UNASSIGNED: MicroRNAs (miRNAs) are small, endogenous non-coding RNA molecules that inhibit gene expression through either destabilization of the target mRNA or translational repression. MiRNAs recognize target sites, most commonly found in the 3\'-untranslated regions of cognate mRNAs. This review aims to provide a state-of-the-art overview of the role of miRNAs in the regulation of major blood group antigens such as ABH as well as cancer-specific glycans.
UNASSIGNED: Besides their known roles in the control of developmental processes, proliferation, apoptosis, and carcinogenesis, miRNAs have recently been identified to play a regulatory role during erythropoiesis and blood group antigen expression. Since only little is known about the function of the red cell membrane proteins carrying blood group antigens, it is of great interest to shed light on the regulatory mechanisms of blood group gene expression. Some carrier proteins of blood group antigens are not restricted to red blood cells and are widely expressed in other bodily fluids and tissues and quite a few play a crucial role in tumor cells, as either tumor suppressors or promoters.
UNASSIGNED: All available data point at a tremendous physiological as well as pathophysiological relevance of miRNAs in context of blood group regulation. Furthermore, miRNAs are involved in the regulation of pleiotropic genetic pathways such as hematopoiesis and tumorigenesis and thus have to be studied in future research on this subject.

Various erythropoietic abnormalities are highly prevalent among patients with pulmonary arterial hypertension (PAH) and associated with worse disease severity. Given the poorly understood yet important roles of dysregulated erythropoiesis and iron metabolism in PAH, we sought to further characterize the hematologic and iron profiles in PAH and their relationship to PAH severity. We recruited 67 patients with PAH and 13 healthy controls. Hemodynamics attained within 1 year of blood sample collection were available for 36 patients. Multiple hematologic, iron, and inflammatory parameters were evaluated for their association with hemodynamics. The subset with hemodynamic data consisted of 29 females (81%). The most common etiologies were idiopathic PAH (47%) and connective tissue disease-related PAH (33%). 19 (53%) had functional class 3 or 4 symptomatology, and 12 (33%) were on triple pulmonary vasodilator therapy. Immature reticulocyte fraction (IRF) had significant positive correlations with mean pulmonary artery (PA) pressure (mPAP) (0.59, p < 0.001), pulmonary vascular resistance (0.52, p = 0.001), and right atrial pressure (0.46, p = 0.005), and significant negative correlations with cardiac index (-0.43, p = 0.009), PA compliance (PAC) (-0.60, p < 0.001), stroke volume index (SVI) (-0.57, p < 0.001), and mixed venous oxygen saturation (-0.51, p = 0.003). IRF correlated with markers of iron deficiency (ID) and erythropoiesis. On multivariable linear regression, IRF was associated with elevated mPAP and reduced SVI and PAC independent of EPO levels, transferrin saturation, and soluble transferrin receptor levels. We identified IRF as a novel and potent biomarker of PAH hemodynamic severity, possibly related to its associations with erythropoiesis, ID, and tissue hypoxia.

BACKGROUND: Nearly 58% of very low birth weight (VLBW) infants receive at least one red blood cell transfusion, which is not without risk. Reticulocyte fluorescence (RF) indicates the degree of cell maturation. The greater the fluorescence, the greater the immaturity of the reticulocytes.
OBJECTIVE: To evaluate RF as a marker of reticulocyte maturity and to investigate its predictive value for transfusion requirement in VLBW infants.
METHODS: Complete blood count was performed at 1, 7, 14, 21, and 28 d of age in 104 VLBW infants at the University Hospital of Parma. Iron supplementation was started at 15 d of life. The infants were divided into two groups: those who required transfusion after 28 d of life. (Tr) and those who did not (NTr).
RESULTS: Twenty-seven of 104 newborns required a red blood cell transfusion after 28 d of life (Tr group). At 14 d of life, the percentage of high fluorescence reticulocyte (HFR) was significantly higher in the r group than in infants who did not receive any transfusion (NTr groups): 18.5 vs. 5%, p = 0.002. The ROC curve (AUC 74%) revealed an HFR cut-off value of 16.5% as a predictor of the need for red blood cell (RBC) transfusion.
CONCLUSIONS: Reticulocyte maturation at 14 d of life is clinically useful for estimating the qualitative impairment of erythropoiesis and predicts the risk of RBC transfusion in VLBW infants. The data suggest the need for tailored iron integration in VLBW infants to improve the quality of hematopoiesis and reduce the risk of blood transfusion.

Optimal targets for red blood cell exchange (RCE) are not well defined in the chronic management of sickle cell disease. We analysed transfusion requirements and iron-related outcomes in 101 patients on chronic RCE with a post-procedure haematocrit (Ht) targeted at 34%, which is higher than typically used. A majority were of HbSS/HbSβ0 genotype (n = 72) and enrolled for neurological complications (n = 53). Fifty patients had a positive Ht balance with RCE (>2% mean increase from pre-procedure level), while 43 patients maintained a neutral balance. The first group required fewer red blood cell units/year (65 vs. 80, p < 0.001), but a significant proportion were iron overloaded based on R2* with liver MRI (32% vs. none performed) and prescription of iron chelation (52% vs. 0%, p < 0.001, after a median of 19 months). The second group was more likely to receive iron supplementation (6% vs. 56%, p < 0.001). Chronic automated RCE with a post-procedure Ht targeted at 34% is not iron-neutral, and personalized Ht goals may be more appropriate in certain settings. This higher target should be compared with a lower Ht strategy in individuals with similar baseline red cell volumes to assess iron homeostasis and blood product requirements.

Low energy availability (LEA) is a growing concern that can lead to several problems for athletes. However, adaptation to LEA occurs to maintain balance over time, making diagnosis difficult. In this review, we categorize LEA into two phases: the initial phase leading to adaptation and the phase in which adaptation is achieved and maintained. We review the influence of LEA on sports performance and health and discuss biomarkers for diagnosing LEA in each phase. This review also proposes future research topics for diagnosing LEA, with an emphasis on the recently discovered association between red blood cell turnover and LEA.

Red blood cells (RBCs) comprise a critical component of the cardiovascular network, which constitutes the first functional organ system of the developing mammalian embryo. Examination of circulating blood cells in mammalian embryos revealed two distinct types of erythroid cells: large, nucleated \"primitive\" erythroblasts followed by smaller, enucleated \"definitive\" erythrocytes. This review describes the current understanding of primitive and definitive erythropoiesis gleaned from studies of mouse and human embryos and induced pluripotent stem cells (iPSCs). Primitive erythropoiesis in the mouse embryo comprises a transient wave of committed primitive erythroid progenitors (primitive erythroid colony-forming cells, EryP-CFC) in the early yolk sac that generates a robust cohort of precursors that mature in the bloodstream and enucleate. In contrast, definitive erythropoiesis has two distinct developmental origins. The first comprises a transient wave of definitive erythroid progenitors (burst-forming units erythroid, BFU-E) that emerge in the yolk sac and seed the fetal liver where they terminally mature to provide the first definitive RBCs. The second comprises hematopoietic stem cell (HSC)-derived BFU-E that terminally mature at sites colonized by HSCs particularly the fetal liver and subsequently the bone marrow. Primitive and definitive erythropoiesis are derived from endothelial identity precursors with distinct developmental origins. Although they share prototypical transcriptional regulation, primitive and definitive erythropoiesis are also characterized by distinct lineage-specific factors. The exquisitely timed, sequential production of primitive and definitive erythroid cells is necessary for the survival and growth of the mammalian embryo.

Erythrocytes have the potential role in erythropoiesis and disease diagnosis. Thought to have lacked nucleic acid content, mammalian erythrocytes are nevertheless able to function for 120-140 days, metabolize heme, maintain oxidative stress, and so on. Mysteriously, erythrocytes proved as largest repositories of microRNAs (miRNAs) some of which are selectively retained and function in mature erythrocytes. They have unique expression patterns and have been found to be linked to specific conditions such as sickle cell anaemia, high-altitude hypoxia, chronic mountain sickness, cardiovascular and metabolic conditions as well as host-parasite interactions. They also have been implicated in cell storage-related damage and the regulation of its survival. However, the mechanism by which miRNAs function in the cell remains unclear. Investigations into the molecular mechanism of miRNAs in erythrocytes via extracellular vesicles have provided important clues in research studies on Plasmodium infection. Erythrocytes are also the primary source of circulating miRNAs but, how they affect the plasma/serum miRNAs profiles are still poorly understood. Erythrocyte-derived exosomal miRNAs, can interact with various body cell types, and have easy access to all regions, making them potentially crucial in various pathophysiological conditions. Which can also improve our understanding to identify potential treatment options and discovery related to non-invasive diagnostic markers. This article emphasizes the importance of erythrocytic miRNAs while focusing on the enigmatic behaviour of erythrocytes. It also sheds light on how this knowledge may be applied in the future to enhance the state of erythrocyte translational research from the standpoint of erythrocytic miRNAs.

Lineage-specific transcription factors (TFs) regulate differentiation of hematopoietic stem cells (HSCs). They are decisive for the establishment and maintenance of lineage-specific gene expression programs during hematopoiesis. For this they create a regulatory network between TFs, epigenetic cofactors, and microRNAs. They activate cell-type specific genes and repress competing gene expression programs. Disturbance of this process leads to impaired lineage fidelity and diseases of the blood system. The TF T-cell acute leukemia 1 (TAL1) is central for erythroid differentiation and contributes to the formation of distinct gene regulatory complexes in progenitor cells and erythroid cells. A TAL1/E47 heterodimer binds to DNA with the TFs GATA-binding factor 1 and 2 (GATA1/2), the cofactors LIM domain only 1 and 2 (LMO1/2), and LIM domain-binding protein 1 (LDB1) to form a core TAL1 complex. Furthermore, cell-type-dependent interactions of TAL1 with other TFs such as with runt-related transcription factor 1 (RUNX1) and Kruppel-like factor 1 (KLF1) are established. Moreover, TAL1 activity is regulated by the formation of TAL1 isoforms, posttranslational modifications (PTMs), and microRNAs. Here, we describe the function of TAL1 in normal hematopoiesis with a focus on erythropoiesis.

Erythroid Krüppel-like factor (KLF1), first discovered in 1992, is an erythroid-restricted transcription factor (TF) that is essential for terminal differentiation of erythroid progenitors. At face value, KLF1 is a rather inconspicuous member of the 26-strong SP/KLF TF family. However, 30 years of research have revealed that KLF1 is a jack of all trades in the molecular control of erythropoiesis. Initially described as a one-trick pony required for high-level transcription of the adult HBB gene, we now know that it orchestrates the entire erythroid differentiation program. It does so not only as an activator but also as a repressor. In addition, KLF1 was the first TF shown to be directly involved in enhancer/promoter loop formation. KLF1 variants underlie a wide range of erythroid phenotypes in the human population, varying from very mild conditions such as hereditary persistence of fetal hemoglobin and the In(Lu) blood type in the case of haploinsufficiency, to much more serious non-spherocytic hemolytic anemias in the case of compound heterozygosity, to dominant congenital dyserythropoietic anemia type IV invariably caused by a de novo variant in a highly conserved amino acid in the KLF1 DNA-binding domain. In this chapter, we present an overview of the past and present of KLF1 research and discuss the significance of human KLF1 variants.

Erythropoietin (EPO) exerts non-canonical roles beyond erythropoiesis that are developmentally, structurally, and physiologically relevant for the heart as a paracrine factor. The role for paracrine EPO signalling and cellular crosstalk in the adult is uncertain. Here, we provided novel evidence showing cardiomyocyte restricted loss of function in Epo in adult mice induced hyper-compensatory increases in Epo expression by adjacent cardiac endothelial cells via HIF-2α independent mechanisms. These hearts showed concentric cellular hypertrophy, elevated contractility and relaxation, and greater resistance to ischemia-reperfusion injury. Voluntary exercise capacity compared to control hearts was improved independent of any changes to whole-body metabolism or blood O2 content or delivery (i.e., hematocrit). Our findings suggest cardiac EPO had a localized effect within the normoxic heart, which was regulated by cell-specific EPO-reciprocity between cardiomyocytes and endothelium. Within the heart, hyper-compensated endothelial Epo expression was accompanied by elevated Vegfr1 and Vegfb RNA, that upon pharmacological pan-inhibition of VEGF-VEGFR signaling, resulted in a paradoxical upregulation in whole-heart Epo. Thus, we provide the first evidence that a novel EPO-EPOR/VEGF-VEGFR axis exists to carefully mediate cardiac homeostasis via cardiomyocyte-endothelial EPO crosstalk.