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Nemkov T, Stauffer E, Cendali F, Stephenson D, Nader E, Robert M, Skinner S, Dzieciatkowska M, Hansen KC, Robach P, Millet G, Connes P, D'Alessandro A. Long-Distance Trail Running Induces Inflammatory-Associated Protein, Lipid, and Purine Oxidation in Red Blood Cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.09.648006. [PMID: 40291720 PMCID: PMC12027326 DOI: 10.1101/2025.04.09.648006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Ultra-endurance exercise places extreme physiological demands on oxygen transport, yet its impact on red blood cells (RBCs) remains underexplored. We conducted a multi-omics analysis of plasma and RBCs from endurance athletes before and after a 40-km trail race (MCC) and a 171-km ultramarathon (UTMB®). Ultra-running led to oxidative stress, metabolic shifts, and inflammation-driven RBC damage, including increased acylcarnitines, kynurenine accumulation, oxidative lipid and protein modifications, reduced RBC deformability, enhanced microparticle release, and decreased hematocrit - hallmarks of accelerated RBC aging and clearance. Post-race interleukin-6 strongly correlated with kynurenine elevation, mirroring inflammatory responses in severe infections. These findings challenge the assumption that RBC damage in endurance exercise is primarily mechanical, revealing systemic inflammation and metabolic remodeling as key drivers. This study underscores RBCs as both mediators and casualties of extreme exercise stress, with implications for optimizing athlete recovery, endurance training, and understanding inflammation-linked RBC dysfunction in clinical settings. Teaser Marathon running imparts molecular damage to red blood cells, the effects of which are exacerbated by increased distances of ultramarathons.
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2
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Claessen MJAG, Yagci N, van Mierlo G, Kersten MJ, von Lindern M, van den Akker E. Human serum albumin or polyvinyl alcohol can only partially replace human plasma during in vitro red cell production from PBMC. Sci Rep 2025; 15:12058. [PMID: 40199875 PMCID: PMC11978868 DOI: 10.1038/s41598-024-81341-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 11/26/2024] [Indexed: 04/10/2025] Open
Abstract
Transfusion of donor-derived red blood cells (RBC) depends on donor availability. Alloimmunization can limit the availability of transfusion units, particularly for chronically transfused patients. In vitro cultured, customizable RBC (cRBC) would negate these concerns and provide infinite RBC products. Previously, we developed a defined medium based on good manufacturing practice (GMP) requirements. To optimize medium conditions with regards to reproducibility and cost effectiveness, we tested the requirement for plasma during the differentiation phase and the replacement of HSA by polyvinyl alcohol (PVA) during the expansion and differentiation phase. We show that 5% plasma is essential to enhance cell count, enucleation% and mostly stability of cRBC during the differentiation phase. During the expansion phase HSA could be replaced by PVA without compromising the expansion capacity. Substitution of HSA by PVA even increased the number of cells at the end of the expansion phase. During the differentiation phase PVA could also replace HSA, but only in the presence of plasma. Plasma is still essential to achieve an optimum yield of enucleated cRBC, likely by stabilizing enucleated cRBC. Substitution of HSA by PVA is a new advancement in the development of a, defined, cost-effective culture medium to culture cRBC for all.
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Affiliation(s)
- Marie-José A G Claessen
- Department Research, Sanquin Blood Supply, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands
- Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Nurcan Yagci
- Department Research, Sanquin Blood Supply, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands
- Landsteiner Laboratory, Amsterdam University Medical Center, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands
| | - Gerard van Mierlo
- Department Research, Sanquin Blood Supply, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands
| | - Marie José Kersten
- Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Marieke von Lindern
- Department Research, Sanquin Blood Supply, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands
- Landsteiner Laboratory, Amsterdam University Medical Center, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands
| | - Emile van den Akker
- Department Research, Sanquin Blood Supply, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands.
- Landsteiner Laboratory, Amsterdam University Medical Center, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands.
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3
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Ma Q, Noda M, Danshiitsoodol N, Sugiyama M. Atractylodes Japonica Rhizome Extract Fermented with a Plant-Derived Lacticaseibacillus paracasei ( Lactobacillus paracasei) IJH-SONE68 Improves the Wheat Gliadin-Induced Food Allergic Reaction in Mice. Nutrients 2025; 17:1151. [PMID: 40218908 PMCID: PMC11990203 DOI: 10.3390/nu17071151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 03/21/2025] [Accepted: 03/24/2025] [Indexed: 04/14/2025] Open
Abstract
Background/Objectives: Medicinal herbs produce valuable substances with therapeutic potential. The chemical structures of those substances are often converted by gut microbiota. Our previous studies showed that several kinds of bioactive molecules are newly generated in fermented medicinal herbal extract with plant-derived lactic acid bacteria (LABs). Methods: The fermented extract of Atractylodes Japonica Rhizoma (AJR), which is designated as "Byakujutsu" in Japan, with a plant-derived LAB strain IJH-SONE68 was prepared and whether the fermented extract could help reduce symptoms of food allergies, especially wheat intolerance, was confirmed using animal model. Results: It has been found that the fermented extract significantly ameliorates the anaphylaxis score (from 3.0 to 1.0, p = 0.003) of gliadin-induced allergic model mice (specific-pathogen-free, BALB/cJ) accompanied with the modulation of serum total immunoglobulin E (IgE) (from 778 to 518 ng/mL, p = 0.006), interferon (IFN)-γ (from 6.6 to 9.5 pg/mL, p < 0.001), and interleukin (IL)-4 (from 32.0 to 9.1 pg/mL, p < 0.001) levels. Conclusions: The fermented AJR extract may modulate the Th1/Th2 cell balance to alleviate the symptoms of gliadin-induced anaphylaxis in mice. The present study supports the view that the fermentation of medicinal herbal extract prepared using LABs may be a useful procedure for producing therapeutic potential compounds to maintain health.
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Affiliation(s)
| | | | | | - Masanori Sugiyama
- Department of Probiotic Science for Preventive Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan; (Q.M.); (M.N.); (N.D.)
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4
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Zhou S, Lyu P, Huang Y, Man X, Xiao S. Nonmonotonous Translocation Dynamics of Highly Deformable Particles across Channels. ACS NANO 2025; 19:10807-10815. [PMID: 40073271 DOI: 10.1021/acsnano.4c11319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/14/2025]
Abstract
The translocation dynamics of cells and particles through geometric constrictions are critical in biological and biomedical processes from splenic filtration to tumor metastasis. While particle stiffness plays a key role, its role in highly nonequilibrium states remains poorly understood. Here, we present a multiscale model to investigate the impact of particle stiffness on the translocation dynamics in microfluidic channels. We find that semielastic particles exhibit superior translocation capabilities compared to both softer and more rigid particles, with a nonmonotonic stiffness dependence observed for highly deformable particles. Additionally, we identify crossover behaviors in translocation time driven by variations in the flow rate, particle size, and particle-plate interactions. Excessive particle deformation significantly regulates these dynamics, with stiffness-induced shape transitions from pancake-like to ellipsoidal forms, controlling frictional forces at the particle-channel interface and the sieve plate. The balance between these forces explains the observed nonmonotonic translocation dynamics. Our work provides insights into the relationship between particle deformability and flow dynamics, highlighting the importance of elasticity in translocation behavior. These findings have implications for designing microfluidic devices for efficient separation and analysis of cells with varying elasticities, advancing applications in human health diagnostics.
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Affiliation(s)
- Shenrong Zhou
- Hefei National Research Center for Physical Sciences at the Microscale, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Peihan Lyu
- School of Physics, Beihang University, Beijing 100191, China
| | - Yu Huang
- Hefei National Research Center for Physical Sciences at the Microscale, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Xingkun Man
- School of Physics, Beihang University, Beijing 100191, China
- Peng Huanwu Collaborative Center for Research and Education, Beihang University, Beijing 100191, China
| | - Shiyan Xiao
- Hefei National Research Center for Physical Sciences at the Microscale, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China
- State Key Laboratory of Precision and Intelligent Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
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5
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Gural A, Pajić-Lijaković I, Barshtein G. Mechanical Stimulation of Red Blood Cells Aging: Focusing on the Microfluidics Application. MICROMACHINES 2025; 16:259. [PMID: 40141870 PMCID: PMC11945212 DOI: 10.3390/mi16030259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/23/2025] [Accepted: 02/24/2025] [Indexed: 03/28/2025]
Abstract
Human red blood cells (RBCs) are highly differentiated cells, essential in almost all physiological processes. During their circulation in the bloodstream, RBCs are exposed to varying levels of shear stress ranging from 0.1-10 Pa under physiological conditions to 50 Pa in arterial stenotic lesions. Moreover, the flow of blood through splenic red pulp and through artificial organs is associated with brief exposure to even higher levels of shear stress, reaching up to hundreds of Pa. As a result of this exposure, some properties of the cytosol, the cytoskeleton, and the cell membrane may be significantly affected. In this review, we aim to systematize the available information on RBC response to shear stress by focusing on reported changes in various red cell properties. We pay special attention to the results obtained using microfluidics, since these devices allow the researcher to accurately simulate blood flow conditions in the capillaries and spleen.
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Affiliation(s)
- Alexander Gural
- Blood Bank, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel;
| | - Ivana Pajić-Lijaković
- Department of Chemical Engineering, Faculty of Technology and Metallurgy, University of Belgrade, 11000 Belgrade, Serbia;
| | - Gregory Barshtein
- Department of Biochemistry, The Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel
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6
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Turpaev K, Bovt E, Shakhidzhanov S, Sinauridze E, Smetanina N, Koleva L, Kushnir N, Suvorova A, Ataullakhanov F. An overview of hereditary spherocytosis and the curative effects of splenectomy. Front Physiol 2025; 16:1497588. [PMID: 40008208 PMCID: PMC11850534 DOI: 10.3389/fphys.2025.1497588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
Hereditary spherocytosis is a common hemolytic anemia with different severity. The causes of hereditary spherocytosis are mutations in genes that encode red blood cell (RBC) membrane and cytoskeletal proteins, including ankyrin-1, Band 3 (or AE1), α spectrin, β spectrin, and protein 4.2. Molecular defects in these proteins decrease membrane integrity, leading to vesiculation, decreased membrane surface area, and reduced deformability of the cells. Eventually, this leads to the trapping the abnormal RBCs (spherocytes) in the spleen. In most severe cases, splenectomy may be necessary to prevent general RBC collapse during the passage of RBCs through the narrow slits of venous sinuses in the spleen. The clinical benefit of splenectomy results from elimination the primary site of RBC damage and destruction. Splenectomy is a curative approach but can cause complications and should be undertaken after examination by various laboratory approaches. Splenectomy does not correct most genetically determined membrane abnormalities in erythrocytes in patients with hereditary spherocytosis. The transformation of biconcave erythrocytes into spherocytes continues, although to a lesser degree than before surgery. Nevertheless, splenectomy increases the lifespan of red cells, significantly reducing the severity of anemia and improving many physiological signs of HS.
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Affiliation(s)
- Kyril Turpaev
- Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia
| | - Elizaveta Bovt
- Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Soslan Shakhidzhanov
- Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Elena Sinauridze
- Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Nataliya Smetanina
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Larisa Koleva
- Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Nikita Kushnir
- Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Anna Suvorova
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Fazoil Ataullakhanov
- Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia
- Moscow Institute of Physics and Technology, National Research University, Dolgoprudny, Russia
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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7
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Yu Q, Zhang L, Wang Z, Wang Q, Sun X, Deng W, Cao X, Yu J, Xu X. Anti-inflammatory oligosaccharide licensed mesenchymal stem cells allow prolonged survival of septic rats via the promotion of glutathione synthesis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156173. [PMID: 39471736 DOI: 10.1016/j.phymed.2024.156173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 08/16/2024] [Accepted: 10/20/2024] [Indexed: 11/01/2024]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) possess the capability to mitigate multiorgan failure (MOF) and reduce mortality rates in sepsis. However, their survival is significantly limited due to oxidative stress responses triggered by excessive sepsis inflammation. Previous studies have demonstrated that the paracrine effect of MSCs can be enhanced by cytokine stimuli such as IL-1β, TNF-α, and IFN-γ, a process known as inflammatory licensing. This enhancement, however, may potentially lead to the apoptosis of MSCs. PURPOSE To investigate the therapeutic effects of Fructus Lycii oligosaccharide (FLO)-nasal mucosa-derived ectodermal MSCs (EMSCs) on septic rats and the underlying mechanisms. STUDY DESIGN AND METHODS FLO was screened from 21 distinct saccharides derived from traditional Chinese medicine (TCM), utilizing macrophage lipid raft chromatography prepared by our laboratory as the primary screening method.. The comparison of EMSCs primed with/without FLO was assessed through RNA-seq. Cecal ligation and puncture (CLP) surgery was performed in the CLP, EMSCs, and FLO-EMSCs groups (n = 10). The NC group underwent cecal ligation without puncture. The therapeutic effects of EMSCs and FLO-EMSCs on septic rats were evaluated through multiple tests including RT-PCR, western blot, histochemical staining, etc. RESULTS: FLO promoted M2 polarization of macrophages and enhanced the paracrine effect of EMSCs, without inducing apoptosis. Furthermore, FLO promoted GSH synthesis in EMSCs, aiding in the removal of reactive oxygen species (ROS) within these cells. The FLO-treated EMSCs demonstrated enhanced protection against pyroptosis in macrophages, thereby preventing immune paralysis during sepsis. CONCLUSION This study presents an innovative approach for enhancing the anti-inflammatory properties of MSCs using a TCM-derived oligosaccharide, thereby improving their therapeutic efficacy in sepsis models.
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Affiliation(s)
- Qingtong Yu
- School of Pharmacy, Jiangsu University, 212013, ZhenJiang, PR China
| | - Linzhi Zhang
- School of Pharmacy, Jiangsu University, 212013, ZhenJiang, PR China
| | - Zhe Wang
- School of Pharmacy, Jiangsu University, 212013, ZhenJiang, PR China
| | - Qilong Wang
- School of Pharmacy, Jiangsu University, 212013, ZhenJiang, PR China
| | - Xuan Sun
- School of Pharmacy, Jiangsu University, 212013, ZhenJiang, PR China
| | - Wenwen Deng
- School of Pharmacy, Jiangsu University, 212013, ZhenJiang, PR China
| | - Xia Cao
- School of Pharmacy, Jiangsu University, 212013, ZhenJiang, PR China
| | - Jiangnan Yu
- School of Pharmacy, Jiangsu University, 212013, ZhenJiang, PR China.
| | - Ximing Xu
- School of Pharmacy, Jiangsu University, 212013, ZhenJiang, PR China.
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8
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Sissoko A, Cissé A, Duverdier C, Marin M, Dumas L, Manceau S, Maître B, Eckly A, Fricot-Monsinjon A, Roussel C, Ndour PA, Dussiot M, Dokmak S, Aussilhou B, Dembinski J, Sauvanet A, Paye F, Lesurtel M, Cros J, Wendum D, Tichit M, Hardy D, Capito C, Allali S, Buffet P. Clearance of pathogenic erythrocytes is maintained despite spleen dysfunction in children with sickle cell disease. Am J Hematol 2024; 99:2267-2278. [PMID: 39286963 PMCID: PMC11560635 DOI: 10.1002/ajh.27481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/01/2024] [Accepted: 09/02/2024] [Indexed: 09/19/2024]
Abstract
In children with sickle cell disease (SCD), splenectomy is immediately beneficial for acute sequestration crises and hypersplenism (ASSC/HyS) but portends a long-term risk of asplenia-related complications. We retrieved peripheral and splenic red blood cells (RBCs) from 17 SCD children/teenagers undergoing partial splenectomy for ASSC/HyS, 12 adult subjects without RBC-related disease undergoing splenectomy (controls), five human spleens perfused ex vivo with HbSS- and HbAA-RBC, and quantified abnormal RBC by microscopy, spleen-mimetic RBC filtration, and adhesion assays. Spleens were analyzed by immunohistochemistry and transmission electron microscopy (TEM). In circulating blood of SCD and control subjects, dysmorphic (elongated/spherocytic) RBCs were <2%, while proportions of pocked-RBC were 4.3-fold higher in SCD children than in controls. Compared to controls, splenic RBCs were more frequently dysmorphic (29.3% vs. 0.4%), stiffer (42.2% vs. 12.4%), and adherent (206 vs. 22 adherent RBC/area) in SCD subjects. By TEM, both polymer-containing and homogenous RBC contributed to spleen congestion, resulting in 3.8-fold higher RBC population density in SCD spleens than in control spleens, predominantly in the cords. Perfused spleens with normal function displayed similar congestion and retention of dysmorphic RBC as SCD spleens. The population density of active macrophages was similar in SCD and control spleens, with a relative deficit in phagocytosis of polymer-containing RBC. Despite the existence of hyposplenism, splenectomy in SCD children removes an organ that still efficiently filters out potentially pathogenic altered RBC. Innovative treatments allowing fine-tuned reduction of RBC retention would alleviate spleen congestion, the major pathogenic process in ASSC/HyS, while preserving spleen protective functions for the future.
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Affiliation(s)
| | - Astan Cissé
- Université Paris Cité, Inserm, BIGR, F-75015 Paris, France
| | | | - Mickaël Marin
- Université Paris Cité, Inserm, BIGR, F-75015 Paris, France
| | - Lucie Dumas
- Université Paris Cité, Inserm, BIGR, F-75015 Paris, France
| | - Sandra Manceau
- Laboratoire d’Excellence GR-Ex, Paris, France
- Assistance publique des hôpitaux de Paris, Paris, France
| | - Blandine Maître
- Université de Strasbourg, UMR_S1255, INSERM, Établissement Français du Sang-Grand Est, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Anita Eckly
- Université de Strasbourg, UMR_S1255, INSERM, Établissement Français du Sang-Grand Est, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | | | - Camille Roussel
- Université Paris Cité, Inserm, BIGR, F-75015 Paris, France
- Assistance publique des hôpitaux de Paris, Paris, France
| | | | - Michael Dussiot
- Université de Paris, U1163, Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques, INSERM, Paris, France
| | - Safi Dokmak
- Department of HPB surgery and Liver Transplantation, AP-HP, Beaujon Hospital, DMU DIGEST, Clichy, France. University of Paris Cité, Paris, France
| | - Béatrice Aussilhou
- Department of HPB surgery and Liver Transplantation, AP-HP, Beaujon Hospital, DMU DIGEST, Clichy, France. University of Paris Cité, Paris, France
| | - Jeanne Dembinski
- Department of HPB surgery and Liver Transplantation, AP-HP, Beaujon Hospital, DMU DIGEST, Clichy, France. University of Paris Cité, Paris, France
| | - Alain Sauvanet
- Department of HPB surgery and Liver Transplantation, AP-HP, Beaujon Hospital, DMU DIGEST, Clichy, France. University of Paris Cité, Paris, France
| | - François Paye
- Assistance publique des hôpitaux de Paris, Paris, France
| | - Mickaël Lesurtel
- Department of HPB surgery and Liver Transplantation, AP-HP, Beaujon Hospital, DMU DIGEST, Clichy, France. University of Paris Cité, Paris, France
| | - Jérôme Cros
- Department of Pathology, Université Paris Cité – FHU MOSAIC, Beaujon Hospital, Clichy, France
| | | | - Magali Tichit
- Institut Pasteur, Université Paris Cité, Histopathology Core Facility, Paris, France
| | - David Hardy
- Institut Pasteur, Université Paris Cité, Histopathology Core Facility, Paris, France
| | - Carmen Capito
- Assistance publique des hôpitaux de Paris, Paris, France
| | - Slimane Allali
- Assistance publique des hôpitaux de Paris, Paris, France
- Reference center for sickle cell disease, Necker-Enfants malades hospital, Paris, France
| | - Pierre Buffet
- Université Paris Cité, Inserm, BIGR, F-75015 Paris, France
- Laboratoire d’Excellence GR-Ex, Paris, France
- Assistance publique des hôpitaux de Paris, Paris, France
- Institut Pasteur, Université Paris Cité, Paris, France
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9
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Meng K, Chen H, Pan Y, Li Y. The dynamics of red blood cells traversing slits of mechanical heart valves under high shear. Biophys J 2024; 123:3780-3797. [PMID: 39340153 PMCID: PMC11560308 DOI: 10.1016/j.bpj.2024.09.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/04/2024] [Accepted: 09/25/2024] [Indexed: 09/30/2024] Open
Abstract
Hemolysis, including subclinical hemolysis, is a potentially severe complications of mechanical heart valves (MHVs), which leads to shortened red blood cell (RBC) lifespan and hemolytic anemia. Serious hemolysis is usually associated with structural deterioration and regurgitation. However, the shear stress in MHVs' narrow leakage slits is much lower than the shear stress threshold causing hemolysis and the mechanisms in this context remain largely unclear. This study investigated the hemolysis mechanism of RBCs in cell-size slits under high shear rates by establishing in vitro microfluidic devices and a coarse-grained molecular dynamics (CGMD) model, considering both fluid and structural effects simultaneously. Microfluidic experiments and computational simulation revealed six distinct dynamic states of RBC traversal through MHVs' microscale slits under various shear rates and slit sizes. It elucidated that RBC dynamic states were influenced by not only by fluid forces but significantly by the compressive force of slit walls. The variation of the potential energy of the cell membrane indicated its stretching, deformation, and rupture during traversal, corresponding to the six dynamic states. The maximum forces exerted on membrane by water particles and slit walls directly determined membrane rupture, serving as a critical determinant. This analysis helps in understanding the contribution of the slit walls to membrane rupture and identifying the threshold force that leads to membrane rupture. The hemolysis mechanism of traversing microscale slits is revealed to effectively explain the occurrences of hemolysis and subclinical hemolysis.
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Affiliation(s)
- Kuilin Meng
- State Key Laboratory of Tribology, Department of Mechanical Engineering, Tsinghua University, Beijing, China
| | - Haosheng Chen
- State Key Laboratory of Tribology, Department of Mechanical Engineering, Tsinghua University, Beijing, China
| | - Yunfan Pan
- State Key Laboratory of Tribology, Department of Mechanical Engineering, Tsinghua University, Beijing, China
| | - Yongjian Li
- State Key Laboratory of Tribology, Department of Mechanical Engineering, Tsinghua University, Beijing, China.
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10
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Li G, Li H, Ndour PA, Franco M, Li X, MacDonald I, Dao M, Buffet PA, Karniadakis GE. Red blood cell passage through deformable interendothelial slits in the spleen: Insights into splenic filtration and hemodynamics. Comput Biol Med 2024; 182:109198. [PMID: 39341110 PMCID: PMC11560667 DOI: 10.1016/j.compbiomed.2024.109198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 09/18/2024] [Accepted: 09/22/2024] [Indexed: 09/30/2024]
Abstract
The spleen constantly clears altered red blood cells (RBCs) from the circulation, tuning the balance between RBC formation (erythropoiesis) and removal. The retention and elimination of RBCs occur predominantly in the open circulation of the spleen, where RBCs must cross submicron-wide inter-endothelial slits (IES). Several experimental and computational studies have illustrated the role of IES in filtrating the biomechanically and morphologically altered RBCs based on a rigid wall assumption. However, these studies also reported that when the size of IES is close to the lower end of clinically observed sizes (less than 0.5 μm), an unphysiologically large pressure difference across the IES is required to drive the passage of normal RBCs, sparking debates on the feasibility of the rigid wall assumption. In this work, We propose two deformable IES models, namely the passive model and the active model, aiming to explore the impact of the deformability of IES on the filtration function of the spleen. In the passive model, we implement the worm-like string model to depict the IES's deformation as it interacts with blood plasma and allows RBC to traverse. In contrast, the active model involved regulating the IES deformation based on the local pressure surrounding the slit. To demonstrate the validity of the deformable model, we simulate the filtration of RBCs with varied size and stiffness by IES under three scenarios: (1) a single RBC traversing a single slit; (2) a suspension of RBCs traversing an array of slits, mimicking in vitro spleen-on-a-chip experiments; (3) RBC suspension passing through the 3D spleen filtration unit known as'the splenon'. Our simulation results of RBC passing through a single slit show that the deformable IES model offers more accurate predictions of the critical cell surface area to volume ratio that dictate the removal of aged RBCs from circulation compared to prior rigid-wall models. Our biophysical models of the spleen-on-a-chip indicate a hierarchy of filtration function stringency: rigid model > passive model > active model, providing a possible explanation of the filtration function of IES. We also illustrate that the biophysical model of 'the splenon' enables us to replicate the ex vivo experiments involving spleen filtration of malaria-infected RBCs. Taken together, our simulation findings indicate that the deformable IES model could serve as a mesoscopic representation of spleen filtration function closer to physiological reality, addressing questions beyond the scope of current experimental and computational models and enhancing our understanding of the fundamental flow dynamics and mechanical clearance processes within in the human spleen.
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Affiliation(s)
- Guansheng Li
- Division of Applied Mathematics, Brown University, Providence, RI, 02906, United States of America.
| | - He Li
- School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens, GA, 30602, United States of America
| | - Papa Alioune Ndour
- Université Paris Cité and Université des Antilles, Inserm, Biologie Intégrée du Globule Rouge, 75015, Paris, France; Laboratoire d'Excellence du Globule Rouge, 75015, Paris, France
| | - Mélanie Franco
- Université Paris Cité and Université des Antilles, Inserm, Biologie Intégrée du Globule Rouge, 75015, Paris, France; Laboratoire d'Excellence du Globule Rouge, 75015, Paris, France
| | - Xuejin Li
- Department of Engineering Mechanics and Center for X-Mechanics, Zhejiang University, Hangzhou, Zhejiang 310027, China
| | - Ian MacDonald
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Ming Dao
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, United States of America
| | - Pierre A Buffet
- Université Paris Cité and Université des Antilles, Inserm, Biologie Intégrée du Globule Rouge, 75015, Paris, France; Laboratoire d'Excellence du Globule Rouge, 75015, Paris, France
| | - George Em Karniadakis
- Division of Applied Mathematics, Brown University, Providence, RI, 02906, United States of America.
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11
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Sissoko A, Othmene YB, Buffet P. Splenic filtration of red blood cells in physiology, malaria and sickle cell disease. Curr Opin Hematol 2024; 31:307-314. [PMID: 39259191 DOI: 10.1097/moh.0000000000000839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/12/2024]
Abstract
PURPOSE OF REVIEW The human spleen clears the blood from circulating microorganisms and red blood cells (RBCs) displaying alterations. This review analyzes how generic mechanisms by which the spleen senses RBC, such pitting, trapping and erythrophagocytosis, impact the pathogenesis of two major spleen-related diseases, malaria and sickle cell disease (SCD). RECENT FINDINGS Scintigraphy, functional histology, comparison of circulating and splenic RBC, ex-vivo perfusion of human spleens and in-silico modeling enable relevant exploration of how the spleen retains and processes RBC in health and disease. Iterative cross-validations between medical observations, in-vitro experiments and in-silico modeling point to mechanical sensing of RBC as a central event in both conditions. Spleen congestion is a common pathogenic process explaining anemia and splenomegaly, the latter carrying a risk of severe complications such as acute splenic sequestration crisis and hypersplenism in SCD. Sickling of hemoglobin S-containing RBC may contribute to these complications without necessarily being the trigger. SUMMARY Ongoing progress in the exploration and understanding of spleen-related complications in malaria and SCD open the way to optimized prognosis evaluation and therapeutic applications.
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Affiliation(s)
| | | | - Pierre Buffet
- Université Paris Cité, Inserm, BIGR
- Assistance publique des hôpitaux de Paris
- Institut Pasteur, Université de Paris Cité, Paris, France
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12
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Li H, Qiang Y, Li X, Brugnara C, Buffet PA, Dao M, Karniadakis GE, Suresh S. Biomechanics of phagocytosis of red blood cells by macrophages in the human spleen. Proc Natl Acad Sci U S A 2024; 121:e2414437121. [PMID: 39453740 PMCID: PMC11536160 DOI: 10.1073/pnas.2414437121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 09/17/2024] [Indexed: 10/27/2024] Open
Abstract
The clearance of senescent and altered red blood cells (RBCs) in the red pulp of the human spleen involves sequential processes of prefiltration, filtration, and postfiltration. While prior work has elucidated the mechanisms underlying the first two processes, biomechanical processes driving the postfiltration phagocytosis of RBCs retained at interendothelial slits (IES) are still poorly understood. We present here a unique computational model of macrophages to study the role of cell biomechanics in modulating the kinetics of phagocytosis of aged and diseased RBCs retained in the spleen. After validating the macrophage model using in vitro phagocytosis experiments, we employ it to probe the mechanisms underlying the kinetics of phagocytosis of mechanically altered RBCs, such as heated RBCs and abnormal RBCs in hereditary spherocytosis (HS) and sickle cell disease (SCD). Our simulations show pronounced deformation of the flexible and healthy RBCs in contrast to minimal shape changes in altered RBCs. Simulations also show that less deformable RBCs are engulfed faster and at lower adhesive strength than flexible RBCs, consistent with our experimental measurements. This efficient sensing and engulfment by macrophages of stiff RBCs retained at IES are expected to temper splenic congestion, a common pathogenic process in malaria, HS, and SCD. Altogether, our combined computational and in vitro experimental studies suggest that mechanical alterations of retained RBCs may suffice to enhance their phagocytosis, thereby adapting the kinetics of their elimination to the kinetics of their mechanical retention, an equilibrium essential for adequately cleaning the splenic filter to preserve its function.
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Affiliation(s)
- He Li
- School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens30602, Georgia
| | - Yuhao Qiang
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA02139
| | - Xuejin Li
- Department of Engineering Mechanics and Center for X-Mechanics, Zhejiang University, Hangzhou310027, China
| | - Carlo Brugnara
- Department of Laboratory Medicine, Boston Children’s Hospital, Boston, MA02115
| | - Pierre A. Buffet
- Université Paris Cité, INSERM, Biologie Intégrée du Globule Rouge, Paris75015, France
| | - Ming Dao
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA02139
| | - George E. Karniadakis
- Division of Applied Mathematics, Brown University, Providence, RI02912
- School of Engineering, Brown University, Providence, RI02912
| | - Subra Suresh
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA02139
- School of Engineering, Brown University, Providence, RI02912
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13
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Zhao Y, Wu Y, Fan D, Deng H, Liu L, Deng S, Zhao R, Lu C. Increased Abnormal Erythrocytes Caused by Spleen Filtration Deficiency Provide a Hypoxic Environment for the Occurrence of Psoriasis. Exp Dermatol 2024; 33:e70003. [PMID: 39435748 DOI: 10.1111/exd.70003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 09/14/2024] [Accepted: 10/03/2024] [Indexed: 10/23/2024]
Abstract
Psoriasis is a chronic autoimmune disease with a long disease course and frequent relapse characteristics. It is now recognised to be associated with epidermal environments of inflammatory cytokines. However, its pathogenesis is still not completely clear. We found the haemorheology of psoriatic patients to be abnormal, and ageing and deformed erythrocytes increased in the blood. The abnormal erythrocytes were more likely to induce psoriasis, which was confirmed in a mouse model induced by different blood components of psoriatic patients/healthy volunteers. Spleen filtration dysfunction, which caused abnormal erythrocytes, was also more likely to induce psoriasis, which was confirmed in a mouse model induced by splenectomy. The mechanism was the weakening of the 'eat me' function of spleen macrophages phagocytizing ageing and deformed erythrocytes, resulting in the dysfunction of spleen filtration and the increase of ageing and deformed erythrocytes in the body. Additionally, the decreased oxygen-carrying capacity and the declined antioxidant capacity of those erythrocytes led to the hypoxia environment, making psoriasis more likely to be induced. These findings demonstrate that spleen filtration dysfunction contributes to the pathogenesis of psoriasis and suggest that improving it may be an effective therapy for psoriasis and control its relapse.
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Affiliation(s)
- Ya Zhao
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yayun Wu
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dancai Fan
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hao Deng
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lijuan Liu
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shigui Deng
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ruizhi Zhao
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chuanjian Lu
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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14
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Han K, Ma S, Wang S, Qi X, Bian X, Li X. Interplay between endothelial glycocalyx layer and red blood cell in microvascular blood flow: A numerical study. Phys Rev E 2024; 110:034409. [PMID: 39425342 DOI: 10.1103/physreve.110.034409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 08/22/2024] [Indexed: 10/21/2024]
Abstract
The endothelial glycocalyx layer (EGL) plays a crucial role in regulating blood flow in microvessels. Experimental evidence suggests that there is greater blood flow resistance in vivo compared to in vitro, partially due to the presence of the EGL. However, the complex relationship between EGL deformation and blood cell behavior in shear flow and its quantification remains incompletely understood. To address this gap, we employ a particle-based numerical simulation technique to examine the interaction of the EGL with flowing red blood cells (RBCs) in microtubes. We examine changes in EGL deformation in response to variations in shear rate, EGL graft density, and contour height. Our results indicate that the alterations in EGL height are influenced by the mechanical properties of the EGL, flow conditions, and the RBC-EGL interaction. The flowing RBC compresses the EGL, causing a notable reduction in EGL height near the RBC flow. Additionally, we find that the presence of the EGL in the microtube results in increased RBC deformation and a wider gap between the RBC and tube wall due to spatial occupancy. The significant impact of the EGL on RBC flow is particularly evident in microtubes with diameters ranging from 7 to 10µm, a range consistent with notable differences in vascular flow resistance observed between in vivo and in vitro experiments. The simulation results shed insight on the dynamic interplay between RBC and the EGL in microvascular blood flow.
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Affiliation(s)
- Keqin Han
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Shuhao Ma
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Shuo Wang
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Xiaojing Qi
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Xin Bian
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Xuejin Li
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
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15
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Bräsel B, Geiger M, Linkhorst J, Wessling M. Transport and clogging dynamics of flexible rods in pore constrictions. SOFT MATTER 2024; 20:6767-6778. [PMID: 39136054 DOI: 10.1039/d4sm00734d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Abstract
The transport and clogging behavior of flexible particles in confined flows is a complex interplay between elastic and hydrodynamic forces and wall interactions. While the motion of non-spherical particles in unbounded flows is well understood, their behavior in confined spaces remains less explored. This study introduces a coupled computational fluid dynamics-discrete element method (CFD-DEM) approach to investigate the transport and clogging dynamics of flexible rod-shaped particles in confined pore constrictions. The spatio-temporal analysis reveals the influence of the rod's initial conditions and flexibility on its transport dynamics through a pore constriction. The simulation results demonstrate an increase in the lateral drift of the rod upon exiting the pore that can be scaled with channel height confinement. The clogging dynamics are explored based on hydrodynamic and mechanical forces, unveiling conditions for mechanical clogging through sieving. The developed method allows for the deconvolution of the forces that contribute to particle trajectories in confined flow, which is highly relevant in particle separation processes, fibrous-shaped virus filtration, biological flows, and related applications. The method is embedded into the open-source CFDEM framework, facilitating future extensions to explore multiple particle dynamics, intermolecular forces, external influences, and complex geometries.
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Affiliation(s)
- Berinike Bräsel
- Chemical Process Engineering AVT.CVT, RWTH Aachen University, Forckenbeckstraße 51, 52074 Aachen, Germany.
| | - Matthias Geiger
- Chemical Process Engineering AVT.CVT, RWTH Aachen University, Forckenbeckstraße 51, 52074 Aachen, Germany.
| | - John Linkhorst
- Chemical Process Engineering AVT.CVT, RWTH Aachen University, Forckenbeckstraße 51, 52074 Aachen, Germany.
| | - Matthias Wessling
- Chemical Process Engineering AVT.CVT, RWTH Aachen University, Forckenbeckstraße 51, 52074 Aachen, Germany.
- DWI - Leibniz Institute for Interactive Materials e.V., Forckenbeckstraße 50, 52074 Aachen, Germany
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16
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Zhang L, Wang Z, Sun X, Rong W, Deng W, Yu J, Xu X, Yu Q. Nasal mucosa-derived mesenchymal stem cells prolonged the survival of septic rats by protecting macrophages from pyroptosis. Cell Immunol 2024; 401-402:104840. [PMID: 38880071 DOI: 10.1016/j.cellimm.2024.104840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 05/18/2024] [Accepted: 06/03/2024] [Indexed: 06/18/2024]
Abstract
Sepsis is characterized by an exacerbated inflammatory response, driven by the overproduction of cytokines, a phenomenon known as a cytokine storm. This condition is further compounded by the extensive infiltration of M1 macrophages and the pyroptosis of these cells, leading to immune paralysis. To counteract this, we sought to transition M1 macrophages into the M2 phenotype and safeguard them from pyroptosis. For this purpose, we employed ectodermal mesenchymal stem cells (EMSCs) sourced from the nasal mucosa to examine their impact on both macrophages and septic animal models. The co-culture protocol involving LPS-stimulated rat bone marrow macrophages and EMSCs was employed to examine the paracrine influence of EMSCs on macrophages. The intravenous administration of EMSCs was utilized to observe the enhancement in the survival rate of septic rat models and the protection of associated organs. The findings indicated that EMSCs facilitated M2 polarization of macrophages, which were stimulated by LPS, and significantly diminished levels of pro-inflammatory cytokines and NLRP3. Furthermore, EMSCs notably restored the mitochondrial membrane potential (MMP) of macrophages through paracrine action, eliminated excess reactive oxygen species (ROS), and inhibited macrophage pyroptosis. Additionally, the systemic integration of EMSCs substantially reduced injuries to multiple organs and preserved the fundamental functions of the heart, liver, and kidney in CLP rats, thereby extending their survival.
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Affiliation(s)
| | - Zhe Wang
- School of Pharmacy, Jiangsu University, China
| | - Xuan Sun
- School of Pharmacy, Jiangsu University, China
| | | | - Wenwen Deng
- School of Pharmacy, Jiangsu University, China
| | - Jiangnan Yu
- School of Pharmacy, Jiangsu University, China
| | - Ximing Xu
- School of Pharmacy, Jiangsu University, China
| | - Qingtong Yu
- School of Pharmacy, Jiangsu University, China.
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17
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Wang S, Ma S, Li H, Dao M, Li X, Karniadakis GE. Two-component macrophage model for active phagocytosis with pseudopod formation. Biophys J 2024; 123:1069-1084. [PMID: 38532625 PMCID: PMC11079866 DOI: 10.1016/j.bpj.2024.03.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 11/20/2023] [Accepted: 03/21/2024] [Indexed: 03/28/2024] Open
Abstract
Macrophage phagocytosis is critical for the immune response, homeostasis regulation, and tissue repair. This intricate process involves complex changes in cell morphology, cytoskeletal reorganization, and various receptor-ligand interactions controlled by mechanical constraints. However, there is a lack of comprehensive theoretical and computational models that investigate the mechanical process of phagocytosis in the context of cytoskeletal rearrangement. To address this issue, we propose a novel coarse-grained mesoscopic model that integrates a fluid-like cell membrane and a cytoskeletal network to study the dynamic phagocytosis process. The growth of actin filaments results in the formation of long and thin pseudopods, and the initial cytoskeleton can be disassembled upon target entry and reconstructed after phagocytosis. Through dynamic changes in the cytoskeleton, our macrophage model achieves active phagocytosis by forming a phagocytic cup utilizing pseudopods in two distinct ways. We have developed a new algorithm for modifying membrane area to prevent membrane rupture and ensure sufficient surface area during phagocytosis. In addition, the bending modulus, shear stiffness, and cortical tension of the macrophage model are investigated through computation of the axial force for the tubular structure and micropipette aspiration. With this model, we simulate active phagocytosis at the cytoskeletal level and investigate the mechanical process during the dynamic interplay between macrophage and target particles.
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Affiliation(s)
- Shuo Wang
- Department of Engineering Mechanics and Center for X-Mechanics, Zhejiang University, Hangzhou, Zhejiang, China
| | - Shuhao Ma
- Department of Engineering Mechanics and Center for X-Mechanics, Zhejiang University, Hangzhou, Zhejiang, China
| | - He Li
- School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens, Georgia
| | - Ming Dao
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Xuejin Li
- Department of Engineering Mechanics and Center for X-Mechanics, Zhejiang University, Hangzhou, Zhejiang, China.
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18
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Yang WP, Li MQ, Ding J, Li JY, Wu G, Liu B, Gao YQ, Wang GH, Luo QQ. High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen. eLife 2024; 12:RP87496. [PMID: 38629942 PMCID: PMC11023697 DOI: 10.7554/elife.87496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/19/2024] Open
Abstract
High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen's ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.
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Affiliation(s)
- Wan-ping Yang
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong UniversityNantongChina
| | - Mei-qi Li
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong UniversityNantongChina
| | - Jie Ding
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong UniversityNantongChina
| | - Jia-yan Li
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong UniversityNantongChina
| | - Gang Wu
- College of High-Altitude Military Medicine, Institute of Medicine and Hygienic Equipment for High Altitude Region, Army Medical UniversityChongqingChina
- Key Laboratory of Extreme Environmental Medicine and High-Altitude Medicine, Ministry of Education of ChinaChongqingChina
| | - Bao Liu
- College of High-Altitude Military Medicine, Institute of Medicine and Hygienic Equipment for High Altitude Region, Army Medical UniversityChongqingChina
- Key Laboratory of Extreme Environmental Medicine and High-Altitude Medicine, Ministry of Education of ChinaChongqingChina
| | - Yu-qi Gao
- College of High-Altitude Military Medicine, Institute of Medicine and Hygienic Equipment for High Altitude Region, Army Medical UniversityChongqingChina
- Key Laboratory of Extreme Environmental Medicine and High-Altitude Medicine, Ministry of Education of ChinaChongqingChina
| | - Guo-hua Wang
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong UniversityNantongChina
- Department of Neurosurgery, Southwest Hospital, Army Medical UniversityChongqingChina
| | - Qian-qian Luo
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong UniversityNantongChina
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19
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Zhang Y, Qiang Y, Li H, Li G, Lu L, Dao M, Karniadakis GE, Popel AS, Zhao C. Signaling-biophysical modeling unravels mechanistic control of red blood cell phagocytosis by macrophages in sickle cell disease. PNAS NEXUS 2024; 3:pgae031. [PMID: 38312226 PMCID: PMC10833451 DOI: 10.1093/pnasnexus/pgae031] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 01/09/2024] [Indexed: 02/06/2024]
Abstract
Red blood cell (RBC) aging manifests through progressive changes in cell morphology, rigidity, and expression of membrane proteins. To maintain the quality of circulating blood, splenic macrophages detect the biochemical signals and biophysical changes of RBCs and selectively clear them through erythrophagocytosis. In sickle cell disease (SCD), RBCs display alterations affecting their interaction with macrophages, leading to aberrant phagocytosis that may cause life-threatening spleen sequestration crises. To illuminate the mechanistic control of RBC engulfment by macrophages in SCD, we integrate a system biology model of RBC-macrophage signaling interactions with a biophysical model of macrophage engulfment, as well as in vitro phagocytosis experiments using the spleen-on-a-chip technology. Our modeling framework accurately predicts the phagocytosis dynamics of RBCs under different disease conditions, reveals patterns distinguishing normal and sickle RBCs, and identifies molecular targets including Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP1) and cluster of differentiation 47 (CD47)/signal regulatory protein α (SIRPα) as therapeutic targets to facilitate the controlled clearance of sickle RBCs in the spleen.
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Affiliation(s)
- Yu Zhang
- Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Yuhao Qiang
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - He Li
- School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens, GA 30602, USA
| | - Guansheng Li
- School of Engineering, Brown University, Providence, RI 02912, USA
| | - Lu Lu
- Department of Statistics and Data Science, Yale University, New Haven, CT 06520, USA
| | - Ming Dao
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | | | - Aleksander S Popel
- Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Chen Zhao
- School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 210029, China
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20
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He Y, Cheng C, Liu Y, Chen FM, Chen Y, Yang C, Zhao Z, Dawulieti J, Shen Z, Zhang Y, Du JZ, Guan S, Shao D. Intravenous Senescent Erythrocyte Vaccination Modulates Adaptive Immunity and Splenic Complement Production. ACS NANO 2024; 18:470-482. [PMID: 38146673 DOI: 10.1021/acsnano.3c07943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2023]
Abstract
Targeted delivery of vaccines to the spleen remains a challenge. Inspired by the erythrophagocytotic process in the spleen, we herein report that intravenous administration of senescent erythrocyte-based vaccines profoundly alters their tropism toward splenic antigen-presenting cells (APCs) for imprinting adaptive immune responses. Compared with subcutaneous inoculation, intravenous vaccination significantly upregulated splenic complement expression in vivo and demonstrated synergistic antibody killing in vitro. Consequently, intravenous senescent erythrocyte vaccination produces potent SARS-CoV-2 antibody-neutralizing effects, with potential protective immune responses. Moreover, the proposed senescent erythrocyte can deliver antigens from resected tumors and adjuvants to splenic APCs, thereby inducing a personalized immune reaction against tumor recurrence after surgery. Hence, our findings suggest that senescent erythrocyte-based vaccines can specifically target splenic APCs and evoke adaptive immunity and complement production, broadening the tools for modulating immunity, helping to understand adaptive response mechanisms to senescent erythrocytes better, and developing improved vaccines against cancer and infectious diseases.
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Affiliation(s)
- Yan He
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, Guangdong 511442, China
| | - Chuanxu Cheng
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, Guangdong 511442, China
| | - Yuheng Liu
- National Engineering Research Center of Immunological Products, Third Military Medical University, Chongqing 400038, China
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
| | - Fang-Man Chen
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, Guangdong 511442, China
| | - Yinglu Chen
- School of Medicine, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 510006, China
| | - Chao Yang
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, Guangdong 511442, China
- Department of Orthopedics, Academy of Orthopedics-Guangdong Province, Orthopedic Hospital of Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510665, China
| | - Zhibin Zhao
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Jianati Dawulieti
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, Guangdong 511442, China
| | - Zikun Shen
- School of Medicine, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 510006, China
| | - Yunjiao Zhang
- School of Medicine, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 510006, China
| | - Jin-Zhi Du
- School of Medicine, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 510006, China
| | - Shan Guan
- National Engineering Research Center of Immunological Products, Third Military Medical University, Chongqing 400038, China
| | - Dan Shao
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, Guangdong 511442, China
- School of Medicine, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, Guangdong 510006, China
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21
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Qi X, Ma S, Jiang X, Wu H, Zheng J, Wang S, Han K, Zhang T, Gao J, Li X. Single-cell characterization of deformation and dynamics of mesenchymal stem cells in microfluidic systems: A computational study. Phys Rev E 2023; 108:054402. [PMID: 38115453 DOI: 10.1103/physreve.108.054402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 10/13/2023] [Indexed: 12/21/2023]
Abstract
Understanding the homing dynamics of individual mesenchymal stem cells (MSCs) in physiologically relevant microenvironments is crucial for improving the efficacy of MSC-based therapies for therapeutic and targeting purposes. This study investigates the passive homing behavior of individual MSCs in micropores that mimic interendothelial clefts through predictive computational simulations informed by previous microfluidic experiments. Initially, we quantified the size-dependent behavior of MSCs in micropores and elucidated the underlying mechanisms. Subsequently, we analyzed the shape deformation and traversal dynamics of each MSC. In addition, we conducted a systematic investigation to understand how the mechanical properties of MSCs impact their traversal process. We considered geometric and mechanical parameters, such as reduced cell volume, cell-to-nucleus diameter ratio, and cytoskeletal prestress states. Furthermore, we quantified the changes in the MSC traversal process and identified the quantitative limits in their response to variations in micropore length. Taken together, the computational results indicate the complex dynamic behavior of individual MSCs in the confined microflow. This finding offers an objective way to evaluate the homing ability of MSCs in an interendothelial-slit-like microenvironment.
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Affiliation(s)
- Xiaojing Qi
- Department of Engineering Mechanics and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Shuhao Ma
- Department of Engineering Mechanics and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Xinchi Jiang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310027, China
| | - Honghui Wu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310027, China
| | - Juanjuan Zheng
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310027, China
| | - Shuo Wang
- Department of Engineering Mechanics and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Keqin Han
- Department of Engineering Mechanics and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Tianyuan Zhang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310027, China
| | - Jianqing Gao
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310027, China
| | - Xuejin Li
- Department of Engineering Mechanics and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
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22
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Moreau A, Yaya F, Lu H, Surendranath A, Charrier A, Dehapiot B, Helfer E, Viallat A, Peng Z. Physical mechanisms of red blood cell splenic filtration. Proc Natl Acad Sci U S A 2023; 120:e2300095120. [PMID: 37874856 PMCID: PMC10622898 DOI: 10.1073/pnas.2300095120] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 09/02/2023] [Indexed: 10/26/2023] Open
Abstract
The splenic interendothelial slits fulfill the essential function of continuously filtering red blood cells (RBCs) from the bloodstream to eliminate abnormal and aged cells. To date, the process by which 8 [Formula: see text]m RBCs pass through 0.3 [Formula: see text]m-wide slits remains enigmatic. Does the slit caliber increase during RBC passage as sometimes suggested? Here, we elucidated the mechanisms that govern the RBC retention or passage dynamics in slits by combining multiscale modeling, live imaging, and microfluidic experiments on an original device with submicron-wide physiologically calibrated slits. We observed that healthy RBCs pass through 0.28 [Formula: see text]m-wide rigid slits at 37 °C. To achieve this feat, they must meet two requirements. Geometrically, their surface area-to-volume ratio must be compatible with a shape in two tether-connected equal spheres. Mechanically, the cells with a low surface area-to-volume ratio (28% of RBCs in a 0.4 [Formula: see text]m-wide slit) must locally unfold their spectrin cytoskeleton inside the slit. In contrast, activation of the mechanosensitive PIEZO1 channel is not required. The RBC transit time through the slits follows a [Formula: see text]1 and [Formula: see text]3 power law with in-slit pressure drop and slip width, respectively. This law is similar to that of a Newtonian fluid in a two-dimensional Poiseuille flow, showing that the dynamics of RBCs is controlled by their cytoplasmic viscosity. Altogether, our results show that filtration through submicron-wide slits is possible without further slit opening. Furthermore, our approach addresses the critical need for in vitro evaluation of splenic clearance of diseased or engineered RBCs for transfusion and drug delivery.
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Affiliation(s)
- Alexis Moreau
- Aix Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, Turing Centre for Living Systems, Marseille13009, France
| | - François Yaya
- Aix Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, Turing Centre for Living Systems, Marseille13009, France
| | - Huijie Lu
- Richard and Loan Hill Department of Biomedical Engineering, University of Illinois, Chicago, IL60612
| | - Anagha Surendranath
- Aix Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, Turing Centre for Living Systems, Marseille13009, France
| | - Anne Charrier
- Aix Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, Turing Centre for Living Systems, Marseille13009, France
| | - Benoit Dehapiot
- Aix Marseille Université, CNRS, Institut de Biologie du Développement de Marseille, Turing Centre for Living Systems, Marseille13009, France
| | - Emmanuèle Helfer
- Aix Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, Turing Centre for Living Systems, Marseille13009, France
| | - Annie Viallat
- Aix Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, Turing Centre for Living Systems, Marseille13009, France
| | - Zhangli Peng
- Richard and Loan Hill Department of Biomedical Engineering, University of Illinois, Chicago, IL60612
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23
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Bakr S, Yousief E, Ezzat EM, Elsary AY, Elamir AM, Gamal M. Screening of subclinical functional hemoglobin and red blood cell abnormalities among blood donors of Fayoum University Hospital in Egypt: Are RET-He, and IRF useful screening tools? Transfus Apher Sci 2023; 62:103781. [PMID: 37524581 DOI: 10.1016/j.transci.2023.103781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/20/2023] [Accepted: 07/26/2023] [Indexed: 08/02/2023]
Abstract
BACKGROUND The effectiveness of red cell transfusion in a given blood unit that relied on both quantity and quality of donated cells undoubtedly affects prognostic outcomes. OBJECTIVE We aimed to determine the frequency of subclinical functional hemoglobin and red cell abnormalities in donated blood of Fayoum University Hospital in Egypt. Additionally, to assess the usefulness of reticulocyte mean hemoglobin content (RET-He) and immature reticulocyte fraction (IRF) as screening measures for such abnormalities. MATERIAL AND METHODS This cross-sectional study enrolled 200 volunteer blood donors who met the national standard criterion of blood donation. Complete blood count with reticulocyte parameters, serum ferritin, sickling test, G6PD assay, Mentzer index, and naked-eye single tube red cell osmotic fragility test were carried out. RESULTS Functional red cell abnormalities represented 44 % of this cohort. Out of them, 4.5 % had iron deficiency, 11 % had a positive sickling test, 19 % had G6PD deficiency, and 9.5 % had suspicious thalassemia. The sensitivity and specificity test for RET-He in selective identification of functional hemoglobin abnormalities in donated blood were 83.3 % and 61.2 %, respectively at a cutoff value of 26.9. Though there was no statistically significant effect of RET-He on the selective detection of G6PD deficiency, IRF had a statistically significant high level with a p-value of 0.04. CONCLUSION Subclinical functional red cell abnormalities seem to be prevalent among blood donors. Reticulocyte/ erythrocyte indices could be useful screening tools for red cell abnormalities. Further studies are required for assessing the impact of transfusing such abnormalities to neonates and other critical recipients.
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Affiliation(s)
- Salwa Bakr
- Department of Clinical Pathology/Hematology, Faculty of Medicine, Fayoum University, Fayoum, Egypt.
| | - Eman Yousief
- Department of Clinical Pathology/Hematology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Eman Mahmoud Ezzat
- Department of Internal Medicine, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Asmaa Younis Elsary
- Department of Public Health and Community Medicine, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Azza M Elamir
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Mona Gamal
- Department of Clinical Pathology/Hematology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
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24
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Cloos AS, Pollet H, Stommen A, Maja M, Lingurski M, Brichard B, Lambert C, Henriet P, Pierreux C, Pyr dit Ruys S, Van Der Smissen P, Vikkula M, Gatto L, Martin M, Brouillard P, Vertommen D, Tyteca D. Splenectomy improves erythrocyte functionality in spherocytosis based on septin abundance, but not maturation defects. Blood Adv 2023; 7:4705-4720. [PMID: 36753606 PMCID: PMC10468371 DOI: 10.1182/bloodadvances.2022009114] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/30/2022] [Accepted: 01/13/2023] [Indexed: 02/10/2023] Open
Abstract
Splenectomy improves the clinical parameters of patients with hereditary spherocytosis, but its potential benefit to red blood cell (RBC) functionality and the mechanism behind this benefit remain largely overlooked. Here, we compared 7 nonsplenectomized and 13 splenectomized patients with mutations in the β-spectrin or the ankyrin gene. We showed that hematological parameters, spherocyte abundance, osmotic fragility, intracellular calcium, and extracellular vesicle release were largely but not completely restored by splenectomy, whereas cryohemolysis was not. Affected RBCs exhibited decreases in β-spectrin and/or ankyrin contents and slight alterations in spectrin membrane distribution, depending on the mutation. These modifications were found in both splenectomized and nonsplenectomized patients and poorly correlated with RBC functionality alteration, suggesting additional impairments. Accordingly, we found an increased abundance of septins, small guanosine triphosphate-binding cytoskeletal proteins. Septins-2, -7, and -8 but not -11 were less abundant upon splenectomy and correlated with the disease severity. Septin-2 membrane association was confirmed by immunolabeling. Except for cryohemolysis, all parameters of RBC morphology and functionality correlated with septin abundance. The increased septin content might result from RBC maturation defects, as evidenced by (1) the decreased protein 4.2 and Rh-associated glycoprotein content in all patient RBCs, (2) increased endoplasmic reticulum remnants and endocytosis proteins in nonsplenectomized patients, and (3) increased lysosomal and mitochondrial remnants in splenectomized patients. Our study paves the way for a better understanding of the involvement of septins in RBC membrane biophysical properties. In addition, the lack of restoration of septin-independent cryohemolysis by splenectomy may call into question its recommendation in specific cases.
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Affiliation(s)
- Anne-Sophie Cloos
- CELL Unit & PICT Imaging Platform, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Hélène Pollet
- CELL Unit & PICT Imaging Platform, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Amaury Stommen
- CELL Unit & PICT Imaging Platform, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Mauriane Maja
- CELL Unit & PICT Imaging Platform, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Maxime Lingurski
- CELL Unit & PICT Imaging Platform, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Bénédicte Brichard
- Pediatric Hematology & Oncology Unit, Saint-Luc Hospital, UCLouvain, Brussels, Belgium
| | | | - Patrick Henriet
- CELL Unit & PICT Imaging Platform, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Christophe Pierreux
- CELL Unit & PICT Imaging Platform, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Sébastien Pyr dit Ruys
- PHOS Unit & MASSPROT Proteomics Platform, de Duve Institute, UCLouvain, Brussels, Belgium
| | | | - Miikka Vikkula
- Human Molecular Genetics Unit, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Laurent Gatto
- Computational Biology and Bioinformatics Unit, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Manon Martin
- Computational Biology and Bioinformatics Unit, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Pascal Brouillard
- Human Molecular Genetics Unit, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Didier Vertommen
- PHOS Unit & MASSPROT Proteomics Platform, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Donatienne Tyteca
- CELL Unit & PICT Imaging Platform, de Duve Institute, UCLouvain, Brussels, Belgium
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25
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Lu Q, Yu H, Zhao T, Zhu G, Li X. Nanoparticles with transformable physicochemical properties for overcoming biological barriers. NANOSCALE 2023; 15:13202-13223. [PMID: 37526946 DOI: 10.1039/d3nr01332d] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/02/2023]
Abstract
In recent years, tremendous progress has been made in the development of nanomedicines for advanced therapeutics, yet their unsatisfactory targeting ability hinders the further application of nanomedicines. Nanomaterials undergo a series of processes, from intravenous injection to precise delivery at target sites. Each process faces different or even contradictory requirements for nanoparticles to pass through biological barriers. To overcome biological barriers, researchers have been developing nanomedicines with transformable physicochemical properties in recent years. Physicochemical transformability enables nanomedicines to responsively switch their physicochemical properties, including size, shape, surface charge, etc., thus enabling them to cross a series of biological barriers and achieve maximum delivery efficiency. In this review, we summarize recent developments in nanomedicines with transformable physicochemical properties. First, the biological dilemmas faced by nanomedicines are analyzed. Furthermore, the design and synthesis of nanomaterials with transformable physicochemical properties in terms of size, charge, and shape are summarized. Other switchable physicochemical parameters such as mobility, roughness and mechanical properties, which have been sought after most recently, are also discussed. Finally, the prospects and challenges for nanomedicines with transformable physicochemical properties are highlighted.
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Affiliation(s)
- Qianqian Lu
- Department of Chemistry, Laboratory of Advanced Materials, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, State Key Laboratory of Molecular Engineering of Polymers, Collaborative Innovation Center of Chemistry for Energy Materials (2011-iChEM), Fudan University, Shanghai 200433, P. R. China.
| | - Hongyue Yu
- Department of Chemistry, Laboratory of Advanced Materials, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, State Key Laboratory of Molecular Engineering of Polymers, Collaborative Innovation Center of Chemistry for Energy Materials (2011-iChEM), Fudan University, Shanghai 200433, P. R. China.
| | - Tiancong Zhao
- Department of Chemistry, Laboratory of Advanced Materials, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, State Key Laboratory of Molecular Engineering of Polymers, Collaborative Innovation Center of Chemistry for Energy Materials (2011-iChEM), Fudan University, Shanghai 200433, P. R. China.
| | - Guanjia Zhu
- Institute of Nanochemistry and Nanobiology, Shanghai University, Shanghai 200444, P. R. China.
| | - Xiaomin Li
- Department of Chemistry, Laboratory of Advanced Materials, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, State Key Laboratory of Molecular Engineering of Polymers, Collaborative Innovation Center of Chemistry for Energy Materials (2011-iChEM), Fudan University, Shanghai 200433, P. R. China.
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26
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Li G, Qiang Y, Li H, Li X, Dao M, Karniadakis GE. In silico and in vitro study of the adhesion dynamics of erythrophagocytosis in sickle cell disease. Biophys J 2023; 122:2590-2604. [PMID: 37231647 PMCID: PMC10323029 DOI: 10.1016/j.bpj.2023.05.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 04/12/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023] Open
Abstract
Erythrophagocytosis occurring in the spleen is a critical process for removing senescent and diseased red blood cells (RBCs) from the microcirculation. Although some progress has been made in understanding how the biological signaling pathways mediate the phagocytic processes, the role of the biophysical interaction between RBCs and macrophages, particularly under pathological conditions such as sickle cell disease, has not been adequately studied. Here, we combine computational simulations with microfluidic experiments to quantify RBC-macrophage adhesion dynamics under flow conditions comparable to those in the red pulp of the spleen. We also investigate the RBC-macrophage interaction under normoxic and hypoxic conditions. First, we calibrate key model parameters in the adhesion model using microfluidic experiments for normal and sickle RBCs under normoxia and hypoxia. We then study the adhesion dynamics between the RBC and the macrophage. Our simulation illustrates three typical adhesion states, each characterized by a distinct dynamic motion of the RBCs, namely firm adhesion, flipping adhesion, and no adhesion (either due to no contact with macrophages or detachment from the macrophages). We also track the number of bonds formed when RBCs and macrophages are in contact, as well as the contact area between the two interacting cells, providing mechanistic explanations for the three adhesion states observed in the simulations and microfluidic experiments. Furthermore, we quantify, for the first time to our knowledge, the adhesive forces between RBCs (normal and sickle) and macrophages under different oxygenated conditions. Our results show that the adhesive forces between normal cells and macrophages under normoxia are in the range of 33-58 pN and 53-92 pN for sickle cells under normoxia and 155-170 pN for sickle cells under hypoxia. Taken together, our microfluidic and simulation results improve our understanding of the biophysical interaction between RBCs and macrophages in sickle cell disease and provide a solid foundation for investigating the filtration function of the splenic macrophages under physiological and pathological conditions.
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Affiliation(s)
- Guansheng Li
- Division of Applied Mathematics, Brown University, Providence, Rhode Island
| | - Yuhao Qiang
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - He Li
- School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens, Georgia.
| | - Xuejin Li
- Department of Engineering Mechanics and Center for X-Mechanics, Zhejiang University, Hangzhou, China
| | - Ming Dao
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
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27
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Li G, Qiang Y, Li H, Li X, Buffet PA, Dao M, Karniadakis GE. A combined computational and experimental investigation of the filtration function of splenic macrophages in sickle cell disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.31.543007. [PMID: 37398427 PMCID: PMC10312537 DOI: 10.1101/2023.05.31.543007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Being the largest lymphatic organ in the body, the spleen also constantly controls the quality of red blood cells (RBCs) in circulation through its two major filtration components, namely interendothelial slits (IES) and red pulp macrophages. In contrast to the extensive studies in understanding the filtration function of IES, there are relatively fewer works on investigating how the splenic macrophages retain the aged and diseased RBCs, i.e., RBCs in sickle cell disease (SCD). Herein, we perform a computational study informed by companion experiments to quantify the dynamics of RBCs captured and retained by the macrophages. We first calibrate the parameters in the computational model based on microfluidic experimental measurements for sickle RBCs under normoxia and hypoxia, as those parameters are not available in the literature. Next, we quantify the impact of a set of key factors that are expected to dictate the RBC retention by the macrophages in the spleen, namely, blood flow conditions, RBC aggregation, hematocrit, RBC morphology, and oxygen levels. Our simulation results show that hypoxic conditions could enhance the adhesion between the sickle RBCs and macrophages. This, in turn, increases the retention of RBCs by as much as five-fold, which could be a possible cause of RBC congestion in the spleen of patients with SCD. Our study on the impact of RBC aggregation illustrates a 'clustering effect', where multiple RBCs in one aggregate can make contact and adhere to the macrophages, leading to a higher retention rate than that resulting from RBC-macrophage pair interactions. Our simulations of sickle RBCs flowing past macrophages for a range of blood flow velocities indicate that the increased blood velocity could quickly attenuate the function of the red pulp macrophages on detaining aged or diseased RBCs, thereby providing a possible rationale for the slow blood flow in the open circulation of the spleen. Furthermore, we quantify the impact of RBC morphology on their tendency to be retained by the macrophages. We find that the sickle and granular-shaped RBCs are more likely to be filtered by macrophages in the spleen. This finding is consistent with the observation of low percentages of these two forms of sickle RBCs in the blood smear of SCD patients. Taken together, our experimental and simulation results aid in our quantitative understanding of the function of splenic macrophages in retaining the diseased RBCs and provide an opportunity to combine such knowledge with the current knowledge of the interaction between IES and traversing RBCs to apprehend the complete filtration function of the spleen in SCD.
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Affiliation(s)
- Guansheng Li
- Division of Applied Mathematics, Brown University, Providence, Rhode Island, 02906
| | - Yuhao Qiang
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139
| | - He Li
- School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens, Georgia, 30602
| | - Xuejin Li
- Department of Engineering Mechanics and Center for X-Mechanics, Zhejiang University, Hangzhou, Zhejiang 310027, China
| | - Pierre A. Buffet
- Université Paris Cité and Université des Antilles, Inserm, Biologie Intégrée du Globule Rouge, 75015, Paris, France
- Laboratoire d′Excellence du Globule Rouge, 75015, Paris, France
| | - Ming Dao
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139
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28
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Wei Q, Wang X, Zhang C, Dao M, Gong X. Evolution of surface area and membrane shear modulus of matured human red blood cells during mechanical fatigue. Sci Rep 2023; 13:8563. [PMID: 37237001 DOI: 10.1038/s41598-023-34605-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 05/04/2023] [Indexed: 05/28/2023] Open
Abstract
Mechanical properties of red blood cells (RBCs) change during their senescence which supports numerous physiological or pathological processes in circulatory systems by providing crucial cellular mechanical environments of hemodynamics. However, quantitative studies on the aging and variations of RBC properties are largely lacking. Herein, we investigate morphological changes, softening or stiffening of single RBCs during aging using an in vitro mechanical fatigue model. Using a microfluidic system with microtubes, RBCs are repeatedly subjected to stretch and relaxation as they squeeze into and out of a sudden contraction region. Geometric parameters and mechanical properties of healthy human RBCs are characterized systematically upon each mechanical loading cycle. Our experimental results identify three typical shape transformations of RBCs during mechanical fatigue, which are all strongly associated with the loss of surface area. We constructed mathematical models for the evolution of surface area and membrane shear modulus of single RBCs during mechanical fatigue, and quantitatively developed an ensemble parameter to evaluate the aging status of RBCs. This study provides not only a novel in vitro fatigue model for investigating the mechanical behavior of RBCs, but also an index closely related to the age and inherent physical properties for a quantitative differentiation of individual RBCs.
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Affiliation(s)
- Qiaodong Wei
- Key Laboratory of Hydrodynamics (Ministry of Education), Department of Engineering Mechanics, School of Naval Architecture Ocean and Civil Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Xiaolong Wang
- Key Laboratory of Hydrodynamics (Ministry of Education), Department of Engineering Mechanics, School of Naval Architecture Ocean and Civil Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Ce Zhang
- Institute of Photonics and Photon Technology, State Key Laboratory of Photon-Technology in Western China Energy, Northwest University, Xi'an, 710100, China
| | - Ming Dao
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Xiaobo Gong
- Key Laboratory of Hydrodynamics (Ministry of Education), Department of Engineering Mechanics, School of Naval Architecture Ocean and Civil Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China.
- State Key Laboratory of Ocean Engineering, School of Naval Architecture, Ocean and Civil Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China.
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29
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Msosa C, Abdalrahman T, Franz T. An analytical model describing the mechanics of erythrocyte membrane wrapping during active invasion of a plasmodium falciparum merozoite. J Mech Behav Biomed Mater 2023; 140:105685. [PMID: 36746046 DOI: 10.1016/j.jmbbm.2023.105685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 12/22/2022] [Accepted: 01/23/2023] [Indexed: 01/27/2023]
Abstract
The invasion of a merozoite into an erythrocyte by membrane wrapping is a hallmark of malaria pathogenesis. The invasion involves biomechanical interactions whereby the merozoite exerts actomyosin-based forces to push itself into and through the erythrocyte membrane while concurrently inducing biochemical damage to the erythrocyte membrane. Whereas the biochemical damage process has been investigated, the detailed mechanistic understanding of the invasion mechanics remains limited. Thus, the current study aimed to develop a mathematical model describing the mechanical factors involved in the merozoite invasion into an erythrocyte and explore the invasion mechanics. A shell theory model was developed comprising constitutive, equilibrium and governing equations of the deformable erythrocyte membrane to predict membrane mechanics during the wrapping of an entire non-deformable ellipsoidal merozoite. Predicted parameters include principal erythrocyte membrane deformations and stresses, wrapping and indentation forces, and indentation work. The numerical investigations considered two limits for the erythrocyte membrane deformation during wrapping (4% and 51% areal strain) and erythrocyte membrane phosphorylation (decrease of membrane elastic modulus from 1 to 0.5 kPa). For an intact erythrocyte, the maximum indentation force was 1 and 8.5 pN, and the indentation work was 1.92 × 10-18 and 1.40 × 10-17 J for 4% and 51% areal membrane strain. Phosphorylation damage in the erythrocyte membrane reduced the required indentation work by 50% to 0.97 × 10-18 and 0.70 × 10-17 J for 4% and 51% areal strain. The current study demonstrated the developed model's feasibility to provide new knowledge on the physical mechanisms of the merozoite invasion process that contribute to the invasion efficiency towards the discovery of new invasion-blocking anti-malaria drugs.
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Affiliation(s)
- Chimwemwe Msosa
- Biomedical Engineering Research Centre, Division of Biomedical Engineering, Department of Human Biology, University of Cape Town, Observatory, 7925, South Africa; Faculty of Engineering, Department of Electrical Engineering, Malawi University of Business and Applied Sciences, Blantyre, Malawi.
| | - Tamer Abdalrahman
- Biomedical Engineering Research Centre, Division of Biomedical Engineering, Department of Human Biology, University of Cape Town, Observatory, 7925, South Africa; Computational Mechanobiology, Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Charité Universitätsmedizin, Berlin, 13353, Germany
| | - Thomas Franz
- Biomedical Engineering Research Centre, Division of Biomedical Engineering, Department of Human Biology, University of Cape Town, Observatory, 7925, South Africa; Bioengineering Science Research Group, Engineering Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, SO171BJ, UK
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30
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Kosenko E, Tikhonova L, Alilova G, Montoliu C. Erythrocytes Functionality in SARS-CoV-2 Infection: Potential Link with Alzheimer's Disease. Int J Mol Sci 2023; 24:5739. [PMID: 36982809 PMCID: PMC10051442 DOI: 10.3390/ijms24065739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/14/2023] [Accepted: 03/15/2023] [Indexed: 03/19/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a rapidly spreading acute respiratory infection caused by SARS-CoV-2. The pathogenesis of the disease remains unclear. Recently, several hypotheses have emerged to explain the mechanism of interaction between SARS-CoV-2 and erythrocytes, and its negative effect on the oxygen-transport function that depends on erythrocyte metabolism, which is responsible for hemoglobin-oxygen affinity (Hb-O2 affinity). In clinical settings, the modulators of the Hb-O2 affinity are not currently measured to assess tissue oxygenation, thereby providing inadequate evaluation of erythrocyte dysfunction in the integrated oxygen-transport system. To discover more about hypoxemia/hypoxia in COVID-19 patients, this review highlights the need for further investigation of the relationship between biochemical aberrations in erythrocytes and oxygen-transport efficiency. Furthermore, patients with severe COVID-19 experience symptoms similar to Alzheimer's, suggesting that their brains have been altered in ways that increase the likelihood of Alzheimer's. Mindful of the partly assessed role of structural, metabolic abnormalities that underlie erythrocyte dysfunction in the pathophysiology of Alzheimer's disease (AD), we further summarize the available data showing that COVID-19 neurocognitive impairments most probably share similar patterns with known mechanisms of brain dysfunctions in AD. Identification of parameters responsible for erythrocyte function that vary under SARS-CoV-2 may contribute to the search for additional components of progressive and irreversible failure in the integrated oxygen-transport system leading to tissue hypoperfusion. This is particularly relevant for the older generation who experience age-related disorders of erythrocyte metabolism and are prone to AD, and provide an opportunity for new personalized therapies to control this deadly infection.
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Affiliation(s)
- Elena Kosenko
- Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, 142290 Pushchino, Russia
| | - Lyudmila Tikhonova
- Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, 142290 Pushchino, Russia
| | - Gubidat Alilova
- Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, 142290 Pushchino, Russia
| | - Carmina Montoliu
- Hospital Clinico Research Foundation, INCLIVA Health Research Institute, 46010 Valencia, Spain
- Pathology Department, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain
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31
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Kato R, Yano TA, Tanaka T. Single-cell infrared vibrational analysis by optical trapping mid-infrared photothermal microscopy. Analyst 2023; 148:1285-1290. [PMID: 36811918 DOI: 10.1039/d2an01917e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/19/2023]
Abstract
Single-cell analysis by means of vibrational spectroscopy combined with optical trapping is a reliable platform for unveiling cell-to-cell heterogeneities in vast populations. Although infrared (IR) vibrational spectroscopy provides rich molecular fingerprint information on biological samples in a label-free manner, its application with optical trapping has never been achieved due to weak gradient forces generated by the diffraction-limited focused IR beam and strong background of water absorption. Herein, we present single-cell IR vibrational analysis that incorporates mid-infrared photothermal (MIP) microscopy with optical trapping. Optically trapped single polymer particles and red blood cells (RBCs) in blood could be chemically identified owing to their IR vibrational fingerprints. This single-cell IR vibrational analysis further allowed us to probe the chemical heterogeneities of RBCs originating from the variation in the intracellular characteristics. Our demonstration paves the way for the IR vibrational analysis of single cells and chemical characterization in various fields.
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Affiliation(s)
- Ryo Kato
- Institute of Post-LED Photonics, Tokushima University, 2-1 Minamijosanjima-cho, Tokushima, Tokushima 770-0856, Japan. .,Innovative Photon Manipulation Research Team, RIKEN Center for Advanced Photonics, Wako, Saitama 351-0198, Japan. .,Metamaterials Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan
| | - Taka-Aki Yano
- Institute of Post-LED Photonics, Tokushima University, 2-1 Minamijosanjima-cho, Tokushima, Tokushima 770-0856, Japan. .,Innovative Photon Manipulation Research Team, RIKEN Center for Advanced Photonics, Wako, Saitama 351-0198, Japan. .,Metamaterials Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan
| | - Takuo Tanaka
- Institute of Post-LED Photonics, Tokushima University, 2-1 Minamijosanjima-cho, Tokushima, Tokushima 770-0856, Japan. .,Innovative Photon Manipulation Research Team, RIKEN Center for Advanced Photonics, Wako, Saitama 351-0198, Japan. .,Metamaterials Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan
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Bogusławska DM, Kraszewski S, Skulski M, Potoczek S, Kuliczkowski K, Sikorski AF. Novel Variant of the SLC4A1 Gene Associated with Hereditary Spherocytosis. Biomedicines 2023; 11:biomedicines11030784. [PMID: 36979763 PMCID: PMC10045460 DOI: 10.3390/biomedicines11030784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/24/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Hereditary spherocytosis (HS) refers to the group of the most frequently occurring non-immune hereditary hemolytic anemia in people of Caucasian central or northern European ancestry. HS is mainly associated with pathogenic variants of genes encoding defects in five membrane proteins, including anion exchanger 1 encoded by the SLC4A1 gene. In this study, in a family affected with HS, we identified a hitherto unreported AE1 defect, variant p.G720W. The result of it is most likely the HS phenotype. Molecular dynamics simulation study of the AE1 transmembrane domain may indicate reasonable changes in AE1 domain structure, i.e., significant displacement of the tryptophan residue towards the membrane surface connected with possible changes in AE1 function. The WES analysis verified by classical sequencing in conjunction with biochemical analysis and molecular simulation studies shed light on the molecular mechanism underlying this case of hereditary spherocytosis, for which the newly discovered AE1 variant p.G720W seems crucial.
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Affiliation(s)
- Dżamila M. Bogusławska
- Department of Biotechnology, Institute of Biological Sciences, University of Zielona Góra, Prof. Szafrana St. 1, 65-516 Zielona Góra, Poland
| | - Sebastian Kraszewski
- Department of Biomedical Engineering, Wroclaw University of Science and Technology, Plac Grunwaldzki 13 (D-1), 50-377 Wroclaw, Poland
| | - Michał Skulski
- Department of Cytobiochemistry, Faculty of Biotechnology, University of Wroclaw, F. Joliot-Curie 14a St., 50-383 Wroclaw, Poland
| | - Stanisław Potoczek
- Department and Clinic of Haematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wybrzeże L. Pasteura 4, 50-367 Wroclaw, Poland
| | - Kazimierz Kuliczkowski
- Silesian Park of Medical Technology Kardio-Med Silesia, ul. M. Curie-Skłodowskiej 10c, 41-800 Zabrze, Poland
| | - Aleksander F. Sikorski
- Research and Development Centre, Regional Specialist Hospital, Kamieńskiego 73a, 51-154 Wroclaw, Poland
- Correspondence: ; Tel.: +48-71-327-05-16; Fax: +48-71-375-62-08
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33
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Jiang N, Mao WY, Peng BX, Yang TY, Mao XR. Clinical manifestations of adult hereditary spherocytosis with novel SPTB gene mutations and hyperjaundice: A case report. World J Clin Cases 2023; 11:1349-1355. [PMID: 36926142 PMCID: PMC10013123 DOI: 10.12998/wjcc.v11.i6.1349] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 12/17/2022] [Accepted: 01/10/2023] [Indexed: 02/23/2023] Open
Abstract
BACKGROUND The aim of the present study was to enhance understanding of the diagnosis and treatment of atypical hereditary spherocytosis (HS), and to broaden the diagnostic thoughts of physicians for patients with jaundice.
CASE SUMMARY A 28-year-old male presented with jaundice, bile duct stone, and splenomegaly, but without anemia. Other causes of jaundice were excluded, and gene sequencing revealed a novel heterozygous variant of c.1801C>T (p.Q601X) in exon 14 of the SPTB (NM_01355436) gene on chromosome 14 (chr14: 65260580) in the patient’s blood; the biological parents and child of the patient did not have similar variants. A splenectomy was performed on the patient and his bilirubin levels returned to normal after surgery. Thus, a novel gene variant causing HS was identified. This variant may result in the truncation of β-hemoglobin in the erythrocyte membrane, leading to loss of normal function, jaundice, and hemolytic anemia. The clinical manifestations of the patient were hyperjaundice and an absence of typical hemolysis during the course of the disease, which caused challenges for diagnosis by the clinicians.
CONCLUSION Following a definitive diagnosis, genetic testing and response to treatment identified a gene variant site for a novel hemolytic anemia.
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Affiliation(s)
- Ni Jiang
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Wu-Yong Mao
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Bing-Xue Peng
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Ting-Ya Yang
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Xiao-Rong Mao
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
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Hareendranath S, Sathian SP. Dynamic response of red blood cells in health and disease. SOFT MATTER 2023; 19:1219-1230. [PMID: 36688330 DOI: 10.1039/d2sm01090a] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
The viscoelastic response of the red blood cells (RBCs) affected by hematological disorders become severely impaired by the altered biophysical and morphological properties. These include traits like reduced deformability, increased membrane viscosity, and change in cell shape, causing substantial changes in the overall hemodynamics. RBCs, by virtue of their highly elastic membrane and low bending rigidity, exhibit complex dynamics when exposed to cyclic, transient forces in the microcirculation. Here, we employ mesoscopic numerical simulations based on the dissipative particle dynamics (DPD) framework to explore the dynamics of healthy, schizont stage malaria-infected and type 2 diabetes mellitus affected RBCs subjected to external time-dependent loads. The paper focuses on the imposition and cessation of external forcing on the cells of two different typologies, saw-tooth cyclic wave loading and sudden loads in the form of creep and relaxation phenomena. The effects of varying the rate of stress and the applied stress magnitude were investigated. Our simulations disclosed unique shape transitions of the hysteresis curves at varied loading rates. A careful analysis reveals a critical threshold of half cycle time of the from wherein the deformation of all cells observed, healthy or otherwise, falls under the nearly reversible deformation regime displaying minimal energy dissipation. Finally, we also examined the individual effects of the different constitutive and geometric characteristics attributed to the pathological cells and observed interesting recovery dynamics of spherocytes and cells having high shear moduli. The distinguished deformation behaviour of healthy and diseased cells could establish external force as a valuable initial biomarker.
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Affiliation(s)
- Sainath Hareendranath
- Department of Applied Mechanics, Indian Institute of Technology Madras, Chennai 600036, India.
| | - Sarith P Sathian
- Department of Applied Mechanics, Indian Institute of Technology Madras, Chennai 600036, India.
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35
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Qiang Y, Sissoko A, Liu ZL, Dong T, Zheng F, Kong F, Higgins JM, Karniadakis GE, Buffet PA, Suresh S, Dao M. Microfluidic study of retention and elimination of abnormal red blood cells by human spleen with implications for sickle cell disease. Proc Natl Acad Sci U S A 2023; 120:e2217607120. [PMID: 36730189 PMCID: PMC9963977 DOI: 10.1073/pnas.2217607120] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 12/16/2022] [Indexed: 02/03/2023] Open
Abstract
The spleen clears altered red blood cells (RBCs) from circulation, contributing to the balance between RBC formation (erythropoiesis) and removal. The splenic RBC retention and elimination occur predominantly in open circulation where RBCs flow through macrophages and inter-endothelial slits (IESs). The mechanisms underlying and interconnecting these processes significantly impact clinical outcomes. In sickle cell disease (SCD), blockage of intrasplenic sickled RBCs is observed in infants splenectomized due to acute splenic sequestration crisis (ASSC). This life-threatening RBC pooling and organ swelling event is plausibly triggered or enhanced by intra-tissular hypoxia. We present an oxygen-mediated spleen-on-a-chip platform for in vitro investigations of the homeostatic balance in the spleen. To demonstrate and validate the benefits of this general microfluidic platform, we focus on SCD and study the effects of hypoxia on splenic RBC retention and elimination. We observe that RBC retention by IESs and RBC-macrophage adhesion are faster in blood samples from SCD patients than those from healthy subjects. This difference is markedly exacerbated under hypoxia. Moreover, the sickled RBCs under hypoxia show distinctly different phagocytosis processes from those non-sickled RBCs under hypoxia or normoxia. We find that reoxygenation significantly alleviates RBC retention at IESs, and leads to rapid unsickling and fragmentation of the ingested sickled RBCs inside macrophages. These results provide unique mechanistic insights into how the spleen maintains its homeostatic balance between splenic RBC retention and elimination, and shed light on how disruptions in this balance could lead to anemia, splenomegaly, and ASSC in SCD and possible clinical manifestations in other hematologic diseases.
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Affiliation(s)
- Yuhao Qiang
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA02139
| | - Abdoulaye Sissoko
- Université Paris Cité, INSERM, Biologie Intégrée du Globule Rouge,75015Paris, France
- Université des Antilles, Biologie Intégrée du Globule Rouge,75015Paris, France
- Laboratoire d'Excellence du Globule Rouge,75015Paris, France
| | - Zixiang L. Liu
- Division of Applied Mathematics, Brown University, Providence, RI02912
| | - Ting Dong
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA02139
| | - Fuyin Zheng
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA02139
- School of Biological Sciences, Nanyang Technological University,639798Singapore, Singapore
| | - Fang Kong
- School of Biological Sciences, Nanyang Technological University,639798Singapore, Singapore
| | - John M. Higgins
- Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
| | | | - Pierre A. Buffet
- Université Paris Cité, INSERM, Biologie Intégrée du Globule Rouge,75015Paris, France
- Université des Antilles, Biologie Intégrée du Globule Rouge,75015Paris, France
- Laboratoire d'Excellence du Globule Rouge,75015Paris, France
| | - Subra Suresh
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA02139
- Nanyang Technological University,639798Singapore, Singapore
| | - Ming Dao
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA02139
- School of Biological Sciences, Nanyang Technological University,639798Singapore, Singapore
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36
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Möller M, Orrico F, Villar S, López AC, Silva N, Donzé M, Thomson L, Denicola A. Oxidants and Antioxidants in the Redox Biochemistry of Human Red Blood Cells. ACS OMEGA 2023; 8:147-168. [PMID: 36643550 PMCID: PMC9835686 DOI: 10.1021/acsomega.2c06768] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 12/09/2022] [Indexed: 06/01/2023]
Abstract
Red blood cells (RBCs) are exposed to both external and internal sources of oxidants that challenge their integrity and compromise their physiological function and supply of oxygen to tissues. Autoxidation of oxyhemoglobin is the main source of endogenous RBC oxidant production, yielding superoxide radical and then hydrogen peroxide. In addition, potent oxidants from other blood cells and the surrounding endothelium can reach the RBCs. Abundant and efficient enzymatic systems and low molecular weight antioxidants prevent most of the damage to the RBCs and also position the RBCs as a sink of vascular oxidants that allow the body to maintain a healthy circulatory system. Among the antioxidant enzymes, the thiol-dependent peroxidase peroxiredoxin 2, highly abundant in RBCs, is essential to keep the redox balance. A great part of the RBC antioxidant activity is supported by an active glucose metabolism that provides reducing power in the form of NADPH via the pentose phosphate pathway. There are several RBC defects and situations that generate oxidative stress conditions where the defense mechanisms are overwhelmed, and these include glucose-6-phosphate dehydrogenase deficiencies (favism), hemoglobinopathies like sickle cell disease and thalassemia, as well as packed RBCs for transfusion that suffer from storage lesions. These oxidative stress-associated pathologies of the RBCs underline the relevance of redox balance in these anucleated cells that lack a mechanism of DNA-inducible antioxidant response and rely on a complex and robust network of antioxidant systems.
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Affiliation(s)
- Matias
N. Möller
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
| | - Florencia Orrico
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
- Laboratorio
de Enzimología, Instituto de Química Biológica,
Facultad de Ciencias, Universidad de la
República, Montevideo 11400, Uruguay
| | - Sebastián
F. Villar
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
| | - Ana C. López
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
- Laboratorio
de Enzimología, Instituto de Química Biológica,
Facultad de Ciencias, Universidad de la
República, Montevideo 11400, Uruguay
| | - Nicolás Silva
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
- Laboratorio
de Enzimología, Instituto de Química Biológica,
Facultad de Ciencias, Universidad de la
República, Montevideo 11400, Uruguay
- Departamento
de Medicina Transfusional, Hospital de Clínicas, Facultad de
Medicina, Universidad de la República, Montevideo 11600, Uruguay
| | - Marcel Donzé
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
| | - Leonor Thomson
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
- Laboratorio
de Enzimología, Instituto de Química Biológica,
Facultad de Ciencias, Universidad de la
República, Montevideo 11400, Uruguay
| | - Ana Denicola
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
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Grigorev GV, Lebedev AV, Wang X, Qian X, Maksimov GV, Lin L. Advances in Microfluidics for Single Red Blood Cell Analysis. BIOSENSORS 2023; 13:117. [PMID: 36671952 PMCID: PMC9856164 DOI: 10.3390/bios13010117] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/04/2022] [Accepted: 12/23/2022] [Indexed: 05/24/2023]
Abstract
The utilizations of microfluidic chips for single RBC (red blood cell) studies have attracted great interests in recent years to filter, trap, analyze, and release single erythrocytes for various applications. Researchers in this field have highlighted the vast potential in developing micro devices for industrial and academia usages, including lab-on-a-chip and organ-on-a-chip systems. This article critically reviews the current state-of-the-art and recent advances of microfluidics for single RBC analyses, including integrated sensors and microfluidic platforms for microscopic/tomographic/spectroscopic single RBC analyses, trapping arrays (including bifurcating channels), dielectrophoretic and agglutination/aggregation studies, as well as clinical implications covering cancer, sepsis, prenatal, and Sickle Cell diseases. Microfluidics based RBC microarrays, sorting/counting and trapping techniques (including acoustic, dielectrophoretic, hydrodynamic, magnetic, and optical techniques) are also reviewed. Lastly, organs on chips, multi-organ chips, and drug discovery involving single RBC are described. The limitations and drawbacks of each technology are addressed and future prospects are discussed.
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Affiliation(s)
- Georgii V. Grigorev
- Data Science and Information Technology Research Center, Tsinghua Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, China
- Mechanical Engineering Department, University of California in Berkeley, Berkeley, CA 94720, USA
- School of Information Technology, Cherepovets State University, 162600 Cherepovets, Russia
| | - Alexander V. Lebedev
- Machine Building Department, Bauman Moscow State University, 105005 Moscow, Russia
| | - Xiaohao Wang
- Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Xiang Qian
- Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - George V. Maksimov
- Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
- Physical metallurgy Department, Federal State Autonomous Educational Institution of Higher Education National Research Technological University “MISiS”, 119049 Moscow, Russia
| | - Liwei Lin
- Mechanical Engineering Department, University of California in Berkeley, Berkeley, CA 94720, USA
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Huo J, Zhang A, Wang S, Cheng H, Fan D, Huang R, Wang Y, Wan B, Zhang G, He H. Splenic-targeting biomimetic nanovaccine for elevating protective immunity against virus infection. J Nanobiotechnology 2022; 20:514. [PMID: 36463277 PMCID: PMC9719655 DOI: 10.1186/s12951-022-01730-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND The prevalence of viral infectious diseases has become a serious threat to public safety, economic and social development. Vaccines have been served as the most effective platform to prevent virus transmission via the activation of host immune responses, while the low immunogenicity or safety, the high cost of production, storage, transport limit their effective clinical application. Therefore, there is a need to develop a promising strategy to improve the immunogenicity and safety of vaccines. METHODS We developed a splenic-targeting biomimetic nanovaccine (NV) that can boost protective humoral and cellular immunity against african swine fever virus (ASFV) infection. The universal PLGA nanoparticles (CMR-PLGA/p54 NPs) coated with mannose and CpG (TLR9 agonist) co-modified red blood cell (RBC) membrane were prepared, which comprised a viral antigen (p54) and can be served as a versatile nanovaccine for elevating protective immunity. RESULTS CMR-PLGA/p54 NVs could be effectively uptaken by BMDC and promoted BMDC maturation in vitro. After subcutaneous immunization, antigen could be effectively delivered to the splenic dendritic cells (DCs) due to the splenic homing ability of RBC and DC targeting capacity of mannose, which promoted antigen presentation and DCs maturation, and further elicited higher levels of cytokines secretion and specific IgG titers, CD4+ and CD8+ T cells activation and B maturation. Moreover, NVs demonstrated notable safety during the immunization period. CONCLUSIONS This study demonstrates the high potential of CMR-PLGA NPs as vaccine delivery carriers to promote humoral and cellular immune responses, and it provides a promising strategy to develop safe and effective vaccines against viral infectious diseases.
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Affiliation(s)
- Jian Huo
- grid.108266.b0000 0004 1803 0494College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Engineering Laboratory of Animal Biological Products, Longhu Laboratory, Henan Agricultural University, Zhengzhou, 450046 China
| | - Angke Zhang
- grid.108266.b0000 0004 1803 0494College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Engineering Laboratory of Animal Biological Products, Longhu Laboratory, Henan Agricultural University, Zhengzhou, 450046 China
| | - Shuqi Wang
- grid.108266.b0000 0004 1803 0494College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Engineering Laboratory of Animal Biological Products, Longhu Laboratory, Henan Agricultural University, Zhengzhou, 450046 China
| | - Hanghang Cheng
- grid.108266.b0000 0004 1803 0494College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Engineering Laboratory of Animal Biological Products, Longhu Laboratory, Henan Agricultural University, Zhengzhou, 450046 China
| | - Daopeng Fan
- grid.108266.b0000 0004 1803 0494College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Engineering Laboratory of Animal Biological Products, Longhu Laboratory, Henan Agricultural University, Zhengzhou, 450046 China
| | - Ran Huang
- grid.108266.b0000 0004 1803 0494College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Engineering Laboratory of Animal Biological Products, Longhu Laboratory, Henan Agricultural University, Zhengzhou, 450046 China
| | - Yanan Wang
- grid.108266.b0000 0004 1803 0494College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Engineering Laboratory of Animal Biological Products, Longhu Laboratory, Henan Agricultural University, Zhengzhou, 450046 China
| | - Bo Wan
- grid.108266.b0000 0004 1803 0494College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Engineering Laboratory of Animal Biological Products, Longhu Laboratory, Henan Agricultural University, Zhengzhou, 450046 China
| | - Gaiping Zhang
- grid.108266.b0000 0004 1803 0494College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Engineering Laboratory of Animal Biological Products, Longhu Laboratory, Henan Agricultural University, Zhengzhou, 450046 China
| | - Hua He
- grid.108266.b0000 0004 1803 0494College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Engineering Laboratory of Animal Biological Products, Longhu Laboratory, Henan Agricultural University, Zhengzhou, 450046 China
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39
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Wu Y, Zhang Z, Wei Y, Qian Z, Wei X. Nanovaccines for cancer immunotherapy: Current knowledge and future perspectives. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.108098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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40
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Pac J, Koo DJ, Cho H, Jung D, Choi MH, Choi Y, Kim B, Park JU, Kim SY, Lee Y. Three-dimensional imaging and analysis of pathological tissue samples with de novo generation of citrate-based fluorophores. SCIENCE ADVANCES 2022; 8:eadd9419. [PMID: 36383671 PMCID: PMC9668299 DOI: 10.1126/sciadv.add9419] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/29/2022] [Indexed: 06/16/2023]
Abstract
Two-dimensional (2D) histopathology based on the observation of thin tissue slides is the current paradigm in diagnosis and prognosis. However, labeling strategies in conventional histopathology are limited in compatibility with 3D imaging combined with tissue clearing techniques. Here, we present a rapid and efficient volumetric imaging technique of pathological tissues called 3D tissue imaging through de novo formation of fluorophores, or 3DNFC, which is the integration of citrate-based fluorogenic reaction DNFC and tissue clearing techniques. 3DNFC markedly increases the fluorescence intensity of tissues by generating fluorophores on nonfluorescent amino-terminal cysteine and visualizes the 3D structure of the tissues to provide their anatomical morphology and volumetric information. Furthermore, the application of 3DNFC to pathological tissue achieves the 3D reconstruction for the unbiased analysis of diverse features of the disorders in their natural context. We suggest that 3DNFC is a promising volumetric imaging method for the prognosis and diagnosis of pathological tissues.
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Affiliation(s)
- Jinyoung Pac
- Department of Chemistry, Seoul National University, Seoul 08826, South Korea
| | - Dong-Jun Koo
- Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, South Korea
| | - Hyeongjun Cho
- Department of Chemistry, Seoul National University, Seoul 08826, South Korea
- Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, South Korea
| | - Dongwook Jung
- Department of Chemistry, Seoul National University, Seoul 08826, South Korea
| | - Min-ha Choi
- Department of Plastic and Reconstructive Surgery, Seoul National University Boramae Hospital, Seoul National University College of Medicine, 5 Gil 20, Boramae Road, Dongjak-Gu, Seoul 07061, South Korea
| | - Yunjung Choi
- Department of Chemistry, Seoul National University, Seoul 08826, South Korea
| | - Bohyun Kim
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, South Korea
| | - Ji-Ung Park
- Department of Plastic and Reconstructive Surgery, Seoul National University Boramae Hospital, Seoul National University College of Medicine, 5 Gil 20, Boramae Road, Dongjak-Gu, Seoul 07061, South Korea
| | - Sung-Yon Kim
- Department of Chemistry, Seoul National University, Seoul 08826, South Korea
- Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, South Korea
| | - Yan Lee
- Department of Chemistry, Seoul National University, Seoul 08826, South Korea
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41
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Elasticity regulates nanomaterial transport as delivery vehicles: Design, characterization, mechanisms and state of the art. Biomaterials 2022; 291:121879. [DOI: 10.1016/j.biomaterials.2022.121879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 10/14/2022] [Accepted: 10/23/2022] [Indexed: 11/22/2022]
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Javadi E, Li H, Gallastegi AD, Frydman GH, Jamali S, Karniadakis GE. Circulating cell clusters aggravate the hemorheological abnormalities in COVID-19. Biophys J 2022; 121:3309-3319. [PMID: 36028998 PMCID: PMC9420024 DOI: 10.1016/j.bpj.2022.08.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 07/14/2022] [Accepted: 08/22/2022] [Indexed: 11/02/2022] Open
Abstract
Microthrombi and circulating cell clusters are common microscopic findings in patients with coronavirus disease 2019 (COVID-19) at different stages in the disease course, implying that they may function as the primary drivers in disease progression. Inspired by a recent flow imaging cytometry study of the blood samples from patients with COVID-19, we perform computational simulations to investigate the dynamics of different types of circulating cell clusters, namely white blood cell (WBC) clusters, platelet clusters, and red blood cell clusters, over a range of shear flows and quantify their impact on the viscosity of the blood. Our simulation results indicate that the increased level of fibrinogen in patients with COVID-19 can promote the formation of red blood cell clusters at relatively low shear rates, thereby elevating the blood viscosity, a mechanism that also leads to an increase in viscosity in other blood diseases, such as sickle cell disease and type 2 diabetes mellitus. We further discover that the presence of WBC clusters could also aggravate the abnormalities of local blood rheology. In particular, the extent of elevation of the local blood viscosity is enlarged as the size of the WBC clusters grows. On the other hand, the impact of platelet clusters on the local rheology is found to be negligible, which is likely due to the smaller size of the platelets. The difference in the impact of WBC and platelet clusters on local hemorheology provides a compelling explanation for the clinical finding that the number of WBC clusters is significantly correlated with thrombotic events in COVID-19 whereas platelet clusters are not. Overall, our study demonstrates that our computational models based on dissipative particle dynamics can serve as a powerful tool to conduct quantitative investigation of the mechanism causing the pathological alterations of hemorheology and explore their connections to the clinical manifestations in COVID-19.
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Affiliation(s)
- Elahe Javadi
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, Massachusetts
| | - He Li
- School of Engineering, Brown University, Providence, Rhode Island; School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens, Georgia.
| | - Ander Dorken Gallastegi
- Division of Trauma, Emergency Surgery and Surgical Critical Care at the Massachusetts General Hospital, Boston, Massachusetts
| | - Galit H Frydman
- Division of Trauma, Emergency Surgery and Surgical Critical Care at the Massachusetts General Hospital, Boston, Massachusetts; Department of Biological Engineering at the Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Safa Jamali
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, Massachusetts.
| | - George Em Karniadakis
- School of Engineering, Brown University, Providence, Rhode Island; Division of Applied Mathematics and School of Engineering, Brown University, Providence, Rhode Island.
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43
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Andryukhova ES, Tashireva LA, Isaeva AV, Vtorushin SV, Zavyalova MV, Perelmuter VM. The Rarity of Metastasis to the Spleen — a Phenomenon with an Unknown Mechanism. Bull Exp Biol Med 2022; 173:575-582. [DOI: 10.1007/s10517-022-05591-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Indexed: 11/05/2022]
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44
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Leterrier C, Pullarkat PA. Mechanical role of the submembrane spectrin scaffold in red blood cells and neurons. J Cell Sci 2022; 135:276327. [PMID: 35972759 DOI: 10.1242/jcs.259356] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Spectrins are large, evolutionarily well-conserved proteins that form highly organized scaffolds on the inner surface of eukaryotic cells. Their organization in different cell types or cellular compartments helps cells withstand mechanical challenges with unique strategies depending on the cell type. This Review discusses our understanding of the mechanical properties of spectrins, their very distinct organization in red blood cells and neurons as two examples, and the contribution of the scaffolds they form to the mechanical properties of these cells.
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Affiliation(s)
- Christophe Leterrier
- Aix Marseille Université, CNRS, INP UMR 7051, NeuroCyto, Marseille 13005, France
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45
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Gerritsma JJ, van der Bolt N, van Bruggen R, Ten Brinke A, van Dam J, Guerrero G, Vermeulen C, de Bruin S, Vlaar APJ, Biemond BJ, Nur E, van der Schoot E, Fijnvandraat K. Measurement of post-transfusion red blood cell survival kinetics in sickle cell disease and β-Thalassemia: A biotin label approach. Transfusion 2022; 62:1984-1996. [PMID: 35916478 DOI: 10.1111/trf.17033] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 04/11/2022] [Accepted: 04/13/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Red blood cell (RBC) transfusions are an important treatment modality for patients with sickle cell disease (SCD) and β-thalassemia. A subgroup of these patients relies on a chronic RBC transfusion regimen. Little is known about RBC survival (RCS) of the transfused allogeneic RBCs. In this study, we aimed to study the RCS kinetics of transfused RBCs in SCD and β-thalassemia and to investigate factors that determine RCS. METHODS AND MATERIALS We performed a prospective cohort study on fourteen adults with SCD and β-thalassemia disease receiving a chronic transfusion regimen. RCS and the influence of donor and patient characteristics on RCS were assessed by simultaneous transfusion of two allogeneic RBCs using RBC biotinylation. Phenotyping of well-known RBC markers over time was performed using flow cytometry. RESULTS RCS of the two transfused RBC units was similar in most patients. Although intra-individual variation was small, inter-individual variation in RCS kinetics was observed. Most patients demonstrated a non-linear trend in RCS that was different from the observed linear RCS kinetics in healthy volunteers. After an initial slight increase in the proportion of biotinylated RBCs during the first 24 h, a rapid decrease within the first 10-12 days was followed by a slower clearance rate. CONCLUSION These are the first data to demonstrate that patient-related factors largely determine post-transfusion RCS behavior of donor RBC in SCD and β-thalassemia, while donor factors exert a negligible effect. Further assessment and modeling of RCS kinetics and its determinants in SCD and β-thalassemia patients may ultimately improve transfusion therapy.
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Affiliation(s)
- Jorn J Gerritsma
- Sanquin Research and Landsteiner Laboratory, Immunopathology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.,Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Pediatric Hematology, Amsterdam, the Netherlands
| | - Nieke van der Bolt
- Sanquin Research and Landsteiner Laboratory, Immunopathology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.,Sanquin Research and Landsteiner Laboratory, Immunohematology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Robin van Bruggen
- Sanquin Research and Landsteiner Laboratory, Blood Cell Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Anja Ten Brinke
- Sanquin Research and Landsteiner Laboratory, Immunopathology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - John van Dam
- Sanquin Research and Landsteiner Laboratory, Molecular Hematology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Guillermo Guerrero
- Sanquin Research and Landsteiner Laboratory, Immunohematology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Christie Vermeulen
- Sanquin Research and Landsteiner Laboratory, Product and Process Development, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Sanne de Bruin
- Amsterdam UMC, University of Amsterdam, Intensive Care Medicine, Amsterdam, the Netherlands
| | - Alexander P J Vlaar
- Amsterdam UMC, University of Amsterdam, Intensive Care Medicine, Amsterdam, the Netherlands
| | - Bart J Biemond
- Amsterdam UMC, University of Amsterdam, Department of Hematology, Amsterdam, the Netherlands
| | - Erfan Nur
- Amsterdam UMC, University of Amsterdam, Department of Hematology, Amsterdam, the Netherlands
| | - Ellen van der Schoot
- Sanquin Research and Landsteiner Laboratory, Immunohematology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Karin Fijnvandraat
- Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Pediatric Hematology, Amsterdam, the Netherlands.,Sanquin Research and Landsteiner Laboratory, Molecular and Cellular Hemostasis, Amsterdam UMC, University of Amsterdam, Sanquin Research, Amsterdam, the Netherlands
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46
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Hromić-Jahjefendić A, Barh D, Ramalho Pinto CH, Gabriel Rodrigues Gomes L, Picanço Machado JL, Afolabi OO, Tiwari S, Aljabali AAA, Tambuwala MM, Serrano-Aroca Á, Redwan EM, Uversky VN, Lundstrom K. Associations and Disease-Disease Interactions of COVID-19 with Congenital and Genetic Disorders: A Comprehensive Review. Viruses 2022; 14:910. [PMID: 35632654 PMCID: PMC9146233 DOI: 10.3390/v14050910] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/23/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Since December 2019, the COVID-19 pandemic, which originated in Wuhan, China, has resulted in over six million deaths worldwide. Millions of people who survived this SARS-CoV-2 infection show a number of post-COVID complications. Although, the comorbid conditions and post-COVID complexities are to some extent well reviewed and known, the impact of COVID-19 on pre-existing congenital anomalies and genetic diseases are only documented in isolated case reports and case series, so far. In the present review, we analyzed the PubMed indexed literature published between December 2019 and January 2022 to understand this relationship from various points of view, such as susceptibility, severity and heritability. Based on our knowledge, this is the first comprehensive review on COVID-19 and its associations with various congenital anomalies and genetic diseases. According to reported studies, some congenital disorders present high-risk for developing severe COVID-19 since these disorders already include some comorbidities related to the structure and function of the respiratory and cardiovascular systems, leading to severe pneumonia. Other congenital disorders rather cause psychological burdens to patients and are not considered high-risk for the development of severe COVID-19 infection.
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Affiliation(s)
- Altijana Hromić-Jahjefendić
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnicka Cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
| | - Debmalya Barh
- Institute of Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri, Purba Medinipur 721172, India
- Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil; (L.G.R.G.); (S.T.)
| | - Cecília Horta Ramalho Pinto
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil;
| | - Lucas Gabriel Rodrigues Gomes
- Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil; (L.G.R.G.); (S.T.)
| | - Jéssica Lígia Picanço Machado
- Department of Bioinformatics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil;
| | - Oladapo Olawale Afolabi
- Department of Physiology and Biophysics, Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil;
| | - Sandeep Tiwari
- Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil; (L.G.R.G.); (S.T.)
| | - Alaa A. A. Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, P.O. Box 566, Irbid 21163, Jordan
| | - Murtaza M. Tambuwala
- School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine BT52 1SA, UK;
| | - Ángel Serrano-Aroca
- Biomaterials and Bioengineering Laboratory, Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, c/Guillem de Castro 94, 46001 Valencia, Spain;
| | - Elrashdy M. Redwan
- Department of Biological Science, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Therapeutic and Protective Proteins Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg EL-Arab 21934, Alexandria, Egypt
| | - Vladimir N. Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer’s Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA;
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47
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Cao H, Mathur A, Robertson C, Antonopoulos A, Henderson S, Girard LP, Wong JH, Davie A, Wright S, Brewin J, Rees DC, Dell A, Haslam SM, Vickers MA. Measurement of erythrocyte membrane mannoses to assess splenic function. Br J Haematol 2022; 198:155-164. [PMID: 35411940 PMCID: PMC9321840 DOI: 10.1111/bjh.18164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 02/25/2022] [Accepted: 03/13/2022] [Indexed: 11/30/2022]
Abstract
Red blood cells (RBCs) lose plasma membrane in the spleen as they age, but the cells and molecules involved are yet to be identified. Sickle cell disease and infection by Plasmodium falciparum cause oxidative stress that induces aggregates of cross‐linked proteins with N‐linked high‐mannose glycans (HMGs). These glycans can be recognised by mannose‐binding lectins, including the mannose receptor (CD206), expressed on macrophages and specialised phagocytic endothelial cells in the spleen to mediate the extravascular haemolysis characteristic of these diseases. We postulated this system might also mediate removal of molecules and membrane in healthy individuals. Surface expression of HMGs on RBCs from patients who had previously undergone splenectomy was therefore assessed: high levels were indeed observable as large membrane aggregates. Glycomic analysis by mass spectrometry identified a mixture of Man5‐9GlcNAc2 structures. HMG levels correlated well with manual pit counts (r = 0.75–0.85). To assess further whether HMGs might act as a splenic reticuloendothelial function test, we measured levels on RBCs from patients with potential functional hyposplenism, some of whom exhibited high levels that may indicate risk of complications.
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Affiliation(s)
- Huan Cao
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
| | - Abhinav Mathur
- Department of Haematology, Aberdeen Royal Infirmary, Aberdeen, UK
| | | | | | - Sadie Henderson
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
| | | | - Jin Hien Wong
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
| | - Adam Davie
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
| | - Sonja Wright
- Department of Haematology, Aberdeen Royal Infirmary, Aberdeen, UK
| | - John Brewin
- Department of Haematology, King's College Hospital, London, UK
| | - David C Rees
- Department of Haematology, King's College Hospital, London, UK
| | - Anne Dell
- Department of Life Sciences, Imperial College London, London, UK
| | - Stuart M Haslam
- Department of Life Sciences, Imperial College London, London, UK
| | - Mark A Vickers
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.,Department of Haematology, Aberdeen Royal Infirmary, Aberdeen, UK.,Scottish National Blood Transfusion Service, Aberdeen, UK
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48
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Molina-Franky J, Patarroyo ME, Kalkum M, Patarroyo MA. The Cellular and Molecular Interaction Between Erythrocytes and Plasmodium falciparum Merozoites. Front Cell Infect Microbiol 2022; 12:816574. [PMID: 35433504 PMCID: PMC9008539 DOI: 10.3389/fcimb.2022.816574] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 02/21/2022] [Indexed: 11/13/2022] Open
Abstract
Plasmodium falciparum is the most lethal human malaria parasite, partly due to its genetic variability and ability to use multiple invasion routes via its binding to host cell surface receptors. The parasite extensively modifies infected red blood cell architecture to promote its survival which leads to increased cell membrane rigidity, adhesiveness and permeability. Merozoites are initially released from infected hepatocytes and efficiently enter red blood cells in a well-orchestrated process that involves specific interactions between parasite ligands and erythrocyte receptors; symptoms of the disease occur during the life-cycle’s blood stage due to capillary blockage and massive erythrocyte lysis. Several studies have focused on elucidating molecular merozoite/erythrocyte interactions and host cell modifications; however, further in-depth analysis is required for understanding the parasite’s biology and thus provide the fundamental tools for developing prophylactic or therapeutic alternatives to mitigate or eliminate Plasmodium falciparum-related malaria. This review focuses on the cellular and molecular events during Plasmodium falciparum merozoite invasion of red blood cells and the alterations that occur in an erythrocyte once it has become infected.
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Affiliation(s)
- Jessica Molina-Franky
- Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC), Bogotá, Colombia
- Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA, United States
- PhD Programme in Biotechnology, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Manuel Elkin Patarroyo
- Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC), Bogotá, Colombia
- Health Sciences Division, Universidad Santo Tomás, Bogotá, Colombia
- Faculty of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Markus Kalkum
- Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA, United States
- *Correspondence: Markus Kalkum, ; Manuel Alfonso Patarroyo,
| | - Manuel Alfonso Patarroyo
- Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC), Bogotá, Colombia
- Health Sciences Division, Universidad Santo Tomás, Bogotá, Colombia
- Faculty of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia
- *Correspondence: Markus Kalkum, ; Manuel Alfonso Patarroyo,
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49
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Stevens-Hernandez CJ, Bruce LJ. Reticulocyte Maturation. MEMBRANES 2022; 12:311. [PMID: 35323786 PMCID: PMC8953437 DOI: 10.3390/membranes12030311] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/03/2022] [Accepted: 03/08/2022] [Indexed: 02/04/2023]
Abstract
Changes to the membrane proteins and rearrangement of the cytoskeleton must occur for a reticulocyte to mature into a red blood cell (RBC). Different mechanisms of reticulocyte maturation have been proposed to reduce the size and volume of the reticulocyte plasma membrane and to eliminate residual organelles. Lysosomal protein degradation, exosome release, autophagy and the extrusion of large autophagic-endocytic hybrid vesicles have been shown to contribute to reticulocyte maturation. These processes may occur simultaneously or perhaps sequentially. Reticulocyte maturation is incompletely understood and requires further investigation. RBCs with membrane defects or cation leak disorders caused by genetic variants offer an insight into reticulocyte maturation as they present characteristics of incomplete maturation. In this review, we compare the structure of the mature RBC membrane with that of the reticulocyte. We discuss the mechanisms of reticulocyte maturation with a focus on incomplete reticulocyte maturation in red cell variants.
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Affiliation(s)
- Christian J Stevens-Hernandez
- Bristol Institute for Transfusion Sciences, National Health Service (NHS) Blood and Transplant, Bristol BS34 7QH, UK
- School of Biochemistry, University of Bristol, Bristol BS8 ITD, UK
| | - Lesley J Bruce
- Bristol Institute for Transfusion Sciences, National Health Service (NHS) Blood and Transplant, Bristol BS34 7QH, UK
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50
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Multiphysics and multiscale modeling of microthrombosis in COVID-19. PLoS Comput Biol 2022; 18:e1009892. [PMID: 35255089 PMCID: PMC8901059 DOI: 10.1371/journal.pcbi.1009892] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 02/02/2022] [Indexed: 12/21/2022] Open
Abstract
Emerging clinical evidence suggests that thrombosis in the microvasculature of patients with Coronavirus disease 2019 (COVID-19) plays an essential role in dictating the disease progression. Because of the infectious nature of SARS-CoV-2, patients’ fresh blood samples are limited to access for in vitro experimental investigations. Herein, we employ a novel multiscale and multiphysics computational framework to perform predictive modeling of the pathological thrombus formation in the microvasculature using data from patients with COVID-19. This framework seamlessly integrates the key components in the process of blood clotting, including hemodynamics, transport of coagulation factors and coagulation kinetics, blood cell mechanics and adhesive dynamics, and thus allows us to quantify the contributions of many prothrombotic factors reported in the literature, such as stasis, the derangement in blood coagulation factor levels and activities, inflammatory responses of endothelial cells and leukocytes to the microthrombus formation in COVID-19. Our simulation results show that among the coagulation factors considered, antithrombin and factor V play more prominent roles in promoting thrombosis. Our simulations also suggest that recruitment of WBCs to the endothelial cells exacerbates thrombogenesis and contributes to the blockage of the blood flow. Additionally, we show that the recent identification of flowing blood cell clusters could be a result of detachment of WBCs from thrombogenic sites, which may serve as a nidus for new clot formation. These findings point to potential targets that should be further evaluated, and prioritized in the anti-thrombotic treatment of patients with COVID-19. Altogether, our computational framework provides a powerful tool for quantitative understanding of the mechanism of pathological thrombus formation and offers insights into new therapeutic approaches for treating COVID-19 associated thrombosis. Emerging clinical evidence suggests that thrombosis in the microvasculature of patients with Coronavirus disease 2019 (COVID-19) plays an essential role in dictating the disease progression. We employ a novel multiphysics and multiscale computational framework to investigate the underlying mechanism of the pathological formation of microthrombi and circulating cell clusters in COVID-19. We quantify the contributions of many prothrombotic factors reported in the literature, such as stasis, the derangement in blood coagulation factor levels and activities, inflammatory responses of endothelial cells and leukocytes to the microthrombus formation in COVID-19, through which we identify the potential targets that should be further evaluated, and prioritized in the anti-thrombotic treatment of patients with COVID-19.
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