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Bhatia R. Don't Lose Your Nerve: Adrenergic Signaling and Bone Marrow Regeneration after Transplantation. Cancer Discov 2025; 15:666-669. [PMID: 40170537 DOI: 10.1158/2159-8290.cd-25-0107] [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: 02/04/2025] [Accepted: 02/04/2025] [Indexed: 04/03/2025]
Abstract
In this issue, Nishino, Hu, Kishtagari, and colleagues report that patients who receive nonselective β-blockers after allogeneic hematopoietic cell transplant exhibit delayed platelet engraftment and reduced survival. See related article by Nishino et al., p. 748.
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Moradi S, Nouri M, Moradi MT, Khodarahmi R, Zarrabi M, Khazaie H. The mutual impacts of stem cells and sleep: opportunities for improved stem cell therapy. Stem Cell Res Ther 2025; 16:157. [PMID: 40158131 PMCID: PMC11954214 DOI: 10.1186/s13287-025-04235-3] [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: 09/30/2024] [Accepted: 02/17/2025] [Indexed: 04/01/2025] Open
Abstract
Sleep is an indispensable physiological function regulated by circadian rhythms, which influence the biological pathways and overall health of the body. Sleep is crucial for the maintenance and restoration of bodily systems, and disturbances can lead to various sleep disorders, which can impair both mental and physical health. Treatment options for these disorders encompass lifestyle modifications, psychotherapy, medications, and therapies such as light therapy and surgery. Not only sleep deprivation has a significant impact on essential organs, but it also influences various types of stem cells in the body. In this review, we explore the connection between sleep and various types of stem cells, highlighting how circadian rhythms regulate stem cell activities that are vital for tissue regeneration and homeostasis. Disruptions in sleep can hinder stem cell self-renewal, homing, proliferation, function, and differentiation, thereby affecting tissue regeneration and overall health. We also discuss how transplantation of stem cells and their products may help improve sleep disorders, how sleep quality affects stem cell behavior, and the implications for stem cell therapies. Notably, while certain stem cell transplantations can disrupt sleep, enhancing sleep quality may improve the efficacy of these therapies. Finally, stem cells can be utilized to model sleep disorders, offering valuable insights into their underlying mechanisms.
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Affiliation(s)
- Sharif Moradi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | - Masoumeh Nouri
- R&D Department, Royan Stem Cell Technology Co, Tehran, Iran
| | - Mohammad-Taher Moradi
- Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Reza Khodarahmi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Morteza Zarrabi
- R&D Department, Royan Stem Cell Technology Co, Tehran, Iran
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Habibolah Khazaie
- Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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3
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Joly P, Labsy R, Silvin A. Aging and neurodegeneration: when systemic dysregulations affect brain macrophage heterogeneity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkae034. [PMID: 40073104 DOI: 10.1093/jimmun/vkae034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 11/14/2024] [Indexed: 03/14/2025]
Abstract
Microglia, the major population of brain resident macrophages, differentiate from yolk sac progenitors in the embryo and play multiple nonimmune roles in brain organization throughout development and life. Various microglia subtypes have been described by transcriptomic and proteomic signatures, involved metabolic pathways, morphology, intracellular complexity, time of residency, and ontogeny, both in development and in disease settings. Such macrophage heterogeneity increases with aging or neurodegeneration. Monocytes' infiltration and differentiation into monocyte-derived macrophages (MDMs) in the brain contribute to this diversity. Microbiota's role in brain diseases has been recently highlighted, revealing how microbial signals, such as metabolites, influence microglia and MDMs. In this brief review, we describe how these signals can influence microglia through their sensome and shape MDMs from their development in the bone marrow to their differentiation in the brain. Monocytes could then be a crucial player in the constitution of a dysbiotic gut-brain axis in neurodegenerative diseases and aging.
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Affiliation(s)
- Paul Joly
- INSERM U1015, Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, Villejuif, 94805, France
| | - Reyhane Labsy
- INSERM U1015, Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, Villejuif, 94805, France
| | - Aymeric Silvin
- INSERM U1015, Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, Villejuif, 94805, France
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4
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Ramsay SD, Nenke MA, Meyer EJ, Torpy DJ, Young RL. Unveiling the novel role of circadian rhythms in sepsis and septic shock: unexplored implications for chronotherapy. Front Endocrinol (Lausanne) 2025; 16:1508848. [PMID: 39968295 PMCID: PMC11832378 DOI: 10.3389/fendo.2025.1508848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 01/15/2025] [Indexed: 02/20/2025] Open
Abstract
Circadian rhythms are critical to coordinating body processes to external environmental cues, such as light and feeding, to ensure efficiency and maintain optimal health. These rhythms are controlled by 'clock' transcription factors, such as Clock, Bmal1, Per1/2, Cry1/2, and Rev-erbs, which are present in almost every tissue. In modern society, disruptions to normal circadian rhythms are increasingly prevalent due to extended lighting, shift work, and long-distance travel. These disruptions misalign external cues to body processes and contribute to diseases such as obesity and non-alcoholic fatty liver disease. They also exacerbate pre-existing health issues, such as depression and inflammatory bowel disease. The normal inflammatory response to acute infection displays remarkable circadian rhythmicity in humans with increased inflammatory activity during the normal night or rest period. Severe bloodborne infections, exemplified in sepsis and the progression to septic shock, can not only disrupt the circadian rhythmicity of inflammatory processes but can be exacerbated by circadian misalignment. Examples of circadian disruptions during sepsis and septic shock include alteration or loss of hormonal rhythms controlling blood pressure and inflammation, white blood cell counts, and cytokine secretions. These changes to circadian rhythms hinder sepsis and septic shock recovery and also increase mortality. Chronotherapy and chronopharmacotherapy are promising approaches to resynchronise circadian rhythms or leverage circadian rhythms to optimise medication efficacy, respectively, and hold much potential in the treatment of sepsis and septic shock. Despite knowledge of how circadian rhythms change in these grave conditions, very little research has been undertaken on the use of these therapies in support of sepsis management. This review details the circadian disruptions associated with sepsis and septic shock, the influence they have on morbidity and mortality, and the potential clinical benefits of circadian-modulating therapies.
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Affiliation(s)
- Stewart D. Ramsay
- Intestinal Nutrient Sensing Group, The University of Adelaide, Adelaide, SA, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
- Lifelong Health, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia
| | - Marni A. Nenke
- Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
| | - Emily J. Meyer
- Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
| | - David J. Torpy
- Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
| | - Richard L. Young
- Intestinal Nutrient Sensing Group, The University of Adelaide, Adelaide, SA, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
- Lifelong Health, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia
- Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
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5
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Chang HH, Liou YS, Sun DS. Unraveling the interplay between inflammation and stem cell mobilization or homing: Implications for tissue repair and therapeutics. Tzu Chi Med J 2024; 36:349-359. [PMID: 39421490 PMCID: PMC11483098 DOI: 10.4103/tcmj.tcmj_100_24] [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: 04/19/2024] [Revised: 04/29/2024] [Accepted: 06/14/2024] [Indexed: 10/19/2024] Open
Abstract
Inflammation and stem cell mobilization or homing play pivotal roles in tissue repair and regeneration. This review explores their intricate interplay, elucidating their collaborative role in maintaining tissue homeostasis and responding to injury or disease. While examining the fundamentals of stem cells, we detail the mechanisms underlying inflammation, including immune cell recruitment and inflammatory mediator release, highlighting their self-renewal and differentiation capabilities. Central to our exploration is the modulation of hematopoietic stem cell behavior by inflammatory cues, driving their mobilization from the bone marrow niche into circulation. Key cytokines, chemokines, growth factors, and autophagy, an intracellular catabolic mechanism involved in this process, are discussed alongside their clinical relevance. Furthermore, mesenchymal stem cell homing in response to inflammation contributes to tissue repair processes. In addition, we discuss stem cell resilience in the face of inflammatory challenges. Moreover, we examine the reciprocal influence of stem cells on the inflammatory milieu, shaping immune responses and tissue repair. We underscore the potential of targeting inflammation-induced stem cell mobilization for regenerative therapies through extensive literature analysis and clinical insights. By unraveling the complex interplay between inflammation and stem cells, this review advances our understanding of tissue repair mechanisms and offers promising avenues for clinical translation in regenerative medicine.
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Affiliation(s)
- Hsin-Hou Chang
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan
| | - Yu-Shan Liou
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan
| | - Der-Shan Sun
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan
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Ruminski PG, Rettig MP, DiPersio JF. Development of VLA4 and CXCR4 Antagonists for the Mobilization of Hematopoietic Stem and Progenitor Cells. Biomolecules 2024; 14:1003. [PMID: 39199390 PMCID: PMC11353233 DOI: 10.3390/biom14081003] [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: 06/28/2024] [Revised: 07/29/2024] [Accepted: 08/02/2024] [Indexed: 09/01/2024] Open
Abstract
The treatment of patients diagnosed with hematologic malignancies typically includes hematopoietic stem cell transplantation (HSCT) as part of a therapeutic standard of care. The primary graft source of hematopoietic stem and progenitor cells (HSPCs) for HSCT is mobilized from the bone marrow into the peripheral blood of allogeneic donors or patients. More recently, these mobilized HSPCs have also been the source for gene editing strategies to treat diseases such as sickle-cell anemia. For a HSCT to be successful, it requires the infusion of a sufficient number of HSPCs that are capable of adequate homing to the bone marrow niche and the subsequent regeneration of stable trilineage hematopoiesis in a timely manner. Granulocyte-colony-stimulating factor (G-CSF) is currently the most frequently used agent for HSPC mobilization. However, it requires five or more daily infusions to produce an adequate number of HSPCs and the use of G-CSF alone often results in suboptimal stem cell yields in a significant number of patients. Furthermore, there are several undesirable side effects associated with G-CSF, and it is contraindicated for use in sickle-cell anemia patients, where it has been linked to serious vaso-occlusive and thrombotic events. The chemokine receptor CXCR4 and the cell surface integrin α4β1 (very late antigen 4 (VLA4)) are both involved in the homing and retention of HSPCs within the bone marrow microenvironment. Preclinical and/or clinical studies have shown that targeted disruption of the interaction of the CXCR4 or VLA4 receptors with their endogenous ligands within the bone marrow niche results in the rapid and reversible mobilization of HSPCs into the peripheral circulation and is synergistic when combined with G-CSF. In this review, we discuss the roles CXCR4 and VLA4 play in bone marrow homing and retention and will summarize more recent development of small-molecule CXCR4 and VLA4 inhibitors that, when combined, can synergistically improve the magnitude, quality and convenience of HSPC mobilization for stem cell transplantation and ex vivo gene therapy after the administration of just a single dose. This optimized regimen has the potential to afford a superior alternative to G-CSF for HSPC mobilization.
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Affiliation(s)
| | | | - John F. DiPersio
- Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63105, USA
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Schleicher WE, Hoag B, De Dominici M, DeGregori J, Pietras EM. CHIP: a clonal odyssey of the bone marrow niche. J Clin Invest 2024; 134:e180068. [PMID: 39087468 PMCID: PMC11290965 DOI: 10.1172/jci180068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2024] Open
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the selective expansion of hematopoietic stem and progenitor cells (HSPCs) carrying somatic mutations. While CHIP is typically asymptomatic, it has garnered substantial attention due to its association with the pathogenesis of multiple disease conditions, including cardiovascular disease (CVD) and hematological malignancies. In this Review, we will discuss seminal and recent studies that have advanced our understanding of mechanisms that drive selection for mutant HSPCs in the BM niche. Next, we will address recent studies evaluating potential relationships between the clonal dynamics of CHIP and hematopoietic development across the lifespan. Next, we will examine the roles of systemic factors that can influence hematopoietic stem cell (HSC) fitness, including inflammation, and exposures to cytotoxic agents in driving selection for CHIP clones. Furthermore, we will consider how - through their impact on the BM niche - lifestyle factors, including diet, exercise, and psychosocial stressors, might contribute to the process of somatic evolution in the BM that culminates in CHIP. Finally, we will review the role of old age as a major driver of selection in CHIP.
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Affiliation(s)
| | - Bridget Hoag
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Marco De Dominici
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - James DeGregori
- Division of Hematology, Department of Medicine, and
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Heshmat-Ghahdarijani K, Fakhrolmobasheri M. Is Red Cell Distribution Width a Reliable Marker for Cardiovascular Diseases? A Narrative Review. Cardiol Rev 2024; 32:362-370. [PMID: 36730493 DOI: 10.1097/crd.0000000000000500] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Red cell distribution width (RDW) is an easy-to-access marker which is routinely measured in complete blood count (CBC) test. Besides the classic use of RDW as a marker for discriminating different types of anemia, recent studies had indicated the relationship between high RDW and cardiovascular diseases. High RDW is not only useful in the diagnosis and prognostication of various cardiovascular conditions but also could be used as a valuable tool for predicting the incidence of cardiovascular diseases. population-based studies have indicated that higher RDW could effectively predict the incidence of heart failure (HF), atherosclerotic diseases, and atrial fibrillation (AF). It has been also demonstrated that higher RDW is associated with worse outcomes in these diseases. Recent studies have shown that high RDW is also associated with other cardiovascular conditions including cardiomyopathies, and pulmonary hypertension. The predictive role of RDW in endovascular interventions has also been demonstrated by many recent studies. Here in this review, we attempt to compile the most recent findings with older reports regarding the relation between high RDW and HF, cardiomyopathies, pulmonary hypertension, AF, atherosclerotic disorders, primary hypertension, and the outcomes of endovascular interventions. we also discussed the role of RDW in the prognostication of different cardiovascular conditions when combined with classic classification criteria.
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Affiliation(s)
- Kiyan Heshmat-Ghahdarijani
- From the Heart Failure Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Fakhrolmobasheri
- Heart Failure Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
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Alves S, Silva F, Esteves F, Costa S, Slezakova K, Alves M, Pereira M, Teixeira J, Morais S, Fernandes A, Queiroga F, Vaz J. The Impact of Sleep on Haematological Parameters in Firefighters. Clocks Sleep 2024; 6:291-311. [PMID: 39051311 PMCID: PMC11270419 DOI: 10.3390/clockssleep6030021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 07/27/2024] Open
Abstract
Sleep is a vital process that impacts biological functions such as cell renewal, bone regeneration, and immune system support. Disrupted sleep can interrupt erythropoiesis, leading to fewer red blood cells, reduced haemoglobin concentration, and decreased haematocrit levels, potentially contributing to haematological disorders. This is particularly concerning for shift workers for example firefighters. While previous studies have explored sleep's adverse effects on various professions, research specific to firefighters is limited. This study investigates the relationship between sleep quality and haematological parameters among firefighters in Northeast Portugal. From a sample of 201 firefighters, variations in red blood cells, haemoglobin, and haematocrit values were linked to sleep quality. The study utilised non-parametric tests (Wilcoxon-Mann-Whitney, Spearman's correlation) to explore the connection between sleep quality and haematological profile. The impact of covariates on haematological parameters was assessed using non-parametric ANCOVA (Quade's). A multiple regression analysis was employed to further understand how sleep quality and various confounding variables impact haematological levels. Findings suggest a negative link between sleep quality and haematological levels, meaning that as sleep quality deteriorates, there is a tendency for haematological levels to decrease, as indicated by Spearman's correlation (rRBC = -0.157, pRBC = 0.026; rHb = -0.158, pHb = 0.025; rHCT = -0.175, pHCT = 0.013). As observed in scientific literature, the correlation found suggests a possible inhibition of erythropoiesis, the process responsible for red blood cell production. Despite firefighters presenting a haematological profile within the reference range (RBC: 5.1 × 106/mm3 (SD ± 0.4), Hb: 15.6 g/dL (SD ± 1.3), 47% (SD ± 1.0), there is already an observable trend towards lower levels. The analysis of co-variables did not reveal a significant impact of sleep quality on haematological levels. In conclusion, this study underscores the importance of sleep quality in determining haematological parameters among firefighters. Future research should investigate the underlying mechanisms and long-term implications of poor sleep quality on firefighter health. Exploring interventions to enhance sleep quality is vital for evidence-based strategies promoting firefighter well-being.
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Affiliation(s)
- Sara Alves
- Instituto Politécnico de Bragança, Campus de Santa Apolónia, 5300-253 Bragança, Portugal
| | - Francisca Silva
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal (F.Q.)
| | - Filipa Esteves
- Environmental Health Department, National Institute of Health, Rua das Taipas 135, 4050-600 Porto, Portugal; (F.E.); (S.C.); (J.T.)
- EPIUnit, National Institute of Public Health, University of Porto, Rua das Taipas 135, 4050-600 Porto, Portugal
| | - Solange Costa
- Environmental Health Department, National Institute of Health, Rua das Taipas 135, 4050-600 Porto, Portugal; (F.E.); (S.C.); (J.T.)
- EPIUnit, National Institute of Public Health, University of Porto, Rua das Taipas 135, 4050-600 Porto, Portugal
| | - Klara Slezakova
- REQUIMTE/LAQV, ISEP, Polytechnic of Porto, Rua Dr. António Bernardino de Almeida, 4249-015 Porto, Portugal; (K.S.); (S.M.)
| | - Maria Alves
- AquaValor-Centro de Valorização e Transferência de Tecnologia da Água-Associação, Rua Dr. Júlio Martins n.º 1, 5400-342 Chaves, Portugal;
- Centro de Investigação de Montanha (CIMO), Instituto Politécnico de Bragança, Campus de Santa Apolónia, 5300-253 Bragança, Portugal;
| | - Maria Pereira
- LEPABE-ALiCE, Faculdade de Engenharia da Universidade do Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
| | - João Teixeira
- Environmental Health Department, National Institute of Health, Rua das Taipas 135, 4050-600 Porto, Portugal; (F.E.); (S.C.); (J.T.)
- EPIUnit, National Institute of Public Health, University of Porto, Rua das Taipas 135, 4050-600 Porto, Portugal
| | - Simone Morais
- REQUIMTE/LAQV, ISEP, Polytechnic of Porto, Rua Dr. António Bernardino de Almeida, 4249-015 Porto, Portugal; (K.S.); (S.M.)
| | - Adília Fernandes
- Research Centre for Active Living and Wellbeing (LiveWell), Instituto Politécnico de Bragança, Campus de Santa Apolónia, 5300-253 Bragança, Portugal
| | - Felisbina Queiroga
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal (F.Q.)
| | - Josiana Vaz
- Centro de Investigação de Montanha (CIMO), Instituto Politécnico de Bragança, Campus de Santa Apolónia, 5300-253 Bragança, Portugal;
- Research Centre for Active Living and Wellbeing (LiveWell), Instituto Politécnico de Bragança, Campus de Santa Apolónia, 5300-253 Bragança, Portugal
- Laboratório Associado para a Sustentabilidade e Tecnologia em Regiões de Montanha (SusTEC), Instituto Politécnico de Bragança, Campus de Santa Apolónia, 5300-253 Bragança, Portugal
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Schill RL, Visser J, Ashby ML, Li Z, Lewis KT, Morales-Hernandez A, Hoose KS, Maung JN, Uranga RM, Hariri H, Hermsmeyer IDK, Mori H, MacDougald OA. Deficiency of glucocorticoid receptor in bone marrow adipocytes has mild effects on bone and hematopoiesis but does not influence expansion of marrow adiposity with caloric restriction. Front Endocrinol (Lausanne) 2024; 15:1397081. [PMID: 38887268 PMCID: PMC11180776 DOI: 10.3389/fendo.2024.1397081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 05/14/2024] [Indexed: 06/20/2024] Open
Abstract
Introduction Unlike white adipose tissue depots, bone marrow adipose tissue (BMAT) expands during caloric restriction (CR). Although mechanisms for BMAT expansion remain unclear, prior research suggested an intermediary role for increased circulating glucocorticoids. Methods In this study, we utilized a recently described mouse model (BMAd-Cre) to exclusively target bone marrow adipocytes (BMAds) for elimination of the glucocorticoid receptor (GR) (i.e. Nr3c1) whilst maintaining GR expression in other adipose depots. Results Mice lacking GR in BMAds (BMAd-Nr3c1 -/-) and control mice (BMAd-Nr3c1 +/+) were fed ad libitum or placed on a 30% CR diet for six weeks. On a normal chow diet, tibiae of female BMAd-Nr3c1-/- mice had slightly elevated proximal trabecular metaphyseal bone volume fraction and thickness. Both control and BMAd-Nr3c1-/- mice had increased circulating glucocorticoids and elevated numbers of BMAds in the proximal tibia following CR. However, no significant differences in trabecular and cortical bone were observed, and quantification with osmium tetroxide and μCT revealed no difference in BMAT accumulation between control or BMAd-Nr3c1 -/- mice. Differences in BMAd size were not observed between BMAd-Nr3c1-/- and control mice. Interestingly, BMAd-Nr3c1-/- mice had decreased circulating white blood cell counts 4 h into the light cycle. Discussion In conclusion, our data suggest that eliminating GR from BMAd has minor effects on bone and hematopoiesis, and does not impair BMAT accumulation during CR.
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Affiliation(s)
- Rebecca L. Schill
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Jack Visser
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Mariah L. Ashby
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Ziru Li
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Kenneth T. Lewis
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Antonio Morales-Hernandez
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, United States
| | - Keegan S. Hoose
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Jessica N. Maung
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Romina M. Uranga
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Hadla Hariri
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Isabel D. K. Hermsmeyer
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Hiroyuki Mori
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Ormond A. MacDougald
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
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11
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Schönberger K, Cabezas-Wallscheid N. How nutrition regulates hematopoietic stem cell features. Exp Hematol 2023; 128:10-18. [PMID: 37816445 DOI: 10.1016/j.exphem.2023.09.008] [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: 08/08/2023] [Revised: 09/26/2023] [Accepted: 09/29/2023] [Indexed: 10/12/2023]
Abstract
Our dietary choices significantly impact all the cells in our body. Increasing evidence suggests that diet-derived metabolites influence hematopoietic stem cell (HSC) metabolism and function, thereby actively modulating blood homeostasis. This is of particular relevance because regulating the metabolic activity of HSCs is crucial for maintaining stem cell fitness and mitigating the risk of hematologic disorders. In this review, we examine the current scientific knowledge of the impact of diet on stemness features, and we specifically highlight the established mechanisms by which dietary components modulate metabolic and transcriptional programs in adult HSCs. Gaining a deeper understanding of how nutrition influences our HSC compartment may pave the way for targeted dietary interventions with the potential to decelerate aging and improve the effectiveness of transplantation and cancer therapies.
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12
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Kim DW, Byun JM, Lee JO, Kim JK, Koh Y. Chemotherapy delivery time affects treatment outcomes of female patients with diffuse large B cell lymphoma. JCI Insight 2023; 8:164767. [PMID: 36512421 PMCID: PMC9977288 DOI: 10.1172/jci.insight.164767] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 12/07/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUNDChronotherapy is a drug intervention at specific times of the day to optimize efficacy and minimize adverse effects. Its value in hematologic malignancy remains to be explored, in particular in adult patients.METHODSWe performed chronotherapeutic analysis using 2 cohorts of patients with diffuse large B cell lymphoma (DLBCL) undergoing chemotherapy with a dichotomized schedule (morning or afternoon). The effect of a morning or afternoon schedule of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on survival and drug tolerability was evaluated in a survival cohort (n = 210) and an adverse event cohort (n = 129), respectively. Analysis of about 14,000 healthy individuals followed to identify the circadian variation in hematologic parameters.RESULTSBoth progression-free survival (PFS) and overall survival (OS) of female, but not male, patients were significantly shorter when patients received chemotherapy mostly in the morning (PFS HR 0.357, P = 0.033; and OS HR 0.141, P = 0.032). The dose intensity was reduced in female patients treated in the morning (cyclophosphamide 10%, P = 0.002; doxorubicin 8%, P = 0.002; and rituximab 7%, P = 0.003). This was mainly attributable to infection and neutropenic fever: female patients treated in the morning had a higher incidence of infections (16.7% vs. 2.4%) and febrile neutropenia (20.8% vs. 9.8%) as compared with those treated in the afternoon. The sex-specific chronotherapeutic effects can be explained by the larger daily fluctuation of circulating leukocytes and neutrophils in female than in male patients.CONCLUSIONIn female DLBCL patients, R-CHOP treatment in the afternoon can reduce toxicity while it improves efficacy and survival outcome.FUNDINGNational Research Foundation of Korea (NRF) grant funded by the Korean government (grant number NRF-2021R1A4A2001553), Institute for Basic Science IBS-R029-C3, and Human Frontiers Science Program Organization Grant RGY0063/2017.
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Affiliation(s)
- Dae Wook Kim
- Department of Mathematical Sciences, KAIST, Daejeon, South Korea.,Biomedical Mathematics Group, Institute for Basic Science, Daejeon, South Korea
| | - Ja Min Byun
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Jeong-Ok Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Jae Kyoung Kim
- Department of Mathematical Sciences, KAIST, Daejeon, South Korea.,Biomedical Mathematics Group, Institute for Basic Science, Daejeon, South Korea
| | - Youngil Koh
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
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13
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Suszynska M, Adamiak M, Thapa A, Cymer M, Ratajczak J, Kucia M, Ratajczak MZ. Purinergic Signaling and Its Role in Mobilization of Bone Marrow Stem Cells. Methods Mol Biol 2023; 2567:263-280. [PMID: 36255707 DOI: 10.1007/978-1-0716-2679-5_17] [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: 06/16/2023]
Abstract
Mobilization or egress of stem cells from bone marrow (BM) into peripheral blood (PB) is an evolutionary preserved and important mechanism in an organism for self-defense and regeneration. BM-derived stem cells circulate always at steady-state conditions in PB, and their number increases during stress situations related to (a) infections, (b) tissue organ injury, (c) stress, and (d) strenuous exercise. Stem cells also show a circadian pattern of their PB circulating level with peak in early morning hours and nadir late at night. The number of circulating in PB stem cells could be pharmacologically increased after administration of some drugs such as cytokine granulocyte colony-stimulating factor (G-CSF) or small molecular antagonist of CXCR4 receptor AMD3100 (Plerixafor) that promote their egress from BM into PB and lymphatic vessels. Circulating can be isolated from PB for transplantation purposes by leukapheresis. This important homeostatic mechanism is governed by several intrinsic complementary pathways. In this chapter, we will discuss the role of purinergic signaling and extracellular nucleotides in regulating this process and review experimental strategies to study their involvement in mobilization of various types of stem cells that reside in murine BM.
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Affiliation(s)
- Malwina Suszynska
- Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
- Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Mateusz Adamiak
- Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland
| | - Arjun Thapa
- Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Monika Cymer
- Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland
| | - Janina Ratajczak
- Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Magdalena Kucia
- Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
- Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland.
| | - Mariusz Z Ratajczak
- Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
- Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland
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14
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Quesenberry PJ, Wen S, Goldberg LR, Dooner MS. The universal stem cell. Leukemia 2022; 36:2784-2792. [PMID: 36307485 PMCID: PMC9712109 DOI: 10.1038/s41375-022-01715-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/26/2022] [Accepted: 09/22/2022] [Indexed: 11/08/2022]
Abstract
Current dogma is that there exists a hematopoietic pluripotent stem cell, resident in the marrow, which is quiescent, but with tremendous proliferative and differentiative potential. Furthermore, the hematopoietic system is essentially hierarchical with progressive differentiation from the pluripotent stem cells to different classes of hematopoietic cells. However, results summarized here indicate that the marrow pluripotent hematopoietic stem cell is actively cycling and thus continually changing phenotype. As it progresses through cell cycle differentiation potential changes as illustrated by sequential changes in surface expression of B220 and GR-1 epitopes. Further data indicated that the potential of purified hematopoietic stem cells extends to multiple other non-hematopoietic cells. It appears that marrow stem cells will give rise to epithelial pulmonary cells at certain points in cell cycle. Thus, it appears that the marrow "hematopoietic" stem cell is also a stem cell for other non-hematopoietic tissues. These observations give rise to the concept of a universal stem cell. The marrow stem cell is not limited to hematopoiesis and its differentiation potential continually changes as it transits cell cycle. Thus, there is a universal stem cell in the marrow which alters its differentiation potential as it progresses through cell cycle. This potential is expressed when it resides in tissues compatible with its differentiation potential, at a particular point in cell cycle transit, or when it interacts with vesicles from that tissue.
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Affiliation(s)
- Peter J Quesenberry
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA.
| | - Sicheng Wen
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA
| | - Laura R Goldberg
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA
- Division of Hematology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Mark S Dooner
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA
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15
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Colombini B, Dinu M, Murgo E, Lotti S, Tarquini R, Sofi F, Mazzoccoli G. Ageing and Low-Level Chronic Inflammation: The Role of the Biological Clock. Antioxidants (Basel) 2022; 11:2228. [PMID: 36421414 PMCID: PMC9686908 DOI: 10.3390/antiox11112228] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/02/2022] [Accepted: 11/09/2022] [Indexed: 09/01/2023] Open
Abstract
Ageing is a multifactorial physiological manifestation that occurs inexorably and gradually in all forms of life. This process is linked to the decay of homeostasis due to the progressive decrease in the reparative and regenerative capacity of tissues and organs, with reduced physiological reserve in response to stress. Ageing is closely related to oxidative damage and involves immunosenescence and tissue impairment or metabolic imbalances that trigger inflammation and inflammasome formation. One of the main ageing-related alterations is the dysregulation of the immune response, which results in chronic low-level, systemic inflammation, termed "inflammaging". Genetic and epigenetic changes, as well as environmental factors, promote and/or modulate the mechanisms of ageing at the molecular, cellular, organ, and system levels. Most of these mechanisms are characterized by time-dependent patterns of variation driven by the biological clock. In this review, we describe the involvement of ageing-related processes with inflammation in relation to the functioning of the biological clock and the mechanisms operating this intricate interaction.
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Affiliation(s)
- Barbara Colombini
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Monica Dinu
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Emanuele Murgo
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS “Casa Sollievo della Sofferenza”, Opera di Padre Pio da Pietrelcina, 71013 San Giovanni Rotondo, Italy
| | - Sofia Lotti
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Roberto Tarquini
- Division of Internal Medicine I, San Giuseppe Hospital, 50053 Empoli, Italy
| | - Francesco Sofi
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Gianluigi Mazzoccoli
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS “Casa Sollievo della Sofferenza”, Opera di Padre Pio da Pietrelcina, 71013 San Giovanni Rotondo, Italy
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16
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Peci F, Dekker L, Pagliaro A, van Boxtel R, Nierkens S, Belderbos M. The cellular composition and function of the bone marrow niche after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2022; 57:1357-1364. [PMID: 35690693 PMCID: PMC9187885 DOI: 10.1038/s41409-022-01728-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 04/29/2022] [Accepted: 05/26/2022] [Indexed: 11/09/2022]
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for patients with a variety of malignant and non-malignant diseases. Despite its life-saving potential, HCT is associated with significant morbidity and mortality. Reciprocal interactions between hematopoietic stem cells (HSCs) and their surrounding bone marrow (BM) niche regulate HSC function during homeostatic hematopoiesis as well as regeneration. However, current pre-HCT conditioning regimens, which consist of high-dose chemotherapy and/or irradiation, cause substantial short- and long-term toxicity to the BM niche. This damage may negatively affect HSC function, impair hematopoietic regeneration after HCT and predispose to HCT-related morbidity and mortality. In this review, we summarize current knowledge on the cellular composition of the human BM niche after HCT. We describe how pre-HCT conditioning affects the cell types in the niche, including endothelial cells, mesenchymal stromal cells, osteoblasts, adipocytes, and neurons. Finally, we discuss therapeutic strategies to prevent or repair conditioning-induced niche damage, which may promote hematopoietic recovery and improve HCT outcome.
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Affiliation(s)
- Flavia Peci
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Linde Dekker
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Anna Pagliaro
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Ruben van Boxtel
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Stefan Nierkens
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Mirjam Belderbos
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
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17
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Wu LM, Valdimarsdottir HB, Amidi A, Reid KJ, Ancoli-Israel S, Bovbjerg K, Fox RS, Walker L, Matharu A, Kaseda ET, Galvin JP, Adekola K, Winkel G, Penedo F, Redd WH. Examining the Efficacy of Bright Light Therapy on Cognitive Function in Hematopoietic Stem Cell Transplant Survivors. J Biol Rhythms 2022; 37:471-483. [PMID: 35904252 DOI: 10.1177/07487304221107833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Patients who have undergone hematopoietic stem cell transplant (HSCT) may experience cognitive impairment that can persist after treatment. Several studies have shown that bright light therapy may improve cognition, potentially due to its effects on the circadian system via brain regions that respond preferentially to light. In this double-blind randomized controlled trial, the efficacy of bright light therapy on cognition was examined in HSCT survivors. Forty-seven HSCT survivors at an urban hospital in the United States were screened for mild cognitive impairment, randomized to either bright white light (BWL) or comparison dim red light (DRL) conditions using a block randomization approach, and instructed to use their assigned light box every morning upon awakening for 30 min for 4 weeks. Assessments occurred at baseline, the end of the second week of the intervention, the end of the intervention, and at follow-up (8 weeks later). The primary outcome was objective cognitive function as measured by a global composite score on neuropsychological tests. Secondary outcomes included cognitive performance in individual domains, self-reported cognitive function, fatigue, sleep and sleep quality, and circadian rhythm robustness. Repeated-measures linear mixed models for both objective and self-reported cognitive function indicated significant main effects for time (ps < 0.05) suggesting significant improvements in both conditions over time. Time by light condition interaction effects were not significant. Models focused on secondary outcomes yielded no significant effects. Both BWL and DRL groups demonstrated significant improvements in objective cognitive and self-reported cognitive function over time, but there was no hypothesized effect of BWL over DRL nor associations with circadian rhythm robustness. Therapeutic effects of both light conditions, practice effects, and/or placebo effects may account for the findings.Trial registration: ClinicalTrials.gov Identifier: NCT02677987 (9 February 2016).
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Affiliation(s)
- Lisa M Wu
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.,Aarhus Institute of Advanced Studies, Aarhus University, Aarhus, Denmark.,Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Heiddis B Valdimarsdottir
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.,Department of Psychology, Reykjavik University, Reykjavik, Iceland
| | - Ali Amidi
- Department of Psychology and Behavioural Sciences, Aarhus University, Aarhus, Denmark
| | - Kathryn J Reid
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Sonia Ancoli-Israel
- Department of Psychiatry, School of Medicine, University of California San Diego, San Diego, California, USA
| | - Katrin Bovbjerg
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Rina S Fox
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.,College of Nursing, The University of Arizona, Tucson, Arizona, USA
| | - Lauren Walker
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Amreen Matharu
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Erin T Kaseda
- Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA
| | - John P Galvin
- Department of Internal Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Kehinde Adekola
- Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Gary Winkel
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Frank Penedo
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA
| | - William H Redd
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
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18
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Rodgers KA, Kigerl KA, Schwab JM, Popovich PG. Immune dysfunction after spinal cord injury - A review of autonomic and neuroendocrine mechanisms. Curr Opin Pharmacol 2022; 64:102230. [PMID: 35489214 PMCID: PMC9372819 DOI: 10.1016/j.coph.2022.102230] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 03/22/2022] [Indexed: 02/05/2023]
Abstract
Infections impair neurological outcome and increase mortality after spinal cord injury (SCI). Emerging data show that pathogens more easily infect individuals with SCI because SCI disrupts neural and humoral control of immune cells, culminating with the development of "SCI-induced immune deficiency syndrome" (SCI-IDS). Here, we review data that implicate autonomic dysfunction and impaired neuroendocrine signaling as key determinants of SCI-IDS. Although it is widely appreciated that mature leukocyte dysfunction is a canonical feature of SCI-IDS, new data indicate that SCI impairs the development and mobilization of immune cell precursors in bone marrow. Thus, this review will also explore how the post-injury acquisition of a "bone marrow failure syndrome" may be the earliest manifestation of SCI-IDS.
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Affiliation(s)
- Kyleigh A Rodgers
- Department of Neuroscience, The Ohio State University, Columbus, OH, USA; Medical Scientist Training Program, The Ohio State University, Columbus, OH, USA
| | - Kristina A Kigerl
- Department of Neuroscience, The Ohio State University, Columbus, OH, USA; Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH, USA; The Belford Center for Spinal Cord Injury, The Ohio State University, Columbus, OH, USA
| | - Jan M Schwab
- Department of Neuroscience, The Ohio State University, Columbus, OH, USA; Medical Scientist Training Program, The Ohio State University, Columbus, OH, USA; Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH, USA; The Belford Center for Spinal Cord Injury, The Ohio State University, Columbus, OH, USA; Departments of Neurology and Physical Medicine and Rehabilitation, The Ohio State University, Columbus, OH 43210, USA
| | - Phillip G Popovich
- Department of Neuroscience, The Ohio State University, Columbus, OH, USA; Medical Scientist Training Program, The Ohio State University, Columbus, OH, USA; Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH, USA; The Belford Center for Spinal Cord Injury, The Ohio State University, Columbus, OH, USA.
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19
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Red Blood Cell Distribution Width in Heart Failure: Pathophysiology, Prognostic Role, Controversies and Dilemmas. J Clin Med 2022; 11:jcm11071951. [PMID: 35407558 PMCID: PMC8999162 DOI: 10.3390/jcm11071951] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/26/2022] [Accepted: 03/30/2022] [Indexed: 12/12/2022] Open
Abstract
Red blood cell distribution width (RDW), an integral parameter of the complete blood count (CBC), has been traditionally used for the classification of several types of anemia. However, over the last decade RDW has been associated with outcome in patients with several cardiovascular diseases including heart failure. The role of RDW in acute, chronic and advanced heart failure is the focus of the present work. Several pathophysiological mechanisms of RDW’s increase in heart failure have been proposed (i.e., inflammation, oxidative stress, adrenergic stimulation, undernutrition, ineffective erythropoiesis, reduced iron mobilization, etc.); however, the exact mechanism remains unknown. Although high RDW values at admission and discharge have been associated with adverse prognosis in hospitalized heart failure patients, the prognostic role of in-hospital RDW changes (ΔRDW) remains debatable. RDW has been incorporated in recent heart failure prognostic models. Utilizing RDW as a treatment target in heart failure may be a promising area of research.
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20
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The P2X4 purinergic receptor has emerged as a potent regulator of hematopoietic stem/progenitor cell mobilization and homing-a novel view of P2X4 and P2X7 receptor interaction in orchestrating stem cell trafficking. Leukemia 2022; 36:248-256. [PMID: 34285343 DOI: 10.1038/s41375-021-01352-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/07/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
Recent evidence indicates that extracellular adenosine triphosphate (eATP), as a major mediator of purinergic signaling, plays an important role in regulating the mobilization and homing of hematopoietic stem progenitor cells (HSPCs). In our previous work we demonstrated that eATP activates the P2X7 ion channel receptor in HSPCs and that its deficiency impairs stem cell trafficking. To learn more about the role of the P2X purinergic receptor family in hematopoiesis, we phenotyped murine and human HSPCs with respect to the seven P2X receptors and observed that, these cells also highly express P2X4 receptors, which shows ~50% sequence similarity to P2X7 subtypes, but that P2X4 cells are more sensitive to eATP and signal much more rapidly. Using the selective P2X4 receptor antagonist PSB12054 as well as P2X4-KO mice, we found that the P2X4 receptor, similar to P2X7 receptor, promotes trafficking of HSPCs in that its deficiency leads to impaired chemotaxis of HSPCs in response to a stromal-derived factor 1 (SDF-1) gradient, less effective pharmacological mobilization, and defective homing and engraftment of HSPCs after transplantation into myeloablated hosts. This correlated with a decrease in SDF-1 expression in the BM microenvironment. Overall, our results confirm the proposed cooperative dependence of both receptors in response to eATP signaling. In G-CSF-induced mobilization, a lack of one receptor is not compensated by the presence of the other one, which supports their mutual dependence in regulating HSPC trafficking.
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21
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Moll G, Ankrum JA, Olson SD, Nolta JA. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:2-13. [PMID: 35641163 PMCID: PMC8895495 DOI: 10.1093/stcltm/szab005] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/27/2021] [Indexed: 11/22/2022] Open
Abstract
The number of mesenchymal stromal/stem cell (MSC) therapeutics and types of clinical applications have greatly diversified during the past decade, including rapid growth of poorly regulated “Stem Cell Clinics” offering diverse “Unproven Stem Cell Interventions.” This product diversification necessitates a critical evaluation of the reliance on the 2006 MSC minimal criteria to not only define MSC identity but characterize MSC suitability for intravascular administration. While high-quality MSC therapeutics have been safely administered intravascularly in well-controlled clinical trials, repeated case reports of mild-to-more-severe adverse events have been reported. These are most commonly related to thromboembolic complications upon infusion of highly procoagulant tissue factor (TF/CD142)-expressing MSC products. As TF/CD142 expression varies widely depending on the source and manufacturing process of the MSC product, additional clinical cell product characterization and guidelines are needed to ensure the safe use of MSC products. To minimize risk to patients receiving MSC therapy, we here propose to supplement the minimal criteria used for characterization of MSCs, to include criteria that assess the suitability of MSC products for intravascular use. If cell products are intended for intravascular delivery, which is true for half of all clinical applications involving MSCs, the effects of MSC on coagulation and hemocompatibility should be assessed and expression of TF/CD142 should be included as a phenotypic safety marker. This adjunct criterion will ensure both the identity of the MSCs as well as the safety of the MSCs has been vetted prior to intravascular delivery of MSC products.
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Affiliation(s)
- Guido Moll
- BIH Center for Regenerative Therapies (BCRT) and Berlin Brandenburg School of Regenerative Therapies (BSRT), Berlin Institute of Health (BIH) at the Charité—Universitätsmedizin Berlin, corporate member of Freie Universität zu Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Corresponding author: Guido Moll, PhD, BIH Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany.
| | - James A Ankrum
- Roy J. Carver Department of Biomedical Engineering and Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA, USA
| | - Scott D Olson
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Sciences Center at Houston, Houston, TX, USA
| | - Jan A Nolta
- Director of the Stem Cell Program, University of California Davis School of Medicine, Sacramento, CA, USA
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22
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Xanthopoulos A, Tryposkiadis K, Dimos A, Bourazana A, Zagouras A, Iakovis N, Papamichalis M, Giamouzis G, Vassilopoulos G, Skoularigis J, Triposkiadis F. Red blood cell distribution width in elderly hospitalized patients with cardiovascular disease. World J Cardiol 2021; 13:503-513. [PMID: 34621495 PMCID: PMC8462048 DOI: 10.4330/wjc.v13.i9.503] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 06/22/2021] [Accepted: 08/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Red blood cell distribution width (RDW) is elevated in patients with cardiovascular disease (CVD). AIM To determine RDW values and impact of CV and non-CV coexisting morbidities in elderly patients hospitalized with chronic CVD. METHODS This prospective study included 204 consecutive elderly patients (age 77.5 [7.41] years, female 94 [46%], left ventricular ejection fraction 53.00% [37.50, 55.00]) hospitalized with chronic CVD at the Cardiology Department of Larissa University General Hospital (Larissa, Greece) from January 2019 to April 2019. Elderly patients were selected due to the high prevalence of coexisting morbidities in this patient population. Hospitalized patients with acute CVD (acute coronary syndromes, new-onset heart failure [HF], and acute pericarditis/myocarditis), primary isolated valvular heart disease, sepsis, and those with a history of blood transfusions or cancer were excluded. The evaluation of the patients within 24 h from admission included clinical examination, laboratory blood tests, and echocardiography. RESULTS The most common cardiac morbidities were hypertension and coronary artery disease, with acutely decompensated chronic heart failure (ADCHF) and atrial fibrillation (AF) also frequently being present. The most common non-cardiac morbidities were anemia and chronic kidney disease followed by diabetes mellitus, chronic obstructive pulmonary disease, and sleep apnea. RDW was significantly elevated 15.48 (2.15); 121 (59.3%) of patients had RDW > 14.5% which represents the upper limit of normal in our institution. Factors associated with RDW in stepwise regression analysis were ADCHF (coefficient: 1.406; 95% confidence interval [CI]: 0.830-1.981; P < 0.001), AF (1.192; 0.673 to 1.711; P < 0.001), and anemia (0.806; 0.256 to 1.355; P = 0.004). ADCHF was the most significant factor associated with RDW. RDW was on average 1.41 higher for patients with than without ADCHF, 1.19 higher for patients with than without AF, and 0.81 higher for patients with than without anemia. When patients were grouped based on the presence or absence of anemia, ADCHF and AF, heart rate was not increased in those with anemia but was significantly increased in those with ADCHF or AF. CONCLUSION RDW was elevated in elderly hospitalized patients with chronic CVD. Factors associated with RDW were anemia and CV factors associated with elevated heart rate (ADCHF, AF), suggesting sympathetic overactivity.
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Affiliation(s)
- Andrew Xanthopoulos
- Department of Cardiology, University Hospital of Larissa, Larissa 41110, Greece.
| | | | - Apostolos Dimos
- Department of Cardiology, University Hospital of Larissa, Larissa 41110, Greece
| | - Angeliki Bourazana
- Department of Cardiology, University Hospital of Larissa, Larissa 41110, Greece
| | - Alexandros Zagouras
- Department of Cardiology, University Hospital of Larissa, Larissa 41110, Greece
| | - Nikolaos Iakovis
- Department of Cardiology, University Hospital of Larissa, Larissa 41110, Greece
| | | | - Grigorios Giamouzis
- Department of Cardiology, University Hospital of Larissa, Larissa 41110, Greece
| | - George Vassilopoulos
- Department of Haematology, University of Thessaly Medical School, Larissa 41110, Greece
| | - John Skoularigis
- Department of Cardiology, University Hospital of Larissa, Larissa 41110, Greece
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23
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Silva WN, Costa AC, Picoli CC, Rocha BGS, Santos GSP, Costa PAC, Azimnasab-sorkhabi P, Soltani-asl M, da Silva RA, Amorim JH, Resende RR, Mintz A, Birbrair A. Hematopoietic stem cell stretches and moves in its bone marrow niche. Crit Rev Oncol Hematol 2021; 163:103368. [PMID: 34051302 PMCID: PMC8277710 DOI: 10.1016/j.critrevonc.2021.103368] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 04/28/2021] [Accepted: 05/03/2021] [Indexed: 12/20/2022] Open
Abstract
Hematopoietic stem cells are the most illustrious inhabitants of the bone marrow. Direct visualization of endogenous hematopoietic stem cells in this niche is essential to study their functions. Until recently this was not possible in live animals. Recent studies, using state-of-the-art technologies, including sophisticated in vivo inducible genetic approaches in combination with two-photon laser scanning microscopy, allow the follow-up of endogenous hematopoietic stem cells' behavior in their habitat. Strikingly, the new findings reveal that quiescent hematopoietic stem cells are more mobile than previously thought, and link their retained steady state within the niche to a mobile behavior. The arising knowledge from this research will be critical for the therapy of several hematological diseases. Here, we review recent progress in our understanding of hematopoietic stem cell biology in their niches.
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Affiliation(s)
- Walison N. Silva
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Alinne C. Costa
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Caroline C. Picoli
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Beatriz G. S. Rocha
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | | | - Pedro A. C. Costa
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | | | - Maryam Soltani-asl
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | | | | | - Rodrigo R. Resende
- Center of Biological Sciences and Health, Federal University of West Bahia, Barreiras, BA, Brazil
| | - Akiva Mintz
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Alexander Birbrair
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
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24
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Ruby CL, Major RJ, Hinrichsen RD. Regulation of tissue regeneration by the circadian clock. Eur J Neurosci 2021; 53:3576-3597. [PMID: 33893679 DOI: 10.1111/ejn.15244] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 03/31/2021] [Accepted: 04/16/2021] [Indexed: 12/12/2022]
Abstract
Circadian rhythms are regulated by a highly conserved transcriptional/translational feedback loop that maintains approximately 24-hr periodicity from cellular to organismal levels. Much research effort is being devoted to understanding how the outputs of the master clock affect peripheral oscillators, and in turn, numerous biological processes. Recent studies have revealed roles for circadian timing in the regulation of numerous cellular behaviours in support of complex tissue regeneration. One such role involves the interaction between the circadian clockwork and the cell cycle. The molecular mechanisms that control the cell cycle create a system of regulation that allows for high fidelity DNA synthesis, mitosis and apoptosis. In recent years, it has become clear that clock gene products are required for proper DNA synthesis and cell cycle progression, and conversely, elements of the cell cycle cascade feedback to influence molecular circadian timing mechanisms. It is through this crosstalk that the circadian system orchestrates stem cell proliferation, niche exit and control of the signalling pathways that govern differentiation and self-renewal. In this review, we discuss the evidence for circadian control of tissue homeostasis and repair and suggest new avenues for research.
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Affiliation(s)
- Christina L Ruby
- Department of Biology, Indiana University of Pennsylvania, Indiana, PA, USA
| | - Robert J Major
- Department of Biology, Indiana University of Pennsylvania, Indiana, PA, USA
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25
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Lin Y, Tsai M, Hsieh I, Wen M, Wang C. Deficiency of circadian gene cryptochromes in bone marrow‐derived cells protects against atherosclerosis in
LDLR
−/−
mice. FASEB J 2021; 35:e21309. [DOI: 10.1096/fj.202001818rrr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 12/09/2020] [Accepted: 12/11/2020] [Indexed: 12/14/2022]
Affiliation(s)
- Yu‐Sheng Lin
- Healthcare Center Chang Gung Memorial Hospital Chang Gung University College of Medicine Taoyuan City Taiwan
- Department of Cardiology Chang Gung Memorial Hospital Chang Gung University College of Medicine Taoyuan City Taiwan
| | - Ming‐Lung Tsai
- Department of Cardiology Chang Gung Memorial Hospital Chang Gung University College of Medicine Taoyuan City Taiwan
| | - I‐Chang Hsieh
- Department of Cardiology Chang Gung Memorial Hospital Chang Gung University College of Medicine Taoyuan City Taiwan
| | - Ming‐Shien Wen
- Department of Cardiology Chang Gung Memorial Hospital Chang Gung University College of Medicine Taoyuan City Taiwan
| | - Chao‐Yung Wang
- Department of Cardiology Chang Gung Memorial Hospital Chang Gung University College of Medicine Taoyuan City Taiwan
- Institute of Cellular and System Medicine National Health Research Institutes Zhunan Taiwan
- Department of Medical Science National Tsing Hua University Hsinchu Taiwan
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26
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Uçkan-Çetinkaya D, Haider KH. Induced Pluripotent Stem Cells in Pediatric Research and Clinical Translation. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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27
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Ahmari N, Hayward LF, Zubcevic J. The importance of bone marrow and the immune system in driving increases in blood pressure and sympathetic nerve activity in hypertension. Exp Physiol 2020; 105:1815-1826. [PMID: 32964557 DOI: 10.1113/ep088247] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/01/2020] [Indexed: 12/27/2022]
Abstract
NEW FINDINGS What is the topic of this review? This manuscript provides a review of the current understanding of the role of the sympathetic nervous system in regulation of bone marrow-derived immune cells and the effect that the infiltrating bone marrow cells may have on perpetuation of the sympathetic over-activation in hypertension. What advances does it highlight? We highlight the recent advances in understanding of the neuroimmune interactions both peripherally and centrally as they relate to blood pressure control. ABSTRACT The sympathetic nervous system (SNS) plays a crucial role in maintaining physiological homeostasis, in part by regulating, integrating and orchestrating processes between many physiological systems, including the immune system. Sympathetic nerves innervate all primary and secondary immune organs, and all cells of the immune system express β-adrenoreceptors. In turn, immune cells can produce cytokines, chemokines and neurotransmitters capable of modulating neuronal activity and, ultimately, SNS activity. Thus, the essential role of the SNS in the regulation of innate and adaptive immune functions is mediated, in part, via β-adrenoreceptor-induced activation of bone marrow cells by noradrenaline. Interestingly, both central and systemic inflammation are well-established hallmarks of hypertension and its co-morbidities, including an inflammatory process involving the transmigration and infiltration of immune cells into tissues. We propose that physiological states that prolong β-adrenoreceptor activation in bone marrow can disrupt neuroimmune homeostasis and impair communication between the immune system and SNS, leading to immune dysregulation, which, in turn, is sustained via a central mechanism involving neuroinflammation.
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Affiliation(s)
- Niousha Ahmari
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Linda F Hayward
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA.,Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
| | - Jasenka Zubcevic
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA.,Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
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28
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Balise VD, Saito-Reis CA, Gillette JM. Tetraspanin Scaffold Proteins Function as Key Regulators of Hematopoietic Stem Cells. Front Cell Dev Biol 2020; 8:598. [PMID: 32754593 PMCID: PMC7381308 DOI: 10.3389/fcell.2020.00598] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 06/19/2020] [Indexed: 02/06/2023] Open
Abstract
Hematopoietic stem and progenitor cells (HSPCs) are responsible for the development, maintenance, and regeneration of all the blood forming cells in the body, and as such, are critical for a number of patient therapies. For successful HSPC transplantation, stem cells must traffic through the blood and home to the bone marrow (BM) microenvironment or “niche,” which is composed of soluble factors, matrix proteins, and supportive cells. HSPC adhesion to, and signaling with, cellular and extracellular components of the niche provide instructional cues to balance stem cell self-renewal and differentiation. In this review, we will explore the regulation of these stem cell properties with a focus on the tetraspanin family of membrane proteins. Tetraspanins are molecular scaffolds that uniquely function to distribute proteins into highly organized microdomains comprising adhesion, signaling, and adaptor proteins. As such, tetraspanins contribute to many aspects of cell physiology as mediators of cell adhesion, trafficking, and signaling. We will summarize the many reports that identify tetraspanins as markers of specific HSPC populations. Moreover, we will discuss the various studies establishing the functional importance of tetraspanins in the regulation of essential HSPC processes including quiescence, migration, and niche adhesion. When taken together, studies outlined in this review suggest that several tetraspanins may serve as potential targets to modulate HSPC interactions with the BM niche, ultimately impacting future HSPC therapies.
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Affiliation(s)
- Victoria D Balise
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Chelsea A Saito-Reis
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Jennifer M Gillette
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.,Comprehensive Cancer Center, The University of New Mexico, Albuquerque, NM, United States
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29
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Eastman AE, Chen X, Hu X, Hartman AA, Pearlman Morales AM, Yang C, Lu J, Kueh HY, Guo S. Resolving Cell Cycle Speed in One Snapshot with a Live-Cell Fluorescent Reporter. Cell Rep 2020; 31:107804. [PMID: 32579930 PMCID: PMC7418154 DOI: 10.1016/j.celrep.2020.107804] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 03/29/2020] [Accepted: 06/02/2020] [Indexed: 12/18/2022] Open
Abstract
Cell proliferation changes concomitantly with fate transitions during reprogramming, differentiation, regeneration, and oncogenesis. Methods to resolve cell cycle length heterogeneity in real time are currently lacking. Here, we describe a genetically encoded fluorescent reporter that captures live-cell cycle speed using a single measurement. This reporter is based on the color-changing fluorescent timer (FT) protein, which emits blue fluorescence when newly synthesized before maturing into a red fluorescent protein. We generated a mouse strain expressing an H2B-FT fusion reporter from a universally active locus and demonstrate that faster cycling cells can be distinguished from slower cycling ones on the basis of the intracellular fluorescence ratio between the FT's blue and red states. Using this reporter, we reveal the native cell cycle speed distributions of fresh hematopoietic cells and demonstrate its utility in analyzing cell proliferation in solid tissues. This system is broadly applicable for dissecting functional heterogeneity associated with cell cycle dynamics in complex tissues.
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Affiliation(s)
- Anna E Eastman
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA
| | - Xinyue Chen
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA
| | - Xiao Hu
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA
| | - Amaleah A Hartman
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA
| | | | - Cindy Yang
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA
| | - Jun Lu
- Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA; Department of Genetics, Yale University, New Haven, CT 06520, USA
| | - Hao Yuan Kueh
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - Shangqin Guo
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.
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30
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García-García A, Méndez-Ferrer S. The Autonomic Nervous System Pulls the Strings to Coordinate Circadian HSC Functions. Front Immunol 2020; 11:956. [PMID: 32508835 PMCID: PMC7251159 DOI: 10.3389/fimmu.2020.00956] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 04/23/2020] [Indexed: 11/16/2022] Open
Abstract
As for many other adult stem cells, the behavior of hematopoietic stem and progenitor cells (HSPCs) is subjected to circadian regulatory patterns. Multiple HSPC functions, such as proliferation, differentiation or trafficking exhibit time-dependent patterns that require a tight coordination to ensure daily blood cell production. The autonomic nervous system, together with circulating hormones, relay circadian signals from the central clock-the suprachiasmatic nucleus in the brain-to synchronize HSC niche physiology according to light/darkness cycles. Research over the last 20 years has revealed how specific neural signals modulate certain aspects of circadian HSC biology. However, only recently some studies have started to decipher the cellular and molecular mechanisms that orchestrate this complex regulation in a time-dependent fashion. Here we firstly review some of the recent key findings illustrating how different neural signals (catecholaminergic or cholinergic) regulate circadian HSC egress, homing, maintenance, proliferation, and differentiation. In particular, we highlight the critical role of different neurotransmitter receptors in the bone marrow microenvironment to channel these neural signals and regulate antagonistic processes according to circadian cues and organismal demands. Then, we discuss the potential biological meaning of HSC circadian regulation and its possible utility for clinical purposes. Finally, we offer our perspective on emerging concepts in HSC chronobiology.
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Affiliation(s)
- Andrés García-García
- Tissue Engineering, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Simón Méndez-Ferrer
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom
- National Health Service Blood and Transplant, Cambridge, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
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31
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Curto-Garcia N, Harrison C, McLornan DP. Bone marrow niche dysregulation in myeloproliferative neoplasms. Haematologica 2020; 105:1189-1200. [PMID: 32241851 PMCID: PMC7193484 DOI: 10.3324/haematol.2019.243121] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 02/06/2020] [Indexed: 12/11/2022] Open
Abstract
The bone marrow niche is a complex and dynamic structure composed of a multitude of cell types which functionally create an interactive network facilitating hematopoietic stem cell development and maintenance. Its specific role in the pathogenesis, response to therapy, and transformation of myeloproliferative neoplasms has only recently been explored. Niche functionality is likely affected not only by the genomic background of the myeloproliferative neoplasm-associated mutated hematopoietic stem cells, but also by disease-associated 'chronic inflammation', and subsequent adaptive and innate immune responses. 'Cross-talk' between mutated hematopoietic stem cells and multiple niche components may contribute to propagating disease progression and mediating drug resistance. In this timely article, we will review current knowledge surrounding the deregulated bone marrow niche in myeloproliferative neoplasms and suggest how this may be targeted, either directly or indirectly, potentially influencing therapeutic choices both now and in the future.
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Affiliation(s)
| | - Claire Harrison
- Department of Hematology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Donal P McLornan
- Department of Hematology, Guy's and St Thomas' NHS Foundation Trust, London, UK
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32
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Abstract
Unhealthy diet, lack of exercise, psychosocial stress, and insufficient sleep are increasingly prevalent modifiable risk factors for cardiovascular disease. Accumulating evidence indicates that these risk factors may fuel chronic inflammatory processes that are active in atherosclerosis and lead to myocardial infarction and stroke. In concert with hyperlipidemia, maladaptive immune system activities can contribute to disease progression and increase the probability of adverse events. In this review, we discuss recent insight into how the above modifiable risk factors influence innate immunity. Specifically, we focus on pathways that raise systemic myeloid cell numbers and modulate immune cell phenotypes, reviewing hematopoiesis, leukocyte trafficking, and innate immune cell accumulation in cardiovascular organs. Often, relevant mechanisms that begin with lifestyle choices and lead to cardiovascular events span multiple organ systems, including the central nervous, endocrine, metabolic, hematopoietic, immune and, finally, the cardiovascular system. We argue that deciphering such pathways provides not only support for preventive interventions but also opportunities to develop biomimetic immunomodulatory therapeutics that mitigate cardiovascular inflammation.
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Affiliation(s)
- Maximilian J Schloss
- From the Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston (M.J.S., F.K.S., M.N.).,Department of Radiology, Massachusetts General Hospital, Boston (M.J.S., F.K.S., M.N.)
| | - Filip K Swirski
- From the Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston (M.J.S., F.K.S., M.N.).,Department of Radiology, Massachusetts General Hospital, Boston (M.J.S., F.K.S., M.N.)
| | - Matthias Nahrendorf
- From the Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston (M.J.S., F.K.S., M.N.).,Department of Radiology, Massachusetts General Hospital, Boston (M.J.S., F.K.S., M.N.).,Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (M.N.).,Department of Internal Medicine I, University Hospital Wuerzburg, Germany (M.N.)
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33
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Adamiak M, Ciechanowicz A, Skoda M, Cymer M, Tracz M, Xu B, Ratajczak MZ. Novel Evidence that Purinergic Signaling - Nlrp3 Inflammasome Axis Regulates Circadian Rhythm of Hematopoietic Stem/Progenitor Cells Circulation in Peripheral Blood. Stem Cell Rev Rep 2020; 16:335-343. [PMID: 31939051 PMCID: PMC7152586 DOI: 10.1007/s12015-020-09953-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We found that circadian changes in ATP level in peripheral blood (PB) activate the Nlrp3 inflammasome, which triggers diurnal release of hematopoietic stem/progenitor cells (HSPCs) from murine bone marrow (BM) into PB. Consistent with this finding, we observed circadian changes in expression of mRNA for Nlrp3 inflammasome-related genes, including Nlrp3, caspase 1, IL-1β, IL-18, gasdermin (GSDMD), HMGB1, and S100A9. Circadian release of HSPCs from BM into PB as well as expression of Nlrp3-associated genes was decreased in mice in which pannexin 1-mediated secretion of ATP was inhibited by the blocking peptide 10Panx and in animals exposed to the specific small-molecule inhibitor of the Nlrp3 inflammasome MCC950. In addition to HSPCs, a similar decrease in diurnal cell counts was observed for mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic-like stem cells (VSELs). These results shed more light on the complexity of circadian regulation of HSPC release into PB, which is coordinated in a purinergic signaling-, innate immunity-dependent manner. Moreover, in addition to circadian changes in expression of the Nlrp3 inflammasome we also observed diurnal changes in expression of other inflammasomes, including Aim2, Nrp1a, and Nlrp1b.
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Affiliation(s)
- Mateusz Adamiak
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Andrzej Ciechanowicz
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Marta Skoda
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Monika Cymer
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Michal Tracz
- Institute of Veterinary Medicine, Department of Food Hygiene and Public Health Protection, Warsaw University of Life Sciences, Warsaw, Poland
| | - Bing Xu
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology of Xiamen University, Xiamen, People’s Republic of China
| | - Mariusz Z. Ratajczak
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY 40202 USA
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34
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Chen S, Qi Y, Wang S, Xu Y, Shen M, Hu M, Du C, Chen F, Chen M, Lu Y, Zhang Z, Quan Y, Wang C, Wang F, Wang J. Melatonin enhances thrombopoiesis through ERK1/2 and Akt activation orchestrated by dual adaptor for phosphotyrosine and 3-phosphoinositides. J Pineal Res 2020; 68:e12637. [PMID: 32052470 DOI: 10.1111/jpi.12637] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 01/22/2020] [Accepted: 02/07/2020] [Indexed: 11/29/2022]
Abstract
Melatonin (MT), endogenously secreted by the pineal gland, is closely related to multiple biological processes; however, its effect on thrombopoiesis is still not well illustrated. Here, we demonstrate that MT administration can elevate peripheral platelet levels. Analysis of different stages in thrombopoiesis reveals that MT has the capacity to promote the expansion of CD34+ and CD41+ cells, and accelerate proplatelet formation (PPF) and platelet production. Furthermore, in vivo experiments show that MT has a potential therapeutic effect on radiation-induced thrombocytopenia. The underlying mechanism suggests that both extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt signaling are involved in the processes of thrombopoiesis facilitated by MT. Interestingly, in addition to the direct regulation of Akt signaling by its upstream phosphoinositide 3-kinase (PI3K), ERK1/2 signaling is also regulated by PI3K via its effector, dual adaptor for phosphotyrosine and 3-phosphoinositides (DAPP1), in megakaryocytes after MT treatment. Moreover, the expression level of DAPP1 during megakaryocyte differentiation is closely related to the activation of ERK1/2 and Akt at different stages of thrombopoiesis. In conclusion, our data suggest that MT treatment can promote thrombopoiesis, which is modulated by the DAPP1-orchestrated activation of ERK1/2 and Akt signaling.
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Affiliation(s)
- Shilei Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Yan Qi
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Song Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Yang Xu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Mingqiang Shen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Mengjia Hu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Changhong Du
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Fang Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Mo Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Yukai Lu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Zihao Zhang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Yong Quan
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Cheng Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Fengchao Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Junping Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
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35
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Coffman JA. Chronic stress, physiological adaptation and developmental programming of the neuroendocrine stress system. FUTURE NEUROLOGY 2020. [DOI: 10.2217/fnl-2019-0014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Chronic stress undermines physical and mental health, in part via dysregulation of the neuroendocrine stress system. Key to understand this dysregulation is recognizing that the problem is not stress per se, but rather its chronicity. The optimally functioning stress system is highly dynamic, and negative feedback regulation enforces transient responses to acute stressors. Chronic stress overrides this, and adaptation to the chronicity can result in persistent dysregulation by altering sensitivity thresholds critical for control of system dynamics. Such adaptation involves plasticity within the central nervous system (CNS) as well as epigenetic regulation. When it occurs during development, it can have persistent effects on neuroendocrine regulation. Understanding how chronic stress programs development of the neuroendocrine stress system requires elucidation of stress-responsive gene regulatory networks that control CNS plasticity and development.
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Affiliation(s)
- James A Coffman
- MDI Biological Laboratory, Kathryn W Davis Center for Regenerative Biology and Aging, Salisbury Cove, ME 04672, USA
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36
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Abstract
Enforced egress of hematopoietic stem cells (HSCs) out of the bone marrow (BM) into the peripheral circulation, termed mobilization, has come a long way since its discovery over four decades ago. Mobilization research continues to be driven by the need to optimize the regimen currently available in the clinic with regard to pharmacokinetic and pharmacodynamic profile, costs, and donor convenience. In this review, we describe the most recent findings in the field and how we anticipate them to affect the development of mobilization strategies in the future. Furthermore, the significance of mobilization beyond HSC collection, i.e. for chemosensitization, conditioning, and gene therapy as well as a means to study the interactions between HSCs and their BM microenvironment, is reviewed. Open questions, controversies, and the potential impact of recent technical progress on mobilization research are also highlighted.
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Affiliation(s)
- Darja Karpova
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, 69120, Germany
| | - Michael P Rettig
- Division of Oncology, Department of Medicine, Washington University School of Medicine,, St. Louis, Missouri, 63110, USA
| | - John F DiPersio
- Division of Oncology, Department of Medicine, Washington University School of Medicine,, St. Louis, Missouri, 63110, USA
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Bujko K, Cymer M, Adamiak M, Ratajczak MZ. An Overview of Novel Unconventional Mechanisms of Hematopoietic Development and Regulators of Hematopoiesis - a Roadmap for Future Investigations. Stem Cell Rev Rep 2019; 15:785-794. [PMID: 31642043 PMCID: PMC6925068 DOI: 10.1007/s12015-019-09920-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hematopoietic stem cells (HSCs) are the best-characterized stem cells in adult tissues. Nevertheless, as of today, many open questions remain. First, what is the phenotype of the most primitive "pre-HSC" able to undergo asymmetric divisions during ex vivo expansion that gives rise to HSC for all hemato-lymphopoietic lineages. Next, most routine in vitro assays designed to study HSC specification into hematopoietic progenitor cells (HPCs) for major hematopoietic lineages are based on a limited number of peptide-based growth factors and cytokines, neglecting the involvement of several other regulators that are endowed with hematopoietic activity. Examples include many hormones, such as pituitary gonadotropins, gonadal sex hormones, IGF-1, and thyroid hormones, as well as bioactive phosphosphingolipids and extracellular nucleotides (EXNs). Moreover, in addition to regulation by stromal-derived factor 1 (SDF-1), trafficking of these cells during mobilization or homing after transplantation is also regulated by bioactive phosphosphingolipids, EXNs, and three ancient proteolytic cascades, the complement cascade (ComC), the coagulation cascade (CoA), and the fibrinolytic cascade (FibC). Finally, it has emerged that bone marrow responds by "sterile inflammation" to signals sent from damaged organs and tissues, systemic stress, strenuous exercise, gut microbiota, and the administration of certain drugs. This review will address the involvement of these unconventional regulators and present a broader picture of hematopoiesis.
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Affiliation(s)
- Kamila Bujko
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY 40202 USA
| | - Monika Cymer
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Mateusz Adamiak
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Mariusz Z. Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY 40202 USA
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
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Golan K, Kollet O, Markus RP, Lapidot T. Daily light and darkness onset and circadian rhythms metabolically synchronize hematopoietic stem cell differentiation and maintenance: The role of bone marrow norepinephrine, tumor necrosis factor, and melatonin cycles. Exp Hematol 2019; 78:1-10. [PMID: 31494174 DOI: 10.1016/j.exphem.2019.08.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 08/29/2019] [Accepted: 08/31/2019] [Indexed: 12/16/2022]
Abstract
Hematopoietic stem and progenitor cells (HSPCs) are essential for daily mature blood cell production, host immunity, and osteoclast-mediated bone turnover. The timing at which stem cells give rise to mature blood and immune cells while maintaining the bone marrow (BM) reservoir of undifferentiated HSPCs and how these opposite tasks are synchronized are poorly understood. Previous studies revealed that daily light onset activates norepinephrine (NE)-induced BM CXCL12 downregulation, followed by CXCR4+ HSPC release to the circulation. Recently, we reported that daily light onset induces transient elevations of BM NE and tumor necrosis factor (TNF), which metabolically program BM HSPC differentiation and recruitment to replenish the blood. In contrast, darkness onset induces lower elevations of BM NE and TNF, activating melatonin production, which metabolically reprograms HSPCs, increasing their short- and long-term repopulation potential, and BM maintenance. How the functions of BM-retained HSPCs are influenced by daily light and darkness cycles and their clinical potential are further discussed.
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Affiliation(s)
- Karin Golan
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Orit Kollet
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Regina P Markus
- Laboratory of Chronopharmacology, Department of Physiology, Institute of Bioscience, University of São Paulo, São Paulo, Brazil
| | - Tsvee Lapidot
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
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39
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Yin and Yang: Why did evolution implement and preserve the circadian rhythmicity? Med Hypotheses 2019; 131:109306. [PMID: 31443763 DOI: 10.1016/j.mehy.2019.109306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/15/2019] [Accepted: 07/06/2019] [Indexed: 02/07/2023]
Abstract
Yin and Yang concept emphasizes the reciprocal and interrelated nature; neither is sufficient, both are needed to sustain the overall balance of the living system. Changing the balance, by implementing deficiency or excess of one of them, upsets the equilibrium (homeostasis) of the whole system. PURPOSE In this opinion article intermittent exposure is presented as the stimulus for development and evolutionary conservation of circadian rhythm, an endogenous, entrainable oscillation of approximately 24 h, to counteract/balance the cells' natural tendency to attenuate their response during long-term exposure to different endogenous substances. RESULTS The concept of Yin and Yang duality is an allegory on which the avoidance of attenuation of the cells' responses hypothesis is presented as an explanation for the circadian rhythmicity, which is integrated in all human cells, with the exception of stem and cancer cells. CONCLUSIONS We hypothesize, that circadian rhythmicity has evolved, during evolution, into a mechanism that prevents disruption of the organism's negative-feedback-loop homeostasis.
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Lenkiewicz AM, Adamiak M, Thapa A, Bujko K, Pedziwiatr D, Abdel-Latif AK, Kucia M, Ratajczak J, Ratajczak MZ. The Nlrp3 Inflammasome Orchestrates Mobilization of Bone Marrow-Residing Stem Cells into Peripheral Blood. Stem Cell Rev Rep 2019; 15:391-403. [PMID: 31089880 PMCID: PMC6534517 DOI: 10.1007/s12015-019-09890-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mobilization of stem cells from bone marrow (BM) into peripheral blood (PB) in response to tissue or organ injury, infections, strenuous exercise, or mobilization-inducing drugs is as we postulated result of a "sterile inflammation" in the BM microenvironment that triggers activation of the Complement Cascade (ComC). Therefore, we became interested in the role of the Nlrp3 inflammasome in this process and show for the first time that its activation in ATP-dependent manner orchestrates BM egress of hematopoietic stem/progenitor cells (HSPCs) as well as other stem cells, including mesenchymal stroma cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic-like stem cells (VSELs). To explain this extracellular ATP is a potent activator of the Nrlp3 inflammasome, which leads to the release of interleukin 1β and interleukin 18, as well as several danger-associated molecular pattern molecules (DAMPs) that activate the mannan-binding lectin (MBL) pathway of the ComC, from cells of the innate immunity network. In support of this mechanism, we demonstrate that the Nlrp3 inflammasome become activated in innate immunity cells by granulocyte colony stimulating factor (G-CSF) and AMD3100 in an ATP-dependent manner. Moreover, administration of the Nlrp3 inflammasome activator nigericin induces mobilization in mice, and the opposite effect is obtained by administration of an Nlrp3 inhibitor (MCC950) to mice mobilized by G-CSF or AMD3100. In summary, our results further support the crucial role of innate immunity, BM sterile inflammation, and novel role of the ATP-Nlrp3-ComC axis in the egress of stem cells into PB.
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Affiliation(s)
- Anna M. Lenkiewicz
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine at Medical University of Warsaw, Warsaw, Poland
| | - Mateusz Adamiak
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine at Medical University of Warsaw, Warsaw, Poland
| | - Arjun Thapa
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY 40202 USA
| | - Kamila Bujko
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY 40202 USA
| | - Daniel Pedziwiatr
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine at Medical University of Warsaw, Warsaw, Poland
| | - Ahmed K. Abdel-Latif
- Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY USA
| | - Magda Kucia
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine at Medical University of Warsaw, Warsaw, Poland
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY 40202 USA
| | - Janina Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY 40202 USA
| | - Mariusz Z. Ratajczak
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine at Medical University of Warsaw, Warsaw, Poland
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY 40202 USA
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41
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Paatela E, Munson D, Kikyo N. Circadian Regulation in Tissue Regeneration. Int J Mol Sci 2019; 20:ijms20092263. [PMID: 31071906 PMCID: PMC6539890 DOI: 10.3390/ijms20092263] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 04/29/2019] [Accepted: 05/03/2019] [Indexed: 12/22/2022] Open
Abstract
Circadian rhythms regulate over 40% of protein-coding genes in at least one organ in the body through mechanisms tied to the central circadian clock and to cell-intrinsic auto-regulatory feedback loops. Distinct diurnal differences in regulation of regeneration have been found in several organs, including skin, intestinal, and hematopoietic systems. Each regenerating system contains a complex network of cell types with different circadian mechanisms contributing to regeneration. In this review, we elucidate circadian regeneration mechanisms in the three representative systems. We also suggest circadian regulation of global translational activity as an understudied global regulator of regenerative capacity. A more detailed understanding of the molecular mechanisms underlying circadian regulation of tissue regeneration would accelerate the development of new regenerative therapies.
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Affiliation(s)
- Ellen Paatela
- Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA.
| | - Dane Munson
- Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
| | - Nobuaki Kikyo
- Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA.
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42
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Laplane L, Duluc D, Bikfalvi A, Larmonier N, Pradeu T. Beyond the tumour microenvironment. Int J Cancer 2019; 145:2611-2618. [PMID: 30989643 PMCID: PMC6766895 DOI: 10.1002/ijc.32343] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 04/05/2019] [Accepted: 04/08/2019] [Indexed: 12/30/2022]
Abstract
In contrast to the once dominant tumour-centric view of cancer, increasing attention is now being paid to the tumour microenvironment (TME), generally understood as the elements spatially located in the vicinity of the tumour. Thinking in terms of TME has proven extremely useful, in particular because it has helped identify and comprehend the role of nongenetic and noncell-intrinsic factors in cancer development. Yet some current approaches have led to a TME-centric view, which is no less problematic than the former tumour-centric vision of cancer, insofar as it tends to overlook the role of components located beyond the TME, in the 'tumour organismal environment' (TOE). In this minireview, we highlight the explanatory and therapeutic shortcomings of the TME-centric view and insist on the crucial importance of the TOE in cancer progression.
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Affiliation(s)
- Lucie Laplane
- INSERM UMR 1170, Normal and Pathological Hematopoiesis, Gustave Roussy, Villejuif, France.,CNRS UMR8590, Institute for History and Philosophy of Science and Techniques, Paris, France.,Department of Philosophy, University Pantheon-Sorbonne, Paris, France
| | - Dorothée Duluc
- CNRS UMR5164, ImmunoConcEpT, Bordeaux, France.,Department of Life and Medical Sciences, University of Bordeaux, Bordeaux, France
| | - Andreas Bikfalvi
- CNRS UMR8590, Institute for History and Philosophy of Science and Techniques, Paris, France.,Department of Philosophy, University Pantheon-Sorbonne, Paris, France.,Department of Life and Medical Sciences, University of Bordeaux, Bordeaux, France.,INSERM U1029, Angiogenesis and Cancer Microenvironment Laboratory, Bordeaux, France
| | - Nicolas Larmonier
- CNRS UMR5164, ImmunoConcEpT, Bordeaux, France.,Department of Life and Medical Sciences, University of Bordeaux, Bordeaux, France
| | - Thomas Pradeu
- CNRS UMR8590, Institute for History and Philosophy of Science and Techniques, Paris, France.,Department of Philosophy, University Pantheon-Sorbonne, Paris, France.,CNRS UMR5164, ImmunoConcEpT, Bordeaux, France.,Department of Life and Medical Sciences, University of Bordeaux, Bordeaux, France
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43
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Ratajczak MZ, Adamiak M, Thapa A, Bujko K, Brzezniakiewicz-Janus K, Lenkiewicz AM. NLRP3 inflammasome couples purinergic signaling with activation of the complement cascade for the optimal release of cells from bone marrow. Leukemia 2019; 33:815-825. [PMID: 30846866 PMCID: PMC6477784 DOI: 10.1038/s41375-019-0436-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 02/17/2019] [Accepted: 02/20/2019] [Indexed: 12/14/2022]
Abstract
The mechanisms that regulate egress of hematopoietic stem/progenitor cells (HSPCs) into peripheral blood (PB) in response to stress, inflammation, tissue/organ injury, or administration of mobilization-inducing drugs are still not well understood, and because of the importance of stem cell trafficking in maintaining organism homeostasis, several complementary pathways are believed to be involved. Our group proposes that mobilization of HSPCs is mainly a result of sterile inflammation in the bone marrow (BM) microenvironment in response to pro-mobilizing stimuli and that during the initiation phase of the mobilization process BM-residing cells belonging to the innate immunity system, including granulocytes and monocytes, release danger-associated molecular pattern molecules (DAMPs, also known as alarmins), reactive oxygen species (ROS), as well as proteolytic and lipolytic enzymes. These factors together orchestrate the release of HSPCs into PB. One of the most important DAMPs released in the initiation phase of mobilization is extracellular adenosine triphosphate, a potent activator of the inflammasome. As a result of its activation, IL-1β and IL-18 as well as other pro-mobilizing mediators, including DAMPs such as high molecular group box 1 (Hmgb1) and S100 calcium-binding protein A9 (S100a9), are released. These DAMPs are important activators of the complement cascade (ComC) in the mannan-binding lectin (MBL)-dependent pathway. Specifically, Hmgb1 and S100a9 bind to MBL, which leads to activation of MBL-associated proteases, which activate the ComC and in parallel also trigger activation of the coagulation cascade (CoaC). In this review, we will highlight the novel role of the innate immunity cell-expressed NLRP3 inflammasome, which, during the initiation phase of HSPC mobilization, couples purinergic signaling with the MBL-dependent pathway of the ComC and, in parallel, the CoaC for optimal release of HSPCs. These data are important to optimize the pharmacological mobilization of HSPCs.
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Affiliation(s)
- Mariusz Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland.
| | - Mateusz Adamiak
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland
| | - Arjun Thapa
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Kamila Bujko
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | | | - Anna M Lenkiewicz
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland
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44
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Hayashi Y, Sezaki M, Takizawa H. Development of the hematopoietic system: Role of inflammatory factors. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY 2019; 8:e341. [PMID: 30916895 DOI: 10.1002/wdev.341] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 02/25/2019] [Accepted: 02/27/2019] [Indexed: 12/24/2022]
Abstract
Hematopoietic stem cells (HSCs) have two defining features, multipotency and self-renewal, both of which are tightly controlled by cell autonomous programs and environmental factors throughout the lifetime of an organism. During development, HSCs are born in the aorta-gonad-mesonephros region, and migrate to distinct hematopoietic organs such as the placenta, fetal liver and spleen, continuously self-renewing and expanding to reach a homeostatic number. HSCs ultimately seed the bone marrow around the time of birth and become dormant to sustain lifelong hematopoiesis. In this review, we will summarize the recent findings on the role of inflammatory factors regulating HSC development, that is, emergence, trafficking and differentiation. An understanding of HSC kinetics during developmental processes will provide useful knowledge on HSC behavior under physiological and pathophysiological conditions. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Adult Stem Cells, Tissue Renewal, and Regeneration > Environmental Control of Stem Cells.
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Affiliation(s)
- Yoshikazu Hayashi
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Maiko Sezaki
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hitoshi Takizawa
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
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45
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Stem cell damage after chemotherapy- can we do better? Best Pract Res Clin Haematol 2019; 32:31-39. [DOI: 10.1016/j.beha.2019.02.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 02/05/2019] [Indexed: 12/18/2022]
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46
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Adrenergic Modulation of Hematopoiesis. J Neuroimmune Pharmacol 2019; 15:82-92. [PMID: 30762159 DOI: 10.1007/s11481-019-09840-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 01/31/2019] [Indexed: 01/11/2023]
Abstract
Hematopoiesis produce every day billions of blood cells and takes place in the bone marrow (BM) by the proliferation and differentiation of hematopoietic stem cells (HSC). HSC are found mainly adjacent to the BM vascular sinusoids where endothelial cells and mesenchimal stromal cells promote HSC maintenance by producing a variety of factors. Other cell types that regulate HSC niches include sympathetic nerves, non-myelinating Schwann cells and a variety of mature hematopoietic cells such as macrophages, neutrophils, and megakaryocytes. This review will focus on the role of adrenergic signals, i.e. of catecholamines, in the regulation of the HSC niche. The available evidence is rather controversial possibly due to the fact that adrenergic receptors are expressed by many cellular components of the niche and also by the often neglected observation that catecholamines may be produced and released also by the BM cells themselves. In addition one has to consider that, physiologically, the sympathetic nervous system (SNS) activity follows a circadian rhythmicity as driven by the suprachiasmatic nucleus (SCN) of the hypothalamus but may be also activated by cognitive and non-cognitive environmental stimuli. The adrenergic modulation of hematopoiesis holds a considerable potential for pharmacological therapeutic approaches in a variety of hematopoietic disorders and for HSC transplantation however the complexity of the system demands further studies. Graphical Abstract Sympathetic nerve termini may release NE while mature BM cells may release norepinephrine (NE) and / or epinephrine (E). Both may bind to β-adrenergic receptor (AR) expressed in nestin+MSC in the hematopoietic stem cell (HSC) niche and regulate the physiological trafficking of HSC by modulating the expression of CXCL12 and SCF. Both NE and E may also activate Lin - c-Kit+ Sca-1+ (LKS) cell via another AR. In addition, NE may also signal to α1-AR expressed in pre-B cells which by TGF-β secretion might regulate proliferation of their lymphoid progenitors in an autocrine manner and/or inhibit myeloid progenitors.
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47
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Daily rhythms influence the ability of lung-derived extracellular vesicles to modulate bone marrow cell phenotype. PLoS One 2018; 13:e0207444. [PMID: 30475846 PMCID: PMC6261033 DOI: 10.1371/journal.pone.0207444] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 10/31/2018] [Indexed: 12/22/2022] Open
Abstract
Extracellular vesicles (EVs) are important mediators of intercellular communication and have been implicated in myriad physiologic and pathologic processes within the hematopoietic system. Numerous factors influence the ability of EVs to communicate with target marrow cells, but little is known about how circadian oscillations alter EV function. In order to explore the effects of daily rhythms on EV-mediated intercellular communication, we used a well-established model of lung-derived EV modulation of the marrow cell transcriptome. In this model, co-culture of whole bone marrow cells (WBM) with lung-derived EVs induces expression of pulmonary specific mRNAs in the target WBM. To determine if daily rhythms play a role in this phenotype modulation, C57BL/6 mice were entrained in 12-hour light/12-hour dark boxes. Lungs harvested at discrete time-points throughout the 24-hour cycle were co-cultured across a cell-impermeable membrane with murine WBM. Alternatively, WBM harvested at discrete time-points was co-cultured with lung-derived EVs. Target WBM was collected 24hrs after co-culture and analyzed for the presence of pulmonary specific mRNA levels by RT-PCR. In both cases, there were clear time-dependent variations in the patterns of pulmonary specific mRNA levels when either the daily time-point of the lung donor or the daily time-point of the recipient marrow cells was altered. In general, WBM had peak pulmonary-specific mRNA levels when exposed to lung harvested at Zeitgeber time (ZT) 4 and ZT 16 (ZT 0 defined as the time of lights on, ZT 12 defined as the time of lights off), and was most susceptible to lung-derived EV modulation when target marrow itself was harvested at ZT 8- ZT 12. We found increased uptake of EVs when the time-point of the receptor WBM was between ZT 20 -ZT 24, suggesting that the time of day-dependent changes in transcriptome modulation by the EVs were not due simply to differential EV uptake. Based on these data, we conclude that circadian rhythms can modulate EV-mediated intercellular communication.
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48
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Elkhenany H, AlOkda A, El-Badawy A, El-Badri N. Tissue regeneration: Impact of sleep on stem cell regenerative capacity. Life Sci 2018; 214:51-61. [PMID: 30393021 DOI: 10.1016/j.lfs.2018.10.057] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 10/23/2018] [Accepted: 10/25/2018] [Indexed: 12/31/2022]
Abstract
The circadian rhythm orchestrates many cellular functions, such as cell division, cell migration, metabolism and numerous intracellular biological processes. The physiological changes during sleep are believed to promote a suitable microenvironment for stem cells to proliferate, migrate and differentiate. These effects are mediated either directly by circadian clock genes or indirectly via hormones and cytokines. Hormones, such as melatonin and cortisol, are secreted in response to neural optic signals and act in harmony to regulate many biological functions during sleep. Herein, we correlate the effects of the main circadian genes on the expression of certain stem cell genes responsible for the regeneration of different tissues, including bone, cartilage, skin, and intestine. We also review the effects of different hormones and cytokines on stem cell activation or suppression and their relationship to the day/night cycle. The correlation of circadian rhythm with tissue regeneration could have implications in understanding the biology of sleep and tissue regeneration and in enhancing the efficacy and timing of surgical procedures.
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Affiliation(s)
- Hoda Elkhenany
- Centre of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 12588, Egypt; Department of Surgery, Faculty of Veterinary Medicine, Alexandria University, 22785, Egypt
| | - Abdelrahman AlOkda
- Centre of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 12588, Egypt
| | - Ahmed El-Badawy
- Centre of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 12588, Egypt
| | - Nagwa El-Badri
- Centre of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 12588, Egypt.
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49
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Hadadi E, Souza LEBD, Bennaceur-Griscelli A, Acloque H. Identification of valid reference genes for circadian gene-expression studies in human mammary epithelial cells. Chronobiol Int 2018; 35:1689-1701. [PMID: 30296179 DOI: 10.1080/07420528.2018.1508151] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The circadian clock controls most of the physiological processes in the body throughout days and nights' alternation. Its dysregulation has a negative impact on many aspects of human health, such as obesity, lipid disorders, diabetes, skin regeneration, hematopoiesis and cancer. To date, poor is known on the molecular mechanisms that links mammary gland homeostasis to the circadian clock but recent reports highlight the importance of loss of circadian genes for mammary gland development and during tumour progression in breast cancer. Gene expression studies are then required to clarify how the circadian clock can modulates the human mammary gland development during ontology and its behaviour in physiological and oncogenic context. For this, in addition to genome-wide studies, real-time quantitative RT-PCR (qPCR) is a powerful and pertinent technique to quantify the expression of a reduced set of genes of interest in many different samples. Relative quantification of qPCR data requires the use of reference genes for normalisation. For circadian studies, reference genes expression must not oscillate in mirror of the circadian clock and must not be affected by the synchronisation protocols required in vitro to reset the circadian clock. Inappropriate selection of reference genes can consequently affect the amplitude of gene expression oscillation and bias data interpretation. Currently, no standard reference genes have been validated regarding these criteria for human mammary epithelial cells and the purpose of this study was to fill this gap. For this, we used the RefFinder tool, which combines four different algorithms, on 9 candidate reference genes. We compared reference genes stability using three different synchronisation protocols applied on four different mammary epithelial cell lines. This allowed us to define a set of reference genes in human mammary epithelial cells whose expression remains stable despite synchronisation protocols. We observed that the synchronisation of cells by serum shock was the most suitable procedure for maintaining the amplitude of oscillation of clock genes over time and we identified RPL4, RPLP0, HSPCB and TBP as an optimal combination of reference genes for the normalisation of the oscillatory expression of clock genes in human mammary epithelial cells.
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Affiliation(s)
- Eva Hadadi
- a Inserm, UMRS935 ESTeam Paris Sud, Malignant and Therapeutic Stem Cell Models , Villejuif , France
| | | | - Annelise Bennaceur-Griscelli
- a Inserm, UMRS935 ESTeam Paris Sud, Malignant and Therapeutic Stem Cell Models , Villejuif , France.,b Service d'hématologie , APHP, GHU Paris Sud , Villejuif , France.,c UFR de Médecine Kremlin Bicêtre , Univ. P.Sud, Univ. Paris Saclay , Le Kremlin Bicêtre , France
| | - Hervé Acloque
- a Inserm, UMRS935 ESTeam Paris Sud, Malignant and Therapeutic Stem Cell Models , Villejuif , France.,d UMR1388 GenPhySE , INRA, Université de Toulouse, INRA, INPT, ENVT , Castanet Tolosan , France
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Aanei CM, Catafal LC. Evaluation of bone marrow microenvironment could change how myelodysplastic syndromes are diagnosed and treated. Cytometry A 2018; 93:916-928. [PMID: 30211968 DOI: 10.1002/cyto.a.23506] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 05/06/2018] [Accepted: 05/17/2018] [Indexed: 12/13/2022]
Abstract
Myelodysplastic syndromes are a heterogeneous group of clonal hematopoietic disorders. However, the therapies used against the hematopoietic stem cells clones have limited efficacy; they slow the evolution toward acute myeloid leukemia rather than stop clonal evolution and eradicate the disease. The progress made in recent years regarding the role of the bone marrow microenvironment in disease evolution may contribute to progress in this area. This review presents the recent updates on the role of the bone marrow microenvironment in myelodysplastic syndromes pathogenesis and tries to find answers regarding how this information could improve myelodysplastic syndromes diagnosis and therapy.
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Affiliation(s)
- Carmen Mariana Aanei
- Laboratoire d'Hématologie, CHU de Saint-Etienne, 42055 Saint-Etienne Cedex 2, France
| | - Lydia Campos Catafal
- Laboratoire d'Hématologie, CHU de Saint-Etienne, 42055 Saint-Etienne Cedex 2, France
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