an integral component of the proteostasis network (PN), the remainder of which we have also surveyed in recent studies. With the addition of molecular chaperones, proteins from autophagy-lysosome pathway, and related activities, the PN includes in total over 3100 components by our estimates. Comprehensive and systematic definition of these pathways should support a range of ongoing investigations in the areas of genomics, proteomics, biochemistry, cell biology, and disease research.

The demand of platelet transfusions is steadily growing worldwide, inter-donor variation, donor dependency, or storability/viability being the main contributing factors to the current global, donor-dependent platelet concentrate shortage concern. In vitro platelet production has been proposed as a plausible alternative to cover, at least partially, the increasing demand. However, in practice, such a logical production strategy does not lack complexity, and hence, efforts are focused internationally on developing large scale industrial methods and technologies to provide efficient, viable, and functional platelet production. This would allow obtaining not only sufficient numbers of platelets but also functional ones fit for all clinical purposes and civil scenarios. In this review, we cover the evolution around the in vitro culture and differentiation of megakaryocytes into platelets, the progress made thus far to bring the culture concept from basic research towards good manufacturing practices certified production, and subsequent clinical trial studies. However, little is known about how these in vitro products should be stored or whether any safety measure should be implemented (e.g., pathogen reduction technology), as well as their quality assessment (how to isolate platelets from the rest of the culture cells, debris, microvesicles, or what their molecular and functional profile is). Importantly, we highlight how the scientific community has overcome the old dogmas and how the new perspectives influence the future of platelet-based therapy for transfusion purposes.