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Konopko A, Łukomska A, Ratajczak J, Kucia M, Ratajczak MZ. Complosome Regulates Hematopoiesis at the Mitochondria Level. Stem Cell Rev Rep 2025; 21:1001-1012. [PMID: 40053308 PMCID: PMC12102138 DOI: 10.1007/s12015-025-10856-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2025] [Indexed: 05/24/2025]
Abstract
The intracellular complement network, known as the complosome, regulates lymphocyte biology, which is well established. Recently, however, we demonstrated that the complosome is also expressed in hematopoietic stem/progenitor cells (HSPCs) in addition to lymphocytes. In our previous work, murine lineage-negative (Lin-) bone marrow (BM) mononuclear cells (BMMNC) from mice lacking the intracellular C3 and C5 complosome proteins displayed different responses to stress. Specifically, while C3-KO cells were more sensitive to oxidative stress, C5-KO cells showed greater resistance. To explore this intriguing observation at the metabolic level, we evaluated anaerobic and aerobic glycolysis, along with mitochondrial function, in Lin- BMMNC purified from C3-KO, C5-KO, and C5aR1-KO mice. We found that cells from complosome-deficient animals under steady-state conditions exhibited elevated lactate production and enhanced lactate dehydrogenase (LDH) release, indicating their reliance on anaerobic glycolysis. Interestingly, the uptake of a glucose fluorescent analog (2-NBDG) increased in C3-KO cells but decreased in C5-KO and C5aR1-KO cells compared to wild-type (WT) mice. Meanwhile, total ATP production in C3-KO cells, unlike that of C5 and C5aR1 mice, was reduced under steady-state conditions and did not change significantly after exposure to the mitochondrial-damaging agent hydrogen peroxide (H2O2). This suggests a greater dependence on anaerobic glycolysis in C3-KO cells than in C5-KO and C5aR1-KO cells. Finally, we assessed the integrity of mitochondrial membranes in the studied cells using MitoTracker green and deep red assays. Compared to WT cells, we observed that mitochondria from complosome mutant Lin-BMMNC accumulated fewer MitoTracker probes, indicating the presence of mitochondrial defects in these cells.
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Affiliation(s)
- Adrian Konopko
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland.
| | - Agnieszka Łukomska
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland
| | - Janina Ratajczak
- Stem Cell Institute at Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA
| | - Magdalena Kucia
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland
| | - Mariusz Z Ratajczak
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland.
- Stem Cell Institute at Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA.
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Ratajczak MZ, Konopko A, Jarczak J, Kazek M, Ratajczak J, Kucia M. Complosome as a new intracellular regulatory network in both normal and malignant hematopoiesis. Leukemia 2025:10.1038/s41375-025-02613-7. [PMID: 40269269 DOI: 10.1038/s41375-025-02613-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 04/01/2025] [Accepted: 04/07/2025] [Indexed: 04/25/2025]
Abstract
Hematopoietic cells and lymphocytes arise from a common stem cell for both lineages. This explains why similar signaling networks regulate the development and biological functions of these cells. One crucial regulatory mechanism involves interactions with soluble mediators of innate immunity, including activated elements of the complement cascade (ComC). For many years, ComC proteins were thought to be synthesized only in the liver and released into blood to be activated by one of the three proteolytic cascades. The regulatory effects of activated components of ComC on hematopoietic stem progenitor cells (HSPCs) and mature hematopoietic cells have been well demonstrated in the past. However, recent data indicate that complement proteins are also expressed in several cell types, including lymphocytes and innate immune cells. This intracellular complement network has been named the "complosome." Recent evidence from our group shows that the complosome is also expressed in HSPCs and plays an important yet underappreciated role in the expansion, trafficking, and metabolism of these cells. We propose that the complosome, like its role in lymphocytes, is necessary for the optimal function of mitochondria in hematopoietic cells, including HSPCs. This opens a new area for investigation and potential pharmacological intervention into the complosome network in normal and malignant hematopoiesis.
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Affiliation(s)
- Mariusz Z Ratajczak
- Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland.
- Stem Cell Institute at Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
| | - Adrian Konopko
- Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland
| | - Justyna Jarczak
- Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland
| | - Michalina Kazek
- Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland
| | - Janina Ratajczak
- Stem Cell Institute at Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Magdalena Kucia
- Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland
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3
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Franczak S, Ulrich H, Ratajczak MZ. Hematopoietic stem cells on the crossroad between purinergic signaling and innate immunity. Purinergic Signal 2025; 21:3-9. [PMID: 37184740 PMCID: PMC11958923 DOI: 10.1007/s11302-023-09943-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 05/09/2023] [Indexed: 05/16/2023] Open
Abstract
Hematopoiesis is regulated by several mediators such as peptide-based growth factors, cytokines, and chemokines, whose biological effects have been studied for many years. However, several other mediators have been identified recently that affect the fate of hematopoietic stem/progenitor cells (HSPC) as well as non-hematopoietic cells in the bone marrow microenvironment. These new mediators comprise members of purinergic signaling pathways and are active mediators of the soluble arm of innate immunity, the complement cascade (ComC). In this review, we will discuss the coordinated effects of these pathways in regulating the biology of HSPC. Importantly, both purinergic signaling and the ComC are activated in stress situations and interact with specific receptors expressed on HSPC. Evidence has accumulated indicating that some of the purinergic as well as ComC receptors could also be activated intracellularly by intrinsically expressed ligands. To support this recent evidence, our work indicates that the major mediator of purinergic signaling, adenosine triphosphate, and the cleavage product of the fifth component of the ComC (C5), C5a anaphylatoxin, can activate their corresponding receptors expressed on the outer mitochondrial membrane in an autocrine manner. We will also discuss recent evidence that these responses, mediated by purinergic signaling and the ComC network, are coordinated by activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 - reactive oxygen species - NLR family pyrin domain containing 3 (NLRP3) inflammasome (Nox2-ROS-NLRP3) axis.
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Affiliation(s)
- Stephanie Franczak
- Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Henning Ulrich
- Department of Biochemistry, University of Sao Paulo, Sao Paulo, Brazil
| | - Mariusz Z Ratajczak
- Laboratory of Regenerative Medicine, 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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Vassalakis JA, Yamashita DHS, Midon LM, Cogliati B, Heinemann MB, Amamura TA, Isaac L. Murine C3 of the complement system affects infection by Leptospira interrogans. Microbes Infect 2025; 27:105413. [PMID: 39284496 DOI: 10.1016/j.micinf.2024.105413] [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: 06/12/2024] [Revised: 08/02/2024] [Accepted: 08/30/2024] [Indexed: 03/14/2025]
Abstract
Leptospirosis is an infectious neglected disease estimated to affect more than one million people worldwide each year. The Complement System plays a vital role in eliminating infectious agents. However, its precise role in leptospirosis remains to be fully understood. We investigated the importance of C3 in L. interrogans serovar Kennewicki strain Pomona Fromm (LPF) infection. Lack of C3 leads to decreased leukocyte number, impaired inflammatory response and failure to eliminate bacteria during the early stages of infection, which may cause interstitial nephritis later. These findings could be explained, at least in part, by the lower presence of local opsonins. Furthermore, antibody production against Leptospira was compromised in the absence of C3, highlighting the importance of CR2 in B lymphocyte proliferation and the adjuvant role of C3d in humoral immunity. Leptospires can be eliminated through the urine, and according to our study, the lack of C3 delays the elimination of LPF through urine during the early stages of the infection. These results strongly suggest the crucial role of C3 protein in orchestrating an appropriate inflammatory response against LPF infection and in effectively eliminating the bacteria from the body during the acute phase of leptospirosis.
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Affiliation(s)
- Julia Avian Vassalakis
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | | | - Leonardo Moura Midon
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Brazil
| | | | - Thaís Akemi Amamura
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Lourdes Isaac
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
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Konopko A, Łukomska A, Kucia M, Ratajczak MZ. The Different Responsiveness of C3- and C5-deficient Murine BM Cells to Oxidative Stress Explains Why C3 Deficiency, in Contrast to C5 Deficiency, Correlates with Better Pharmacological Mobilization and Engraftment of Hematopoietic Cells. Stem Cell Rev Rep 2025; 21:59-67. [PMID: 39340736 PMCID: PMC11762589 DOI: 10.1007/s12015-024-10792-6] [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] [Accepted: 09/23/2024] [Indexed: 09/30/2024]
Abstract
The liver-derived circulating in peripheral blood and intrinsic cell-expressed complement known as complosome orchestrate the trafficking of hematopoietic stem/progenitor cells (HSPCs) both during pharmacological mobilization and homing/engraftment after transplantation. Our previous research demonstrated that C3 deficient mice are easy mobilizers, and their HSPCs engraft properly in normal mice. In contrast, C5 deficiency correlates with poor mobilization and defects in HSPCs' homing and engraftment. The trafficking of HSPCs during mobilization and homing/engraftment follows the sterile inflammation cues in the BM microenvironment caused by stress induced by pro-mobilizing drugs or myeloablative conditioning for transplantation. Therefore, to explain deficiencies in HSPC trafficking between C3-KO and C5-KO mice, we evaluated the responsiveness of C3 and C5 deficient cells to low oxidative stress. As reported, oxidative stress in BM is mediated by the activation of purinergic signaling, which is triggered by the elevated level of extracellular adenosine triphosphate (eATP) and by the activation of the complement cascade (ComC). In the current work, we noticed that BM lineage negative cells (lin-) isolated from C3-KO mice display several mitochondrial defects reflected by an impaired ability to adapt to oxidative stress. In contrast, C5-KO-derived BM cells show a high level of adaptation to this challenge. To support this data, C3-KO BM lin- cells were highly responsive to eATP stimulation, which correlates with enhanced levels of reactive oxygen species (ROS) generation and more efficient activation of intracellular Nlrp3 inflammasome. We conclude that the enhanced sensitivity of C3-KO mice cells to oxidative stress and better activation of the Nox2-ROS-Nlrp3 inflammasome signaling axis explains the molecular level differences in trafficking between C3- and C5-deficient HSPCs.
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Affiliation(s)
- Adrian Konopko
- Center for Preclinical Studies and Technology, Laboratory of Regenerative Medicine at Medical University of Warsaw, Warsaw, Poland.
| | - Agnieszka Łukomska
- Center for Preclinical Studies and Technology, Laboratory of Regenerative Medicine at Medical University of Warsaw, Warsaw, Poland
| | - Magdalena Kucia
- Center for Preclinical Studies and Technology, Laboratory of Regenerative Medicine at Medical University of Warsaw, Warsaw, Poland
| | - Mariusz Z Ratajczak
- Center for Preclinical Studies and Technology, Laboratory 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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Beeraka NM, Basappa B, Nikolenko VN, Mahesh PA. Role of Neurotransmitters in Steady State Hematopoiesis, Aging, and Leukemia. Stem Cell Rev Rep 2025; 21:2-27. [PMID: 38976142 DOI: 10.1007/s12015-024-10761-z] [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] [Accepted: 07/02/2024] [Indexed: 07/09/2024]
Abstract
Haematopoiesis within the bone marrow (BM) represents a complex and dynamic process intricately regulated by neural signaling pathways. This delicate orchestration is susceptible to disruption by factors such as aging, diabetes, and obesity, which can impair the BM niche and consequently affect haematopoiesis. Genetic mutations in Tet2, Dnmt3a, Asxl1, and Jak2 are known to give rise to clonal haematopoiesis of intermediate potential (CHIP), a condition linked to age-related haematological malignancies. Despite these insights, the exact roles of circadian rhythms, sphingosine-1-phosphate (S1P), stromal cell-derived factor-1 (SDF-1), sterile inflammation, and the complement cascade on various BM niche cells remain inadequately understood. Further research is needed to elucidate how BM niche cells contribute to these malignancies through neural regulation and their potential in the development of gene-corrected stem cells. This literature review describes the updated functional aspects of BM niche cells in haematopoiesis within the context of haematological malignancies, with a particular focus on neural signaling and the potential of radiomitigators in acute radiation syndrome. Additionally, it underscores the pressing need for technological advancements in stem cell-based therapies to alleviate the impacts of immunological stressors. Recent studies have illuminated the microheterogeneity and temporal stochasticity of niche cells within the BM during haematopoiesis, emphasizing the updated roles of neural signaling and immunosurveillance. The development of gene-corrected stem cells capable of producing blood, immune cells, and tissue-resident progeny is essential for combating age-related haematological malignancies and overcoming immunological challenges. This review aims to provide a comprehensive overview of these evolving insights and their implications for future therapeutic strategies.
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Affiliation(s)
- Narasimha M Beeraka
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 1044 W. Walnut Street, R4-168, Indianapolis, IN, 46202, USA.
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow, 119991, Russia.
- Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapuramu, Chiyyedu, Andhra Pradesh, 515721, India.
| | - Basappa Basappa
- Department of Studies in Organic Chemistry, Laboratory of Chemical Biology, University of Mysore, Mysore, Karnataka, 570006, India
| | - Vladimir N Nikolenko
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow, 119991, Russia
| | - P A Mahesh
- Department of Pulmonary Medicine, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India
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Luo J, Zhou Y, Wang M, Zhang J, Jiang E. Inflammasomes: potential therapeutic targets in hematopoietic stem cell transplantation. Cell Commun Signal 2024; 22:596. [PMID: 39695742 DOI: 10.1186/s12964-024-01974-3] [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: 10/05/2024] [Accepted: 11/30/2024] [Indexed: 12/20/2024] Open
Abstract
The realm of hematopoietic stem cell transplantation (HSCT) has witnessed remarkable advancements in elevating the cure and survival rates for patients with both malignant and non-malignant hematologic diseases. Nevertheless, a considerable number of patients continue to face challenges, including transplant-related complications, infection, graft failure, and mortality. Inflammasomes, the multi-protein complexes of the innate immune system, respond to various danger signals by releasing inflammatory cytokines and even mediating cell death. While moderate activation of inflammasomes is essential for immune defense and homeostasis maintenance, excessive activation precipitates inflammatory damage. The intricate interplay between HSCT and inflammasomes arises from their pivotal roles in immune responses and inflammation. This review examines the molecular architecture and composition of various types of inflammasomes, highlighting their activation and effector mechanisms within the context of the HSCT process and its associated complications. Additionally, we summarize the therapeutic implications of targeting inflammasomes and related factors in HSCT.
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Affiliation(s)
- Jieya Luo
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
| | - Yunxia Zhou
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Haihe Laboratory of Cell Ecosystem, Tianjin Medical University, Tianjin, 300051, China
| | - Mingyang Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
| | - Junan Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
| | - Erlie Jiang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
- Tianjin Institutes of Health Science, Tianjin, 301600, China.
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8
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Oakes A, Liu Y, Dubielecka PM. Complement or insult: the emerging link between complement cascade deficiencies and pathology of myeloid malignancies. J Leukoc Biol 2024; 116:966-984. [PMID: 38836653 PMCID: PMC11531810 DOI: 10.1093/jleuko/qiae130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/01/2024] [Accepted: 05/03/2024] [Indexed: 06/06/2024] Open
Abstract
The complement cascade is an ancient and highly conserved arm of the immune system. The accumulating evidence highlights elevated activity of the complement cascade in cancer microenvironment and emphasizes its effects on the immune, cancer, and cancer stroma cells, pointing to a role in inflammation-mediated etiology of neoplasms. The role the cascade plays in development, progression, and relapse of solid tumors is increasingly recognized, however its role in hematological malignancies, especially those of myeloid origin, has not been thoroughly assessed and remains obscure. As the role of inflammation and autoimmunity in development of myeloid malignancies is becoming recognized, in this review we focus on summarizing the links that have been identified so far for complement cascade involvement in the pathobiology of myeloid malignancies. Complement deficiencies are primary immunodeficiencies that cause an array of clinical outcomes including an increased risk of a range of infectious as well as local or systemic inflammatory and thrombotic conditions. Here, we discuss the impact that deficiencies in complement cascade initiators, mid- and terminal-components and inhibitors have on the biology of myeloid neoplasms. The emergent conclusions indicate that the links between complement cascade, inflammatory signaling, and the homeostasis of hematopoietic system exist, and efforts should continue to detail the mechanistic involvement of complement cascade in the development and progression of myeloid cancers.
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Affiliation(s)
- Alissa Oakes
- Department of Medicine, Alpert Medical School, Brown University, 69 Brown St, Providence, RI 02906, USA
- Division of Hematology/Oncology, Rhode Island Hospital, 69 Brown St, Providence, RI 02906, USA
- Therapeutic Sciences Graduate program, Brown University, 69 Brown St, Providence, RI 02906, USA
| | - Yuchen Liu
- Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, 22. S. Greene St., Baltimore, MD 21201-1595, USA
| | - Patrycja M Dubielecka
- Department of Medicine, Alpert Medical School, Brown University, 69 Brown St, Providence, RI 02906, USA
- Division of Hematology/Oncology, Rhode Island Hospital, 69 Brown St, Providence, RI 02906, USA
- Therapeutic Sciences Graduate program, Brown University, 69 Brown St, Providence, RI 02906, USA
- Legorreta Cancer Center, Brown University, One Hoppin St., Coro West, Suite 5.01, Providence, RI 02903, USA
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Țichil I, Mitre I, Zdrenghea MT, Bojan AS, Tomuleasa CI, Cenariu D. A Review of Key Regulators of Steady-State and Ineffective Erythropoiesis. J Clin Med 2024; 13:2585. [PMID: 38731114 PMCID: PMC11084473 DOI: 10.3390/jcm13092585] [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: 03/13/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Erythropoiesis is initiated with the transformation of multipotent hematopoietic stem cells into committed erythroid progenitor cells in the erythroblastic islands of the bone marrow in adults. These cells undergo several stages of differentiation, including erythroblast formation, normoblast formation, and finally, the expulsion of the nucleus to form mature red blood cells. The erythropoietin (EPO) pathway, which is activated by hypoxia, induces stimulation of the erythroid progenitor cells and the promotion of their proliferation and survival as well as maturation and hemoglobin synthesis. The regulation of erythropoiesis is a complex and dynamic interaction of a myriad of factors, such as transcription factors (GATA-1, STAT5), cytokines (IL-3, IL-6, IL-11), iron metabolism and cell cycle regulators. Multiple microRNAs are involved in erythropoiesis, mediating cell growth and development, regulating oxidative stress, erythrocyte maturation and differentiation, hemoglobin synthesis, transferrin function and iron homeostasis. This review aims to explore the physiology of steady-state erythropoiesis and to outline key mechanisms involved in ineffective erythropoiesis linked to anemia, chronic inflammation, stress, and hematological malignancies. Studying aberrations in erythropoiesis in various diseases allows a more in-depth understanding of the heterogeneity within erythroid populations and the development of gene therapies to treat hematological disorders.
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Affiliation(s)
- Ioana Țichil
- Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania; (I.M.); (M.T.Z.); (A.S.B.); (C.I.T.); (D.C.)
- Department of Haematology, “Ion Chiricuta” Institute of Oncology, 34–36 Republicii Street, 400015 Cluj-Napoca, Romania
| | - Ileana Mitre
- Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania; (I.M.); (M.T.Z.); (A.S.B.); (C.I.T.); (D.C.)
| | - Mihnea Tudor Zdrenghea
- Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania; (I.M.); (M.T.Z.); (A.S.B.); (C.I.T.); (D.C.)
- Department of Haematology, “Ion Chiricuta” Institute of Oncology, 34–36 Republicii Street, 400015 Cluj-Napoca, Romania
| | - Anca Simona Bojan
- Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania; (I.M.); (M.T.Z.); (A.S.B.); (C.I.T.); (D.C.)
- Department of Haematology, “Ion Chiricuta” Institute of Oncology, 34–36 Republicii Street, 400015 Cluj-Napoca, Romania
| | - Ciprian Ionuț Tomuleasa
- Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania; (I.M.); (M.T.Z.); (A.S.B.); (C.I.T.); (D.C.)
- Department of Haematology, “Ion Chiricuta” Institute of Oncology, 34–36 Republicii Street, 400015 Cluj-Napoca, Romania
- MEDFUTURE—Research Centre for Advanced Medicine, 8 Louis Pasteur Street, 400347 Cluj-Napoca, Romania
| | - Diana Cenariu
- Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania; (I.M.); (M.T.Z.); (A.S.B.); (C.I.T.); (D.C.)
- MEDFUTURE—Research Centre for Advanced Medicine, 8 Louis Pasteur Street, 400347 Cluj-Napoca, Romania
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10
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Ratajczak MZ, Adamiak M, Abdelbaset-Ismail A, Bujko K, Thapa A, Chumak V, Franczak S, Brzezniakiewicz-Janus K, Ratajczak J, Kucia M. Intracellular complement (complosome) is expressed in hematopoietic stem/progenitor cells (HSPCs) and regulates cell trafficking, metabolism and proliferation in an intracrine Nlrp3 inflammasome-dependent manner. Leukemia 2023; 37:1401-1405. [PMID: 37055506 PMCID: PMC10244163 DOI: 10.1038/s41375-023-01894-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 03/27/2023] [Accepted: 03/30/2023] [Indexed: 04/15/2023]
Affiliation(s)
- Mariusz Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
- Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland.
| | - Mateusz Adamiak
- Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland
| | - Ahmed Abdelbaset-Ismail
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Kamila Bujko
- 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
| | - Vira Chumak
- Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland
| | - Stephanie Franczak
- Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland
| | | | - Janina Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Magdalena Kucia
- Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland
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11
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Zarantonello A, Revel M, Grunenwald A, Roumenina LT. C3-dependent effector functions of complement. Immunol Rev 2023; 313:120-138. [PMID: 36271889 PMCID: PMC10092904 DOI: 10.1111/imr.13147] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
C3 is the central effector molecule of the complement system, mediating its multiple functions through different binding sites and their corresponding receptors. We will introduce the C3 forms (native C3, C3 [H2 O], and intracellular C3), the C3 fragments C3a, C3b, iC3b, and C3dg/C3d, and the C3 expression sites. To highlight the important role that C3 plays in human biological processes, we will give an overview of the diseases linked to C3 deficiency and to uncontrolled C3 activation. Next, we will present a structural description of C3 activation and of the C3 fragments generated by complement regulation. We will proceed by describing the C3a interaction with the anaphylatoxin receptor, followed by the interactions of opsonins (C3b, iC3b, and C3dg/C3d) with complement receptors, divided into two groups: receptors bearing complement regulatory functions and the effector receptors without complement regulatory activity. We outline the molecular architecture of the receptors, their binding sites on the C3 activation fragments, the cells expressing them, the diversity of their functions, and recent advances. With this review, we aim to give an up-to-date analysis of the processes triggered by C3 activation fragments on different cell types in health and disease contexts.
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Affiliation(s)
- Alessandra Zarantonello
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
| | - Margot Revel
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
| | - Anne Grunenwald
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
| | - Lubka T Roumenina
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
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12
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Thapa A, Abdelbaset-Ismail A, Chumak V, Adamiak M, Brzezniakiewicz-Janus K, Ratajczak J, Kucia M, Ratajczak MZ. Extracellular Adenosine (eAdo) - A 2B Receptor Axis Inhibits in Nlrp3 Inflammasome-dependent Manner Trafficking of Hematopoietic Stem/progenitor Cells. Stem Cell Rev Rep 2022; 18:2893-2911. [PMID: 35870082 PMCID: PMC9622533 DOI: 10.1007/s12015-022-10417-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/19/2022] [Indexed: 10/16/2022]
Abstract
We postulated that mobilization, homing, and engraftment of hematopoietic stem/progenitor cells (HSCPs) is facilitated by a state of sterile inflammation induced in bone marrow (BM) after administration of pro-mobilizing drugs or in response to pre-transplant myeloablative conditioning. An important role in this phenomenon plays purinergic signaling that by the release of extracellular adenosine triphosphate (eATP) activates in HSPCs and in cells in the hematopoietic microenvironment an intracellular pattern recognition receptor (PPR) known as Nlrp3 inflammasome. We reported recently that its deficiency results in defective trafficking of HSPCs. Moreover, it is known that eATP after release into extracellular space is processed by cell surface expressed ectonucleotidases CD39 and CD73 to extracellular adenosine (eAdo) that in contrast to eATP shows an anti-inflammatory effect. Based on data that the state of sterile inflammation promotes trafficking of HSPCs, and since eAdo is endowed with anti-inflammatory properties we become interested in how eAdo will affect the mobilization, homing, and engraftment of HSPCs and which of eAdo receptors are involved in these processes. As expected, eAdo impaired HSPCs trafficking and this occurred in autocrine- and paracrine-dependent manner by direct stimulation of these cells or by affecting cells in the BM microenvironment. We report herein for the first time that this defect is mediated by activation of the A2B receptor and a specific inhibitor of this receptor improves eAdo-aggravated trafficking of HSPCs. To explain this at the molecular level eAdo-A2B receptor interaction upregulates in HSPCs in NF-kB-, NRF2- and cAMP-dependent manner heme oxygenase-1 (HO-1), that is Nlrp3 inflammasome inhibitor. This corroborated with our analysis of proteomics signature in murine HSPCs exposed to eAdo that revealed that A2B inhibition promotes cell migration and proliferation. Based on this we postulate that blockage of A2B receptor may accelerate the mobilization of HSPCs as well as their hematopoietic reconstitution and this approach could be potentially considered in the future to be tested in the clinic.
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Affiliation(s)
- Arjun Thapa
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, 40202 Louisville, KY USA
| | - Ahmed Abdelbaset-Ismail
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, 40202 Louisville, KY USA
- Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Vira Chumak
- 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
| | | | - Janina Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, 40202 Louisville, KY USA
| | - Magdalena Kucia
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, 40202 Louisville, KY USA
- 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, 40202 Louisville, KY USA
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
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Garg V, Chandanala S, David-Luther M, Govind M, Prasad RR, Kumar A, Prasanna SJ. The Yin and Yang of Immunity in Stem Cell Decision Guidance in Tissue Ecologies: An Infection Independent Perspective. Front Cell Dev Biol 2022; 10:793694. [PMID: 35198558 PMCID: PMC8858808 DOI: 10.3389/fcell.2022.793694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 01/10/2022] [Indexed: 11/13/2022] Open
Abstract
The impact of immune system and inflammation on organ homeostasis and tissue stem cell niches in the absence of pathogen invasion has long remained a conundrum in the field of regenerative medicine. The paradoxical role of immune components in promoting tissue injury as well as resolving tissue damage has complicated therapeutic targeting of inflammation as a means to attain tissue homeostasis in degenerative disease contexts. This confound could be resolved by an integrated intricate assessment of cross-talk between inflammatory components and micro- and macro-environmental factors existing in tissues during health and disease. Prudent fate choice decisions of stem cells and their differentiated progeny are key to maintain tissue integrity and function. Stem cells have to exercise this fate choice in consultation with other tissue components. With this respect tissue immune components, danger/damage sensing molecules driving sterile inflammatory signaling cascades and barrier cells having immune-surveillance functions play pivotal roles in supervising stem cell decisions in their niches. Stem cells learn from their previous damage encounters, either endogenous or exogenous, or adapt to persistent micro-environmental changes to orchestrate their decisions. Thus understanding the communication networks between stem cells and immune system components is essential to comprehend stem cell decisions in endogenous tissue niches. Further the systemic interactions between tissue niches integrated through immune networks serve as patrolling systems to establish communication links and orchestrate micro-immune ecologies to better organismal response to injury and promote regeneration. Understanding these communication links is key to devise immune-centric regenerative therapies. Thus the present review is an integrated attempt to provide a unified purview of how inflammation and immune cells provide guidance to stem cells for tissue sculpting during development, organismal aging and tissue crisis based on the current knowledge in the field.
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R4 RGS proteins suppress engraftment of human hematopoietic stem/progenitor cells by modulating SDF-1/CXCR4 signaling. Blood Adv 2021; 5:4380-4392. [PMID: 34500454 PMCID: PMC8579266 DOI: 10.1182/bloodadvances.2020003307] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 06/10/2021] [Indexed: 12/14/2022] Open
Abstract
Specific R4 RGS members are expressed in human HSPCs and regulated by the SDF-1/CXCR4 axis. RGS1/13/16 suppress HSPC engraftment, SDF-1 signaling, and key effectors of stem cell trafficking/maintenance. Homing and engraftment of hematopoietic stem/progenitor cells (HSPCs) into the bone marrow (BM) microenvironment are tightly regulated by the chemokine stromal cell–derived factor-1 (SDF-1) and its G-protein–coupled receptor C-X-C motif chemokine receptor 4 (CXCR4), which on engagement with G-protein subunits, trigger downstream migratory signals. Regulators of G-protein signaling (RGS) are GTPase-accelerating protein of the Gα subunit and R4 subfamily members have been implicated in SDF-1–directed trafficking of mature hematopoietic cells, yet their expression and influence on HSPCs remain mostly unknown. Here, we demonstrated that human CD34+ cells expressed multiple R4 RGS genes, of which RGS1, RGS2, RGS13, and RGS16 were significantly upregulated by SDF-1 in a CXCR4-dependent fashion. Forced overexpression of RGS1, RGS13, or RGS16 in CD34+ cells not only inhibited SDF-1–directed migration, calcium mobilization, and phosphorylation of AKT, ERK, and STAT3 in vitro, but also markedly reduced BM engraftment in transplanted NOD/SCID mice. Genome-wide microarray analysis of RGS-overexpressing CD34+ cells detected downregulation of multiple effectors with established roles in stem cell trafficking/maintenance. Convincingly, gain-of-function of selected effectors or ex vivo priming with their ligands significantly enhanced HSPC engraftment. We also constructed an evidence-based network illustrating the overlapping mechanisms of RGS1, RGS13, and RGS16 downstream of SDF-1/CXCR4 and Gαi. This model shows that these RGS members mediate compromised kinase signaling and negative regulation of stem cell functions, complement activation, proteolysis, and cell migration. Collectively, this study uncovers an essential inhibitory role of specific R4 RGS proteins in stem cell engraftment, which could potentially be exploited to develop improved clinical HSPC transplantation protocols.
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15
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CD11c regulates hematopoietic stem and progenitor cells under stress. Blood Adv 2021; 4:6086-6097. [PMID: 33351105 DOI: 10.1182/bloodadvances.2020002504] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 11/09/2020] [Indexed: 12/28/2022] Open
Abstract
β2 integrins are well-known leukocyte adhesion molecules consisting of 4 members: CD11a-d. Their known biological functions range widely from leukocyte recruitment, phagocytosis, to immunological synapse formation, but the studies have been primarily focused on CD11a and CD11b. CD11c is 1 of the 4 members and is extremely homologous to CD11b. It has been well known as a dendritic cell marker, but the characterization of its function has been limited. We found that CD11c was expressed on the short-term hematopoietic stem cells and multipotent progenitor cells. The lack of CD11c did not affect the number of hematopoietic stem and progenitor cells (HSPCs) in healthy CD11c knockout mice. Different from other β2 integrin members, however, CD11c deficiency was associated with increased apoptosis and significant loss of HSPCs in sepsis and bone marrow transplantation. Although integrins are generally known for their overlapping and redundant roles, we showed that CD11c had a distinct role of regulating the expansion of HSPCs under stress. This study shows that CD11c, a well-known dendritic cell marker, is expressed on HSPCs and serves as their functional regulator. CD11c deficiency leads to the loss of HSPCs via apoptosis in sepsis and bone marrow transplantation.
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Xiong J, Kuang X, Lu T, Yu K, Liu X, Zhang Z, Wang W, Zhao L, Fang Q, Wu D, Wang J. C3a and C5a facilitates the metastasis of myeloma cells by activating Nrf2. Cancer Gene Ther 2021; 28:265-278. [PMID: 32873871 DOI: 10.1038/s41417-020-00217-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 08/11/2020] [Accepted: 08/17/2020] [Indexed: 11/09/2022]
Abstract
Multiple myeloma (MM) is still an incurable hematological malignancy, with even poorer prognosis in MM patients with distant invasion. The present study was designed to explore the effects of C3a and C5a on the migration, invasion, and adhesion of MM tumor cells and to investigate the underlying mechanisms. As a result, the levels of C3a and C5a in plasma of MM patients were significantly higher than those of healthy donors. Consistently, the expression of C3a and C5a receptors on myeloma cells of MM patients was also significantly higher than that on sorted plasma cells of normal donors. C3a and C5a have been confirmed to increase the migration, invasion and adhesion of MM cell lines by activating the MEK/ERK pathway and increasing the nuclear transfer of Nrf2 in vitro. Moreover, the MM cell line U266 with Nrf2 downregulation was incubated with C3a and C5a, followed by injection into the tail vein of NOD-SCID mice. We found that Nrf2 downregulation attenuated the migration of anaphylatoxin C3a and C5a to MM tumor cells in bone marrow, liver and lung in vivo. In conclusion, our results indicate that activation of the complement cascade in MM patients may contribute to the migration, invasion and adhesion of MM cells, and this type of tumor cells dissemination in MM is, at least partially, regulated by Nrf2. Thereby, complement suppression or Nrf2 downregulation might offer a novel therapeutic opportunity for MM.
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Affiliation(s)
- Jie Xiong
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis under Ministry of Health, Collaborative Innovation Center of Hematology, Suzhou Institute of Blood and Marrow Transplantation, 188 Shizi Street, 215006, Suzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Xingyi Kuang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Tingting Lu
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Kunlin Yu
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Xu Liu
- Department of Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, 550001, Guiyang, China
| | - Zhaoyuan Zhang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Weili Wang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Lu Zhao
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Qin Fang
- Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, 550001, Guiyang, China
| | - Depei Wu
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis under Ministry of Health, Collaborative Innovation Center of Hematology, Suzhou Institute of Blood and Marrow Transplantation, 188 Shizi Street, 215006, Suzhou, Jiangsu, China.
| | - Jishi Wang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China.
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17
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Vandendriessche S, Cambier S, Proost P, Marques PE. Complement Receptors and Their Role in Leukocyte Recruitment and Phagocytosis. Front Cell Dev Biol 2021; 9:624025. [PMID: 33644062 PMCID: PMC7905230 DOI: 10.3389/fcell.2021.624025] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/15/2021] [Indexed: 12/21/2022] Open
Abstract
The complement system is deeply embedded in our physiology and immunity. Complement activation generates a multitude of molecules that converge simultaneously on the opsonization of a target for phagocytosis and activation of the immune system via soluble anaphylatoxins. This response is used to control microorganisms and to remove dead cells, but also plays a major role in stimulating the adaptive immune response and the regeneration of injured tissues. Many of these effects inherently depend on complement receptors expressed on leukocytes and parenchymal cells, which, by recognizing complement-derived molecules, promote leukocyte recruitment, phagocytosis of microorganisms and clearance of immune complexes. Here, the plethora of information on the role of complement receptors will be reviewed, including an analysis of how this functionally and structurally diverse group of molecules acts jointly to exert the full extent of complement regulation of homeostasis.
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Affiliation(s)
- Sofie Vandendriessche
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Seppe Cambier
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Pedro E Marques
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
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18
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Li XX, Kumar V, Clark RJ, Lee JD, Woodruff TM. The "C3aR Antagonist" SB290157 is a Partial C5aR2 Agonist. Front Pharmacol 2021; 11:591398. [PMID: 33551801 PMCID: PMC7859635 DOI: 10.3389/fphar.2020.591398] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 12/02/2020] [Indexed: 12/29/2022] Open
Abstract
Innate immune complement activation generates the C3 and C5 protein cleavage products C3a and C5a, defined classically as anaphylatoxins. C3a activates C3aR, while C5a activates two receptors (C5aR1 and C5aR2) to exert their immunomodulatory activities. The non-peptide compound, SB290157, was originally reported in 2001 as the first C3aR antagonist. In 2005, the first report on the non-selective nature of SB290157 was published, where the compound exerted clear agonistic, not antagonistic, activity in variety of cells. Other studies also documented the non-selective activities of this drug in vivo. These findings severely hamper data interpretation regarding C3aR when using this compound. Unfortunately, given the dearth of C3aR inhibitors, SB290157 still remains widely used to explore C3aR biology (>70 publications to date). Given these issues, in the present study we aimed to further explore SB290157's pharmacological selectivity by screening the drug against three human anaphylatoxin receptors, C3aR, C5aR1 and C5aR2, using cell models. We identified that SB290157 exerts partial agonist activity at C5aR2 by mediating β-arrestin recruitment at higher compound doses. This translated to a functional outcome in both human and mouse primary macrophages, where SB290157 significantly dampened C5a-induced ERK signaling. We also confirmed that SB290157 acts as a potent agonist at human C3aR in transfected cells, but as an antagonist in primary human macrophages. Our results therefore provide even more caution against using SB290157 as a research tool to explore C3aR function. Given the reported immunomodulatory and anti-inflammatory activities of C5aR2 agonism, any function observed with SB290157 could be due to these off-target activities.
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Affiliation(s)
| | | | | | | | - Trent M. Woodruff
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
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19
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Park JW, Kim JE, Choi YJ, Kang MJ, Choi HJ, Bae SJ, Hong JT, Lee H, Hwang DY. Deficiency of complement component 3 may be linked to the development of constipation in FVB/N-C3 em1Hlee /Korl mice. FASEB J 2021; 35:e21221. [PMID: 33337564 DOI: 10.1096/fj.202000376r] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 11/03/2020] [Accepted: 11/10/2020] [Indexed: 12/15/2022]
Abstract
Alterations in complement component 3 (C3) expression has been reported to be linked to several bowel diseases including Crohn's disease, inflammatory bowel disease, and ulcerative colitis; however, the association with constipation has never been investigated. In this study, we aimed to investigate the correlation between C3 regulation and constipation development using a C3 deficiency model. To achieve these, alterations in stool excretion, transverse colon histological structure, and mucin secretion were analyzed in FVB/N-C3em1Hlee /Korl (C3 knockout, C3 KO) mice with the deletion of 11 nucleotides in exon 2 of the C3 gene. The stool excretion parameters, gastrointestinal transit, and intestine length were remarkably decreased in C3 KO mice compared with wild-type (WT) mice, although there was no specific change in feeding behavior. Furthermore, C3 KO mice showed a decrease in mucosal and muscle layer thickness, alterations in crypt structure, irregular distribution of goblet cells, and an increase of mucin droplets in the transverse colon. Mucin secretion was suppressed, and they accumulated in the crypts of C3 KO mice. In addition, the constipation phenotypes detected during C3 deficiency were confirmed in FVB/N mice treated with C3 convertase inhibitor (rosmarinic acid (RA)). Similar phenotypes were observed with respect to stool excretion parameters, gastrointestinal transit, intestine length, alterations in crypt structure, and mucin secretion in RA-treated FVB/N mice. Therefore, the results of the present study provide the first scientific evidence that C3 deficiency may play an important role in the development of constipation phenotypes in C3 KO mice.
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Affiliation(s)
- Ji Won Park
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Ji Eun Kim
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Yun Ju Choi
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Mi Ju Kang
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Hyeon Jun Choi
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Su Ji Bae
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Jin Tae Hong
- College of Pharmacy, Chungbuk National University, Chungju, Korea
| | - Ho Lee
- Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Goyang, Korea
| | - Dae Youn Hwang
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
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20
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Cell type specific gene expression profiling reveals a role for complement component C3 in neutrophil responses to tissue damage. Sci Rep 2020; 10:15716. [PMID: 32973200 PMCID: PMC7518243 DOI: 10.1038/s41598-020-72750-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 08/27/2020] [Indexed: 01/09/2023] Open
Abstract
Tissue damage induces rapid recruitment of leukocytes and changes in the transcriptional landscape that influence wound healing. However, the cell-type specific transcriptional changes that influence leukocyte function and tissue repair have not been well characterized. Here, we employed translating ribosome affinity purification (TRAP) and RNA sequencing, TRAP-seq, in larval zebrafish to identify genes differentially expressed in neutrophils, macrophages, and epithelial cells in response to wounding. We identified the complement pathway and c3a.1, homologous to the C3 component of human complement, as significantly increased in neutrophils in response to wounds. c3a.1−/− zebrafish larvae have impaired neutrophil directed migration to tail wounds with an initial lag in recruitment early after wounding. Moreover, c3a.1−/− zebrafish larvae have impaired recruitment to localized bacterial infections and reduced survival that is, at least in part, neutrophil mediated. Together, our findings support the power of TRAP-seq to identify cell type specific changes in gene expression that influence neutrophil behavior in response to tissue damage.
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21
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Shivshankar P, Fekry B, Eckel-Mahan K, Wetsel RA. Circadian Clock and Complement Immune System-Complementary Control of Physiology and Pathology? Front Cell Infect Microbiol 2020; 10:418. [PMID: 32923410 PMCID: PMC7456827 DOI: 10.3389/fcimb.2020.00418] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 07/08/2020] [Indexed: 12/11/2022] Open
Abstract
Mammalian species contain an internal circadian (i.e., 24-h) clock that is synchronized to the day and night cycles. Large epidemiological studies, which are supported by carefully controlled studies in numerous species, support the idea that chronic disruption of our circadian cycles results in a number of health issues, including obesity and diabetes, defective immune response, and cancer. Here we focus specifically on the role of the complement immune system and its relationship to the internal circadian clock system. While still an incompletely understood area, there is evidence that dysregulated proinflammatory cytokines, complement factors, and oxidative stress can be induced by circadian disruption and that these may feed back into the oscillator at the level of circadian gene regulation. Such a feedback cycle may contribute to impaired host immune response against pathogenic insults. The complement immune system including its activated anaphylatoxins, C3a and C5a, not only facilitate innate and adaptive immune response in chemotaxis and phagocytosis, but they can also amplify chronic inflammation in the host organism. Consequent development of autoimmune disorders, and metabolic diseases associated with additional environmental insults that activate complement can in severe cases, lead to accelerated tissue dysfunction, fibrosis, and ultimately organ failure. Because several promising complement-targeted therapeutics to block uncontrolled complement activation and treat autoimmune diseases are in various phases of clinical trials, understanding fully the circadian properties of the complement system, and the reciprocal regulation by these two systems could greatly improve patient treatment in the long term.
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Affiliation(s)
- Pooja Shivshankar
- Research Center for Immunology and Autoimmune Diseases, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Baharan Fekry
- Center for Metabolic and Degenerative Diseases, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Kristin Eckel-Mahan
- Center for Metabolic and Degenerative Diseases, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Rick A. Wetsel
- Research Center for Immunology and Autoimmune Diseases, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
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22
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Selheim F, Aasebø E, Ribas C, Aragay AM. An Overview on G Protein-coupled Receptor-induced Signal Transduction in Acute Myeloid Leukemia. Curr Med Chem 2019; 26:5293-5316. [PMID: 31032748 DOI: 10.2174/0929867326666190429153247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 03/22/2019] [Accepted: 04/05/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Acute Myeloid Leukemia (AML) is a genetically heterogeneous disease characterized by uncontrolled proliferation of precursor myeloid-lineage cells in the bone marrow. AML is also characterized by patients with poor long-term survival outcomes due to relapse. Many efforts have been made to understand the biological heterogeneity of AML and the challenges to develop new therapies are therefore enormous. G Protein-coupled Receptors (GPCRs) are a large attractive drug-targeted family of transmembrane proteins, and aberrant GPCR expression and GPCR-mediated signaling have been implicated in leukemogenesis of AML. This review aims to identify the molecular players of GPCR signaling, focusing on the hematopoietic system, which are involved in AML to help developing novel drug targets and therapeutic strategies. METHODS We undertook an exhaustive and structured search of bibliographic databases for research focusing on GPCR, GPCR signaling and expression in AML. RESULTS AND CONCLUSION Many scientific reports were found with compelling evidence for the involvement of aberrant GPCR expression and perturbed GPCR-mediated signaling in the development of AML. The comprehensive analysis of GPCR in AML provides potential clinical biomarkers for prognostication, disease monitoring and therapeutic guidance. It will also help to provide marker panels for monitoring in AML. We conclude that GPCR-mediated signaling is contributing to leukemogenesis of AML, and postulate that mass spectrometrybased protein profiling of primary AML cells will accelerate the discovery of potential GPCR related biomarkers for AML.
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Affiliation(s)
- Frode Selheim
- The Proteomics Unit at the University of Bergen, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway
| | - Elise Aasebø
- The Proteomics Unit at the University of Bergen, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.,Department of Clinical Science, University of Bergen, Jonas Lies vei 87, 5021 Bergen, Norway
| | - Catalina Ribas
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), 28049 Madrid, Spain.,Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain.,CIBER de Enfermedades Cardiovasculares, ISCIII (CIBERCV), 28029 Madrid, Spain
| | - Anna M Aragay
- Departamento de Biologia Celular. Instituto de Biología Molecular de Barcelona (IBMB-CSIC), Spanish National Research Council (CSIC), Baldiri i Reixac, 15, 08028 Barcelona, Spain
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23
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Current and future perspectives on allogeneic transplantation using ex vivo expansion or manipulation of umbilical cord blood cells. Int J Hematol 2019; 110:50-58. [PMID: 31123927 DOI: 10.1007/s12185-019-02670-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 05/14/2019] [Accepted: 05/15/2019] [Indexed: 01/05/2023]
Abstract
In patients with hematologic malignancies, the outcome of umbilical cord blood transplantation has improved and is now comparable to that of matched unrelated donor transplantation. However, the limitation of using umbilical cord blood has been a delay in both hematopoietic and immunologic recovery. Strategies have been proposed to overcome these limitations. One strategy involves ex vivo expansion of the umbilical cord blood unit prior to transplantation. A second strategy involves exposure of the umbilical cord blood graft to compounds aimed at improving homing and engraftment following transplantation. Many of these strategies are now being tested in late phase multi-center clinical trials. If proven cost effective and efficacious, they may alter the landscape of donor options for allogeneic stem cell transplantation.
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24
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Brennan FH, Jogia T, Gillespie ER, Blomster LV, Li XX, Nowlan B, Williams GM, Jacobson E, Osborne GW, Meunier FA, Taylor SM, Campbell KE, MacDonald KP, Levesque JP, Woodruff TM, Ruitenberg MJ. Complement receptor C3aR1 controls neutrophil mobilization following spinal cord injury through physiological antagonism of CXCR2. JCI Insight 2019; 4:98254. [PMID: 31045582 DOI: 10.1172/jci.insight.98254] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 03/21/2019] [Indexed: 12/18/2022] Open
Abstract
Traumatic spinal cord injury (SCI) triggers an acute-phase response that leads to systemic inflammation and rapid mobilization of bone marrow (BM) neutrophils into the blood. These mobilized neutrophils then accumulate in visceral organs and the injured spinal cord where they cause inflammatory tissue damage. The receptor for complement activation product 3a, C3aR1, has been implicated in negatively regulating the BM neutrophil response to tissue injury. However, the mechanism via which C3aR1 controls BM neutrophil mobilization, and also its influence over SCI outcomes, are unknown. Here, we show that the C3a/C3aR1 axis exerts neuroprotection in SCI by acting as a physiological antagonist against neutrophil chemotactic signals. We show that C3aR1 engages phosphatase and tensin homolog (PTEN), a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, to restrain C-X-C chemokine receptor type 2-driven BM neutrophil mobilization following trauma. These findings are of direct clinical significance as lower circulating neutrophil numbers at presentation were identified as a marker for improved recovery in human SCI. Our work thus identifies C3aR1 and its downstream intermediary, PTEN, as therapeutic targets to broadly inhibit neutrophil mobilization/recruitment following tissue injury and reduce inflammatory pathology.
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Affiliation(s)
| | - Trisha Jogia
- School of Biomedical Sciences, Faculty of Medicine
| | | | | | - Xaria X Li
- School of Biomedical Sciences, Faculty of Medicine
| | - Bianca Nowlan
- Blood and Bone Diseases Program, Mater Research Institute
| | | | | | - Geoff W Osborne
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
| | - Frederic A Meunier
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
| | | | - Kate E Campbell
- Orthopaedic Department, Princess Alexandra Hospital, Brisbane, Australia.,Princess Alexandra Hospital - Southside Clinical School, Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Kelli Pa MacDonald
- Antigen Presentation and Immunoregulation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane Australia
| | | | | | - Marc J Ruitenberg
- School of Biomedical Sciences, Faculty of Medicine.,Trauma, Critical Care and Recovery, Brisbane Diamantina Health Partners, Brisbane, Australia
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25
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de Kruijf EJFM, Fibbe WE, van Pel M. Cytokine-induced hematopoietic stem and progenitor cell mobilization: unraveling interactions between stem cells and their niche. Ann N Y Acad Sci 2019; 1466:24-38. [PMID: 31006885 PMCID: PMC7217176 DOI: 10.1111/nyas.14059] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 02/15/2019] [Accepted: 02/28/2019] [Indexed: 02/06/2023]
Abstract
Peripheral blood hematopoietic stem and progenitor cells (HSPCs), mobilized by granulocyte colony‐stimulating factor, are widely used as a source for both autologous and allogeneic stem cell transplantation. The use of mobilized HSPCs has several advantages over traditional bone marrow–derived HSPCs, including a less invasive harvesting process for the donor, higher HSPC yields, and faster hematopoietic reconstitution in the recipient. For years, the mechanisms by which cytokines and other agents mobilize HSPCs from the bone marrow were not fully understood. The field of stem cell mobilization research has advanced significantly over the past decade, with major breakthroughs in the elucidation of the complex mechanisms that underlie stem cell mobilization. In this review, we provide an overview of the events that underlie HSPC mobilization and address the relevant cellular and molecular components of the bone marrow niche. Furthermore, current and future mobilizing agents will be discussed.
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Affiliation(s)
- Evert-Jan F M de Kruijf
- Section of Stem Cell Biology, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
| | - Willem E Fibbe
- Section of Stem Cell Biology, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
| | - Melissa van Pel
- Section of Stem Cell Biology, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
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26
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Fan Z, Qin J, Wang D, Geng S. Complement C3a promotes proliferation, migration and stemness in cutaneous squamous cell carcinoma. J Cell Mol Med 2019; 23:3097-3107. [PMID: 30825266 PMCID: PMC6484302 DOI: 10.1111/jcmm.13959] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 09/17/2018] [Indexed: 12/11/2022] Open
Abstract
Background Complement C3 has been shown to be highly expressed in cutaneous squamous cell carcinoma (cSCC) tumour tissues and is correlated with tumour cell growth. This study aimed to investigate the mechanism of C3 in cSCC malignant transformation. Methods C3 expression was analysed in cSCC cell lines A431, Tca8113, SCC13, HSC‐5 and HSC‐1 and in immortalized HaCaT keratinocytes. Proliferation and migration of cSCC were determined after C3a exposure. Expression of cyclin D1, cyclin E, vascular endothelial growth factor (VEGF), pro‐matrix metalloproteinase 1 (pro‐MMP1), pro‐matrix metalloproteinase 2 (pro‐MMP2), stemness factors, GSK‐3β, and β‐catenin were analyzed. Tumour growth was examined in a murine xenograft model. Results C3 expression was much more highly expressed in all cSCC cell lines than in HaCaT cells. C3a treatment significantly promoted cSCC cell proliferation and migration and upregulated cyclin D1, cyclin E, VEGF, pro‐MMP1 and pro‐MMP2 expression, which were impeded by the C3aR antagonist. Moreover, the expression of stemness factors Sox‐2, Nanog, Oct‐4, c‐Myc and CD‐44 was stimulated by C3a and slowed by C3aR disruption. Knockdown of Sox‐2 by siRNA transfection suppressed cell proliferation and migration, constrained VEGF secretion and inhibited pro‐MMP1 and pro‐MMP2 expression. C3a also activated the Wnt and β‐catenin pathway in cSCC cells. Disruption of C3aR expression dampened tumour growth and the expression of Wnt‐1, β‐catenin and Sox‐2 in the xenograft model. Conclusions C3a enhanced cell proliferation, migration and stemness in cSCC, and this activity was correlated with activation of the Wnt and β‐catenin pathway.
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Affiliation(s)
- Zhuo Fan
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Dermatology, The First Affiliated Hospital of Xi'an Medical University, Xi'an, China
| | - Jingjing Qin
- Department of Dermatology, The First Affiliated Hospital of Xi'an Medical University, Xi'an, China
| | - Dandan Wang
- Department of Dermatology, The First Affiliated Hospital of Xi'an Medical University, Xi'an, China
| | - Songmei Geng
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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27
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Fernandez-Godino R, Pierce EA. C3a triggers formation of sub-retinal pigment epithelium deposits via the ubiquitin proteasome pathway. Sci Rep 2018; 8:9679. [PMID: 29946065 PMCID: PMC6018664 DOI: 10.1038/s41598-018-28143-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Accepted: 06/15/2018] [Indexed: 01/25/2023] Open
Abstract
The mechanisms that connect complement system activation and basal deposit formation in early stages of age-related macular degeneration (AMD) are insufficiently understood, which complicates the design of efficient therapies to prevent disease progression. Using human fetal (hf) retinal pigment epithelial (RPE) cells, we have established an in vitro model to investigate the effect of complement C3a on RPE cells and its role in the formation of sub-RPE deposits. The results of these studies revealed that C3a produced after C3 activation is sufficient to induce the formation of sub-RPE deposits via complement-driven proteasome inhibition. C3a binds the C3a receptor (C3aR), stimulates deposition of collagens IV and VI underneath the RPE, and impairs the extracellular matrix (ECM) turnover by increased MMP-2 activity, all mediated by downregulation of the ubiquitin proteasome pathway (UPP). The formation of basal deposits can be prevented by the addition of a C3aR antagonist, which restores the UPP activity and ECM turnover. These findings indicate that the cell-based model can be used to test potential therapeutic agents in vitro. The data suggest that modulation of C3aR-mediated events could be a therapeutic approach for treatment of early AMD.
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Affiliation(s)
- Rosario Fernandez-Godino
- Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, 02114, USA.
| | - Eric A Pierce
- Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, 02114, USA
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28
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Ratajczak MZ, Adamiak M, Kucia M, Tse W, Ratajczak J, Wiktor-Jedrzejczak W. The Emerging Link Between the Complement Cascade and Purinergic Signaling in Stress Hematopoiesis. Front Immunol 2018; 9:1295. [PMID: 29922299 PMCID: PMC5996046 DOI: 10.3389/fimmu.2018.01295] [Citation(s) in RCA: 19] [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: 03/26/2018] [Accepted: 05/24/2018] [Indexed: 01/08/2023] Open
Abstract
Innate immunity plays an important role in orchestrating the immune response, and the complement cascade (ComC) is a major component of this ancient defense system, which is activated by the classical-, alternative-, or mannan-binding lectin (MBL) pathways. However, the MBL-dependent ComC-activation pathway has been somewhat underappreciated for many years; recent evidence indicates that it plays a crucial role in regulating the trafficking of hematopoietic stem/progenitor cells (HSPCs) by promoting their egress from bone marrow (BM) into peripheral blood (PB). This process is initiated by the release of danger-associated molecular patterns (DAMPs) from BM cells, including the most abundant member of this family, adenosine triphosphate (ATP). This nucleotide is well known as a ubiquitous intracellular molecular energy source, but when secreted becomes an important extracellular nucleotide signaling molecule and mediator of purinergic signaling. What is important for the topic of this review, ATP released from BM cells is recognized as a DAMP by MBL, and the MBL-dependent pathway of ComC activation induces a state of "sterile inflammation" in the BM microenvironment. This activation of the ComC by MBL leads to the release of several potent mediators, including the anaphylatoxins C5a and desArgC5a, which are crucial for egress of HSPCs into the circulation. In parallel, as a ligand for purinergic receptors, ATP affects mobilization of HSPCs by activating other pro-mobilizing pathways. This emerging link between the release of ATP, which on the one hand is an activator of the MBL pathway of the ComC and on the other hand is a purinergic signaling molecule, will be discussed in this review. This mechanism plays an important role in triggering defense mechanisms in response to tissue/organ injury but may also have a negative impact by triggering autoimmune disorders, aging of HSPCs, induction of myelodysplasia, and graft-versus-host disease after transplantation of histoincompatible hematopoietic cells.
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Affiliation(s)
- Mariusz Z. Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Warsaw Medical University, Warsaw, Poland
| | - Mateusz Adamiak
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Warsaw Medical University, Warsaw, Poland
| | - Magda Kucia
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Warsaw Medical University, Warsaw, Poland
| | - William Tse
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States
| | - Janina Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States
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29
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Abstract
From its discovery in the late nineteenth century, as a 'complement' to the cellular immune response, the complement system has been widely affirmed as a powerful controller of innate and adaptive immune responses. In recent decades however, new roles for complement have been discovered, with multiple complement proteins now known to function in a broad array of non-immune systems. This includes during development, where complement exerts control over stem cell populations from fertilization and implantation throughout embryogenesis and beyond post-natal development. It is involved in processes as diverse as cell localisation, tissue morphogenesis, and the growth and refinement of the brain. Such physiological actions of complement have also been described in adult stem cell populations, with roles in proliferation, differentiation, survival, and regeneration. With such a broad range of complement functions now described, it is likely that current research only describes a fraction of the full reach of complement proteins. Here, we review how complement control of physiological cell processes has been harnessed in stem cell populations throughout both development and in adult physiology.
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Affiliation(s)
- Owen A Hawksworth
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia
| | - Liam G Coulthard
- School of Clinical Medicine, Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia; Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Susanna Mantovani
- Centre for Clinical Research, Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia; Wesley Medical Research, Auchenflower, Brisbane, Queensland, Australia
| | - Trent M Woodruff
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia; Wesley Medical Research, Auchenflower, Brisbane, Queensland, Australia.
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30
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Halbgebauer R, Schmidt CQ, Karsten CM, Ignatius A, Huber-Lang M. Janus face of complement-driven neutrophil activation during sepsis. Semin Immunol 2018; 37:12-20. [PMID: 29454576 DOI: 10.1016/j.smim.2018.02.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 02/06/2018] [Accepted: 02/07/2018] [Indexed: 12/28/2022]
Abstract
During local and systemic inflammation, the complement system and neutrophil granulocytes are activated not only by pathogens, but also by released endogenous danger signals. It is recognized increasingly that complement-mediated neutrophil activation plays an ambivalent role in sepsis pathophysiology. According to the current definition, the onset of organ dysfunction is a hallmark of sepsis. The preceding organ damage can be caused by excessive complement activation and neutrophil actions against the host, resulting in bystander injury of healthy tissue. However, in contrast, persistent and overwhelming inflammation also leads to a reduction in neutrophil responsiveness as well as complement components and thus may render patients at enhanced risk of spreading infection. This review provides an overview on the molecular and cellular processes that link complement with the two-faced functional alterations of neutrophils in sepsis. Finally, we describe novel tools to modulate this interplay beneficially in order to improve outcome.
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Affiliation(s)
- R Halbgebauer
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Hospital, Helmholtzstr. 8/1, 89081 Ulm, Germany.
| | - C Q Schmidt
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Helmholtzstr. 20, 89081 Ulm, Germany.
| | - C M Karsten
- Institute for Systemic Inflammation Research, University of Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany.
| | - A Ignatius
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Helmholtzstr. 14, 89081 Ulm, Germany.
| | - M Huber-Lang
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Hospital, Helmholtzstr. 8/1, 89081 Ulm, Germany.
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31
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Jabłoński M, Mazur JK, Tarnowski M, Dołęgowska B, Pędziwiatr D, Kubiś E, Budkowska M, Sałata D, Wysiecka JP, Kazimierczak A, Reginia A, Ratajczak MZ, Samochowiec J. Mobilization of Peripheral Blood Stem Cells and Changes in the Concentration of Plasma Factors Influencing their Movement in Patients with Panic Disorder. Stem Cell Rev Rep 2017; 13:217-225. [PMID: 27914035 PMCID: PMC5380702 DOI: 10.1007/s12015-016-9700-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In this paper we examined whether stem cells and factors responsible for their movement may serve as new biological markers of anxiety disorders. The study was carried out on a group of 30 patients diagnosed with panic disorder (examined before and after treatment), compared to 30 healthy individuals forming the control group. We examined the number of circulating HSCs (hematopoetic stem cells) (Lin−/CD45 +/CD34 +) and HSCs (Lin−/CD45 +/AC133 +), the number of circulating VSELs (very small embryonic-like stem cells) (Lin−/CD45−/CD34 +) and VSELs (Lin−/CD45−/AC133 +), as well as the concentration of complement components: C3a, C5a and C5b-9, SDF-1 (stromal derived factor) and S1P (sphingosine-1-phosphate). Significantly lower levels of HSCs (Lin−/CD45 +/AC133 +) have been demonstrated in the patient group compared to the control group both before and after treatment. The level of VSELs (Lin−/CD45−/CD133 +) was significantly lower in the patient group before treatment as compared to the patient group after treatment. The levels of factors responsible for stem cell movement were significantly lower in the patient group compared to the control group before and after treatment. It was concluded that the study of stem cells and factors associated with their movement can be useful in the diagnostics of panic disorder, as well as differentiating between psychotic and anxiety disorders.
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Affiliation(s)
- Marcin Jabłoński
- Department of Psychiatry, Pomeranian University of Medicine, Broniewskiego 26, 71-460, Szczecin, Poland
| | - Jolanta Kucharska Mazur
- Department of Psychiatry, Pomeranian University of Medicine, Broniewskiego 26, 71-460, Szczecin, Poland.
| | - Maciej Tarnowski
- Department of Physiology, Pomeranian University of Medicine, Szczecin, Poland
| | - Barbara Dołęgowska
- Department of Medical Analytics, Pomeranian University of Medicine, Szczecin, Poland
| | - Daniel Pędziwiatr
- Department of Physiology, Pomeranian University of Medicine, Szczecin, Poland
| | - Ewa Kubiś
- Department of Physiology, Pomeranian University of Medicine, Szczecin, Poland
| | - Marta Budkowska
- Department of Medical Analytics, Pomeranian University of Medicine, Szczecin, Poland
| | - Daria Sałata
- Department of Medical Analytics, Pomeranian University of Medicine, Szczecin, Poland
| | - Justyna Pełka Wysiecka
- Department of Psychiatry, Pomeranian University of Medicine, Broniewskiego 26, 71-460, Szczecin, Poland
| | | | - Artur Reginia
- Department of Psychiatry, Pomeranian University of Medicine, Broniewskiego 26, 71-460, Szczecin, Poland
| | - Mariusz Z Ratajczak
- Stem Cell Biology Program at the James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA
| | - Jerzy Samochowiec
- Department of Psychiatry, Pomeranian University of Medicine, Broniewskiego 26, 71-460, Szczecin, Poland
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32
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Zape JP, Lizama CO, Cautivo KM, Zovein AC. Cell cycle dynamics and complement expression distinguishes mature haematopoietic subsets arising from hemogenic endothelium. Cell Cycle 2017; 16:1835-1847. [PMID: 28820341 PMCID: PMC5628647 DOI: 10.1080/15384101.2017.1361569] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
The emergence of haematopoietic stem and progenitor cells (HSPCs) from hemogenic endothelium results in the formation of sizeable HSPC clusters attached to the vascular wall. We evaluate the cell cycle and proliferation of HSPCs involved in cluster formation, as well as the molecular signatures from their initial appearance to the point when cluster cells are capable of adult engraftment (definitive HSCs). We uncover a non-clonal origin of HSPC clusters with differing cell cycle, migration, and cell signaling attributes. In addition, we find that the complement cascade is highly enriched in mature HSPC clusters, possibly delineating a new role for this pathway in engraftment.
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Affiliation(s)
- Joan P Zape
- a Cardiovascular Research Institute , University of California San Francisco , San Francisco , CA , USA
| | - Carlos O Lizama
- a Cardiovascular Research Institute , University of California San Francisco , San Francisco , CA , USA
| | - Kelly M Cautivo
- c Department of Laboratory of Medicine , University of California San Francisco, School of Medicine , San Francisco , CA , USA
| | - Ann C Zovein
- a Cardiovascular Research Institute , University of California San Francisco , San Francisco , CA , USA.,b Department of Pediatrics, Division of Neonatology , University of California San Francisco School of Medicine , San Francisco , CA , USA
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33
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Grajales-Esquivel E, Luz-Madrigal A, Bierly J, Haynes T, Reis ES, Han Z, Gutierrez C, McKinney Z, Tzekou A, Lambris JD, Tsonis PA, Del Rio-Tsonis K. Complement component C3aR constitutes a novel regulator for chick eye morphogenesis. Dev Biol 2017; 428:88-100. [PMID: 28576690 PMCID: PMC5726978 DOI: 10.1016/j.ydbio.2017.05.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 08/05/2016] [Accepted: 05/17/2017] [Indexed: 12/22/2022]
Abstract
Complement components have been implicated in a wide variety of functions including neurogenesis, proliferation, cell migration, differentiation, cancer, and more recently early development and regeneration. Following our initial observations indicating that C3a/C3aR signaling induces chick retina regeneration, we analyzed its role in chick eye morphogenesis. During eye development, the optic vesicle (OV) invaginates to generate a bilayer optic cup (OC) that gives rise to the retinal pigmented epithelium (RPE) and neural retina. We show by immunofluorescence staining that C3 and the receptor for C3a (the cleaved and active form of C3), C3aR, are present in chick embryos during eye morphogenesis in the OV and OC. Interestingly, C3aR is mainly localized in the nuclear compartment at the OC stage. Loss of function studies at the OV stage using morpholinos or a blocking antibody targeting the C3aR (anti-C3aR Ab), causes eye defects such as microphthalmia and defects in the ventral portion of the eye that result in coloboma. Such defects were not observed when C3aR was disrupted at the OC stage. Histological analysis demonstrated that microphthalmic eyes were unable to generate a normal optic stalk or a closed OC. The dorsal/ventral patterning defects were accompanied by an expansion of the ventral markers Pax2, cVax and retinoic acid synthesizing enzyme raldh-3 (aldh1a3) domains, an absence of the dorsal expression of Tbx5 and raldh-1 (aldh1a1) and a re-specification of the ventral RPE to neuroepithelium. In addition, the eyes showed overall decreased expression of Gli1 and a change in distribution of nuclear β-catenin, suggesting that Shh and Wnt pathways have been affected. Finally, we observed prominent cell death along with a decrease in proliferating cells, indicating that both processes contribute to the microphthalmic phenotype. Together our results show that C3aR is necessary for the proper morphogenesis of the OC. This is the first report implicating C3aR in eye development, revealing an unsuspected hitherto regulator for proper chick eye morphogenesis.
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Affiliation(s)
- Erika Grajales-Esquivel
- Department of Biology, Miami University and Center for Visual Sciences at Miami University (CVSMU), Oxford, OH 45056, USA.
| | - Agustin Luz-Madrigal
- Department of Biology, Miami University and Center for Visual Sciences at Miami University (CVSMU), Oxford, OH 45056, USA; Department of Biology, University of Dayton and Center for Tissue Regeneration and Engineering at the University of Dayton (TREND), Dayton, OH 45469, USA.
| | - Jeffrey Bierly
- Department of Biology, Miami University and Center for Visual Sciences at Miami University (CVSMU), Oxford, OH 45056, USA.
| | - Tracy Haynes
- Department of Biology, Miami University and Center for Visual Sciences at Miami University (CVSMU), Oxford, OH 45056, USA.
| | - Edimara S Reis
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
| | - Zeyu Han
- Department of Biology, Miami University and Center for Visual Sciences at Miami University (CVSMU), Oxford, OH 45056, USA.
| | - Christian Gutierrez
- Department of Biology, Miami University and Center for Visual Sciences at Miami University (CVSMU), Oxford, OH 45056, USA.
| | - Zachary McKinney
- Department of Biology, Miami University and Center for Visual Sciences at Miami University (CVSMU), Oxford, OH 45056, USA.
| | - Apostolia Tzekou
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
| | - John D Lambris
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
| | - Panagiotis A Tsonis
- Department of Biology, University of Dayton and Center for Tissue Regeneration and Engineering at the University of Dayton (TREND), Dayton, OH 45469, USA.
| | - Katia Del Rio-Tsonis
- Department of Biology, Miami University and Center for Visual Sciences at Miami University (CVSMU), Oxford, OH 45056, USA.
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Richter R, Forssmann W, Henschler R. Current Developments in Mobilization of Hematopoietic Stem and Progenitor Cells and Their Interaction with Niches in Bone Marrow. Transfus Med Hemother 2017. [PMID: 28626366 DOI: 10.1159/000477262] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The clinical application of hematopoietic stem and progenitor cells (HSPCs) has evolved from a highly experimental stage in the 1980s to a currently clinically established treatment for more than 20,000 patients annually who suffer from hematological malignancies and other severe diseases. Studies in numerous murine models have demonstrated that HSPCs reside in distinct niches within the bone marrow environment. Whereas transplanted HSPCs travel through the bloodstream and home to sites of hematopoiesis, HSPCs can be mobilized from these niches into the blood either physiologically or induced by pharmaceutical drugs. Firstly, this review aims to give a synopsis of milestones defining niches and mobilization pathways for HSPCs, including the identification of several cell types involved such as osteoblasts, adventitial reticular cells, endothelial cells, monocytic cells, and granulocytic cells. The main factors that anchor HSPCs in the niche, and/or induce their quiescence are vascular cell adhesion molecule(VCAM)-1, CD44, hematopoietic growth factors, e.g. stem cell factor (SCF) and FLT3 Ligand, chemokines including CXCL12, growth-regulated protein beta and IL-8, proteases, peptides, and other chemical transmitters such as nucleotides. In the second part of the review, we revise the current understanding of HSPC mobilization. Here, we discuss which mechanisms found to be active in HSPC mobilization correspond to the mechanisms relevant for HSPC interaction with niche cells, but also deal with other mediators and signals that target individual cell types and receptors to mobilize HSPCs. A multitude of questions remain to be addressed for a better understanding of HSPC biology and its implications for therapy, including more comprehensive concepts for regulatory circuits such as calcium homeostasis and parathormone, metabolic regulation such as by leptin, the significance of autonomic nervous system, the consequences of alteration of niches in aged patients, or the identification of more easily accessible markers to better predict the efficiency of HSPC mobilization.
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Affiliation(s)
- Rudolf Richter
- Department of Internal Medicine, Clinic of Immunology, Hanover Medical School, Hanover, Germany.,MVZ Labor PD Dr. Volkmann & Kollegen, Karlsruhe, Germany
| | - Wolfgang Forssmann
- Department of Internal Medicine, Clinic of Immunology, Hanover Medical School, Hanover, Germany
| | - Reinhard Henschler
- Swiss Red Cross Blood Transfusion Services Zurich and Chur, Zurich, Switzerland
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Nowlan B, Futrega K, Brunck ME, Walkinshaw G, Flippin LE, Doran MR, Levesque JP. HIF-1α-stabilizing agent FG-4497 rescues human CD34 + cell mobilization in response to G-CSF in immunodeficient mice. Exp Hematol 2017; 52:50-55.e6. [PMID: 28527810 DOI: 10.1016/j.exphem.2017.05.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 05/09/2017] [Accepted: 05/10/2017] [Indexed: 12/13/2022]
Abstract
Granulocyte colony-stimulating factor (G-CSF) is used routinely in the clinical setting to mobilize hematopoietic stem progenitor cells (HSPCs) into the patient's blood for collection and subsequent transplantation. However, a significant proportion of patients who have previously received chemotherapy or radiotherapy and require autologous HSPC transplantation cannot mobilize the minimal threshold of mobilized HSPCs to achieve rapid and successful hematopoietic reconstitution. Although several alternatives to the G-CSF regime have been tested, few are used in the clinical setting. We have shown previously in mice that administration of prolyl 4-hydroxylase domain enzyme (PHD) inhibitors, which stabilize hypoxia-inducible factor (HIF)-1α, synergize with G-CSF in vivo to enhance mouse HSPC mobilization into blood, leading to enhanced engraftment via an HSPC-intrinsic mechanism. To evaluate whether PHD inhibitors could be used to enhance mobilization of human HSPCs, we humanized nonobese, diabetic severe combined immune-deficient Il2rg-/- mice by transplanting them with human umbilical cord blood CD34+ HSPCs and then treating them with G-CSF with and without co-administration of the PHD inhibitor FG-4497. We observed that combination treatment with G-CSF and FG-4497 resulted in significant mobilization of human lineage-negative (Lin-) CD34+ HSPCs and more primitive human Lin-CD34+CD38- HSPCs into blood and spleen, whereas mice treated with G-CSF alone did not mobilize human HSPCs significantly. These results suggest that the PHD inhibitor FG-4497 also increases human HSPC mobilization in a xenograft mouse model, suggesting the possibility of testing PHD inhibitors to boost HSPC mobilization in response to G-CSF in humans.
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Affiliation(s)
- Bianca Nowlan
- Stem Cell Therapies Laboratory, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland, Australia; Mater Research Institute, Translational Research Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Kathryn Futrega
- Stem Cell Therapies Laboratory, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland, Australia
| | - Marion E Brunck
- Mater Research Institute, Translational Research Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | | | | | - Michael R Doran
- Stem Cell Therapies Laboratory, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland, Australia; Mater Research Institute, Translational Research Institute, University of Queensland, Woolloongabba, Queensland, Australia; Australian National Centre for the Public Awareness of Science - Australian National University, Australia.
| | - Jean-Pierre Levesque
- Mater Research Institute, Translational Research Institute, University of Queensland, Woolloongabba, Queensland, Australia.
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Abdelbaset-Ismail A, Borkowska-Rzeszotek S, Kubis E, Bujko K, Brzeźniakiewicz-Janus K, Bolkun L, Kloczko J, Moniuszko M, Basak GW, Wiktor-Jedrzejczak W, Ratajczak MZ. Activation of the complement cascade enhances motility of leukemic cells by downregulating expression of HO-1. Leukemia 2017; 31:446-458. [PMID: 27451975 PMCID: PMC5288274 DOI: 10.1038/leu.2016.198] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 07/06/2016] [Accepted: 07/08/2016] [Indexed: 02/07/2023]
Abstract
As a crucial arm of innate immunity, the complement cascade (ComC) is involved both in mobilization of normal hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood and in their homing to BM. Despite the fact that ComC cleavage fragments alone do not chemoattract normal HSPCs, we found that leukemia cell lines as well as clonogenic blasts from chronic myeloid leukemia and acute myeloid leukemia patients respond robustly to C3 and C5 cleavage fragments by chemotaxis and increased adhesion. This finding was supported by the detection of C3a and C5a receptors in cells from human malignant hematopoietic cell lines and patient blasts at the mRNA (reverse transcriptase-polymerase chain reaction) and protein level (fluorescence-activated cell sorting), and by the demonstration that these receptors respond to stimulation by C3a and C5a by phosphorylation of p42/44 and p38 mitogen-activated protein kinases (MAPK), and protein kinase B (PKB/AKT). We also found that inducible heme oxygenase 1 (HO-1) is a negative regulator of ComC-mediated trafficking of leukemic cells, and that stimulation of leukemic cells by C3 or C5 cleavage fragments activates p38 MAPK, which downregulates HO-1 expression, rendering cells more mobile. We conclude that activation of the ComC in leukemia/lymphoma patients (for example, as a result of accompanying infections) enhances the motility of malignant cells and contributes to their spread in a p38 MAPK-HO-1-dependent manner. Therefore, inhibition of p38 MAPK or upregulation of HO-1 by small-molecule modulators would have a beneficial effect on ameliorating cell migration-mediated expansion of leukemia/lymphoma cells when the ComC becomes activated.
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Affiliation(s)
- A Abdelbaset-Ismail
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | | | - E Kubis
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland
| | - K Bujko
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | | | - L Bolkun
- Department of Regenerative Medicine, Medical University of Bialystok, Bialystok, Poland
- Department of Hematology, Medical University of Bialystok, Bialystok, Poland
| | - J Kloczko
- Department of Regenerative Medicine, Medical University of Bialystok, Bialystok, Poland
- Department of Hematology, Medical University of Bialystok, Bialystok, Poland
| | - M Moniuszko
- Department of Regenerative Medicine, Medical University of Bialystok, Bialystok, Poland
| | - G W Basak
- Department of Hematology, Warsaw Medical University, Warsaw, Poland
| | | | - M Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
- Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland
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Cellular players of hematopoietic stem cell mobilization in the bone marrow niche. Int J Hematol 2016; 105:129-140. [PMID: 27943116 DOI: 10.1007/s12185-016-2162-4] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 11/21/2016] [Accepted: 11/29/2016] [Indexed: 12/23/2022]
Abstract
Hematopoietic stem cells (HSC) reside in perivascular regions of the bone marrow (BM) embedded within a complex regulatory unit called the niche. Cellular components of HSC niches include vascular endothelial cells, mesenchymal stromal progenitor cells and a variety of mature hematopoietic cells such as macrophages, neutrophils, and megakaryocytes-further regulated by sympathetic nerves and complement components as described in this review. Three decades ago the discovery that cytokines induce a large number of HSC to mobilize from the BM into the blood where they are easily harvested, revolutionised the field of HSC transplantation-curative for immune-deficiencies and some malignancies. However, despite now routine use of granulocyte-colony stimulating factor (G-CSF) to mobilise HSC for transplant, only in last 15 years has research on the mechanisms behind why and how HSC can be induced to move into the blood began. These studies have revealed the complexity of the niche that retains HSC in the BM. This review describes how BM niches and HSC themselves change during administration of G-CSF-or in the recovery phase of chemotherapy-to facilitate movement of HSC into the blood, and research now leading to development of novel therapeutics to further boost HSC mobilization and transplant success.
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38
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Hawksworth OA, Coulthard LG, Woodruff TM. Complement in the fundamental processes of the cell. Mol Immunol 2016; 84:17-25. [PMID: 27894513 DOI: 10.1016/j.molimm.2016.11.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 11/18/2016] [Indexed: 11/30/2022]
Abstract
Once regarded solely as an activator of innate immunity, it is now clear that the complement system acts in an assortment of cells and tissues, with immunity only one facet of a diverse array of functions under the influence of the complement proteins. Throughout development, complement activity has now been demonstrated from early sperm-egg interactions in fertilisation, to regulation of epiboly and organogenesis, and later in refinement of cerebral synapses. Complement has also been shown to regulate homeostasis of adult tissues, controlling cell processes such as migration, survival, repair, and regeneration. Given the continuing emergence of such novel actions of complement, the existing research likely represents only a fraction of the myriad of functions of this complex family of proteins. This review is focussed on outlining the current knowledge of complement family members in the regulation of cell processes in non-immune systems. It is hoped this will spur research directed towards revealing more about the role of complement in these fundamental cell processes.
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Affiliation(s)
- Owen A Hawksworth
- School of Biomedical Sciences, University of Queensland, St. Lucia, Australia; Australian Institute of Bioengineering and Nanotechnology, University of Queensland, St. Lucia, Australia
| | - Liam G Coulthard
- School of Medicine, University of Queensland, Herston, Australia; Royal Brisbane and Women's Hospital, Herston, Australia
| | - Trent M Woodruff
- School of Biomedical Sciences, University of Queensland, St. Lucia, Australia.
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Bendall L. Extracellular molecules in hematopoietic stem cell mobilisation. Int J Hematol 2016; 105:118-128. [PMID: 27826715 DOI: 10.1007/s12185-016-2123-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 11/01/2016] [Indexed: 01/11/2023]
Abstract
Hematopoietic stem cells are a remarkable resource currently used for the life saving treatment, hematopoietic stem cell transplantation. Today, hematopoietic stem cells are primarily obtained from mobilized peripheral blood following treatment of the donor with the cytokine G-CSF, and in some settings, chemotherapy and/or the CXCR4 antagonist plerixafor. The collection of hematopoietic stem cells is contingent on adequate and timely mobilization of these cells into the peripheral blood. The use of healthy donors, particularly when unrelated to the patient, requires mobilization strategies be safe for the donor. While current mobilization strategies are largely successful, adequate mobilization fails to occur in a significant portion of donors. Understanding the mechanisms involved in the egress of stem cells from the bone marrow provides opportunities to further improve the process of collecting hematopoietic stem cells. Here, the role extracellular components of the blood and bone marrow in the mobilization process are discussed.
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Affiliation(s)
- Linda Bendall
- Centre for Cancer Research, Westmead Institute for Medical Research, University of Sydney, 176 Hawkesbury Rd, Westmead, Sydney, NSW, 2145, Australia.
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40
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Elahimehr R, Scheinok AT, McKay DB. Hematopoietic stem cells and solid organ transplantation. Transplant Rev (Orlando) 2016; 30:227-34. [PMID: 27553809 DOI: 10.1016/j.trre.2016.07.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 07/21/2016] [Accepted: 07/22/2016] [Indexed: 10/21/2022]
Abstract
Solid organ transplantation provides lifesaving therapy for patients with end stage organ disease. In order for the transplanted organ to survive, the recipient must take a lifelong cocktail of immunosuppressive medications that increase the risk for infections, malignancies and drug toxicities. Data from many animal studies have shown that recipients can be made tolerant of their transplanted organ by infusing stem cells, particularly hematopoietic stem cells, prior to the transplant. The animal data have been translated into humans and now several clinical trials have demonstrated that infusion of hematopoietic stem cells, along with specialized conditioning regimens, can permit solid organ allograft survival without immunosuppressive medications. This important therapeutic advance has been made possible by understanding the immunologic mechanisms by which stem cells modify the host immune system, although it must be cautioned that the conditioning regimens are often severe and associated with significant morbidity. This review discusses the role of hematopoietic stem cells in solid organ transplantation, provides an understanding of how these stem cells modify the host immune system and describes how newer information about adaptive and innate immunity might lead to improvements in the use of hematopoietic stem cells to induce tolerance to transplanted organs.
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Affiliation(s)
- Reza Elahimehr
- Department of Medicine, Division of Nephrology/Hypertension, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Andrew T Scheinok
- Department of Medicine, Division of Nephrology/Hypertension, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Dianne B McKay
- Department of Medicine, Division of Nephrology/Hypertension, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
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41
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Adamiak M, Poniewierska-Baran A, Borkowska S, Schneider G, Abdelbaset-Ismail A, Suszynska M, Abdel-Latif A, Kucia M, Ratajczak J, Ratajczak MZ. Evidence that a lipolytic enzyme--hematopoietic-specific phospholipase C-β2--promotes mobilization of hematopoietic stem cells by decreasing their lipid raft-mediated bone marrow retention and increasing the promobilizing effects of granulocytes. Leukemia 2016; 30:919-928. [PMID: 26582648 PMCID: PMC4823158 DOI: 10.1038/leu.2015.315] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Revised: 10/14/2015] [Accepted: 10/26/2015] [Indexed: 12/26/2022]
Abstract
Hematopoietic stem/progenitor cells (HSPCs) reside in the bone marrow (BM) microenvironment and are retained there by the interaction of membrane lipid raft-associated receptors, such as the α-chemokine receptor CXCR4 and the α4β1-integrin (VLA-4, very late antigen 4 receptor) receptor, with their respective specific ligands, stromal-derived factor 1 and vascular cell adhesion molecule 1, expressed in BM stem cell niches. The integrity of the lipid rafts containing these receptors is maintained by the glycolipid glycosylphosphatidylinositol anchor (GPI-A). It has been reported that a cleavage fragment of the fifth component of the activated complement cascade, C5a, has an important role in mobilizing HSPCs into the peripheral blood (PB) by (i) inducing degranulation of BM-residing granulocytes and (ii) promoting their egress from the BM into the PB so that they permeabilize the endothelial barrier for subsequent egress of HSPCs. We report here that hematopoietic cell-specific phospholipase C-β2 (PLC-β2) has a crucial role in pharmacological mobilization of HSPCs. On the one hand, when released during degranulation of granulocytes, it digests GPI-A, thereby disrupting membrane lipid rafts and impairing retention of HSPCs in BM niches. On the other hand, it is an intracellular enzyme required for degranulation of granulocytes and their egress from BM. In support of this dual role, we demonstrate that PLC-β2-knockout mice are poor mobilizers and provide, for the first time, evidence for the involvement of this lipolytic enzyme in the mobilization of HSPCs.
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Affiliation(s)
- M Adamiak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - A Poniewierska-Baran
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - S Borkowska
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - G Schneider
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - A Abdelbaset-Ismail
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - M Suszynska
- Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY, USA
| | - A Abdel-Latif
- Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY, USA
| | - M Kucia
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
- Department of Regenerative Medicine Medical University, Warsaw, Poland
| | - J Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - M Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
- Department of Regenerative Medicine Medical University, Warsaw, Poland
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Lim J, Kim Y, Heo J, Kim KH, Lee S, Lee SW, Kim K, Kim IG, Shin DM. Priming with ceramide-1 phosphate promotes the therapeutic effect of mesenchymal stem/stromal cells on pulmonary artery hypertension. Biochem Biophys Res Commun 2016; 473:35-41. [DOI: 10.1016/j.bbrc.2016.03.046] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 03/09/2016] [Indexed: 01/07/2023]
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The relative merits of therapies being developed to tackle inappropriate ('self'-directed) complement activation. AUTOIMMUNITY HIGHLIGHTS 2016; 7:6. [PMID: 26935316 PMCID: PMC4775539 DOI: 10.1007/s13317-016-0078-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 02/03/2016] [Indexed: 12/11/2022]
Abstract
The complement system is an enzyme cascade that helps defend against infection. Many complement proteins occur in serum as inactive enzyme precursors or reside on cell surfaces. Complement components have many biologic functions and their activation can eventually damage the plasma membranes of cells and some bacteria. Although a direct link between complement activation and autoimmune diseases has not been found, there is increasing evidence that complement activation significantly contributes to the pathogenesis of a large number of inflammatory diseases that may have autoimmune linkage. The inhibition of complement may therefore be very important in a variety of autoimmune diseases since their activation may be detrimental to the individual involved. However, a complete and long-term inhibition of complement may have some contra side effects such as increased susceptibility to infection. The site of complement activation will, however, determine the type of inhibitor to be used, its route of application and dosage level. Compared with conventional drugs, complement inhibitors may be the best option for treatment of autoimmune diseases. The review takes a critical look at the relative merits of therapies being developed to tackle inappropriate complement activation that are likely to result in sporadic autoimmune diseases or worsen already existing one. It covers the complement system, general aspects of complement inhibition therapy, therapeutic strategies and examples of complement inhibitors. It concludes by highlighting on the possibility that a better inhibitor of complement activation when found will help provide a formidable treatment for autoimmune diseases as well as preventing one.
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Beksac M, Yurdakul P. How to Improve Cord Blood Engraftment? Front Med (Lausanne) 2016; 3:7. [PMID: 26925402 PMCID: PMC4756107 DOI: 10.3389/fmed.2016.00007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Accepted: 02/05/2016] [Indexed: 01/03/2023] Open
Abstract
Various factors make cord blood (CB) a significant source of hematopoietic stem cells (HSCs), including ease of procurement and lack of donor attrition, with the ability to process and store the donor cells long term. Importantly, high proliferative potential of the immature HSCs allows one log less use of cells compared to bone marrow or peripheral blood stem cells. As total nucleated cell (TNC) and CD34(+) cell content of CB grafts are correlated to engraftment rate and speed, strategies to expand HSC and homing have been developed. This chapter will focus only on modalities such as intrabone administration, fucosylation, CD26 inhibition, prostaglandin E2 derivative or complement 3 exposure, and SDF-1/CXCR4/CXCL-12 pathway interventions that have been experimented successfully. Furthermore, increasing evidence in line with better recognition of CB progenitors that are involved in engraftment and homing will also be addressed.
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Affiliation(s)
- Meral Beksac
- Department of Hematology, Ankara University School of Medicine , Ankara , Turkey
| | - Pinar Yurdakul
- Cord Blood Bank, Ankara University School of Medicine , Ankara , Turkey
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Ex Vivo Expansion or Manipulation of Stem Cells to Improve Outcome of Umbilical Cord Blood Transplantation. Curr Hematol Malig Rep 2015; 11:12-8. [DOI: 10.1007/s11899-015-0297-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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46
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Schraufstatter IU, Khaldoyanidi SK, DiScipio RG. Complement activation in the context of stem cells and tissue repair. World J Stem Cells 2015; 7:1090-1108. [PMID: 26435769 PMCID: PMC4591784 DOI: 10.4252/wjsc.v7.i8.1090] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 07/27/2015] [Indexed: 02/06/2023] Open
Abstract
The complement pathway is best known for its role in immune surveillance and inflammation. However, its ability of opsonizing and removing not only pathogens, but also necrotic and apoptotic cells, is a phylogenetically ancient means of initiating tissue repair. The means and mechanisms of complement-mediated tissue repair are discussed in this review. There is increasing evidence that complement activation contributes to tissue repair at several levels. These range from the chemo-attraction of stem and progenitor cells to areas of complement activation, to increased survival of various cell types in the presence of split products of complement, and to the production of trophic factors by cells activated by the anaphylatoxins C3a and C5a. This repair aspect of complement biology has not found sufficient appreciation until recently. The following will examine this aspect of complement biology with an emphasis on the anaphylatoxins C3a and C5a.
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47
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Sallustio F, Serino G, Schena FP. Potential Reparative Role of Resident Adult Renal Stem/Progenitor Cells in Acute Kidney Injury. Biores Open Access 2015; 4:326-33. [PMID: 26309808 PMCID: PMC4509615 DOI: 10.1089/biores.2015.0011] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Human kidney is particularly susceptible to ischemia and toxins with consequential tubular necrosis and activation of inflammatory processes. This process can lead to the acute renal injury, and even if the kidney has a great capacity for regeneration after tubular damage, in several circumstances, the normal renal repair program may not be sufficient to achieve a successful regeneration. Resident adult renal stem/progenitor cells could participate in this repair process and have the potentiality to enhance the renal regenerative mechanism. This could be achieved both directly, by means of their capacity to differentiate and integrate into the renal tissues, and by means of paracrine factors able to induce or improve the renal repair or regeneration. Recent genetic fate-tracing studies indicated that tubular damage is instead repaired by proliferative duplication of epithelial cells, acquiring a transient progenitor phenotype and by fate-restricted clonal cell progeny emerging from different nephron segments. In this review, we discuss about the properties and the reparative characteristics of high regenerative CD133(+)/CD24(+) cells, with a view to a future application of these cells for the treatment of acute renal injury.
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Affiliation(s)
- Fabio Sallustio
- Department of Emergency and Organ Transplantation, University of Bari , Bari, Italy . ; C.A.R.S.O. Consortium, Strada Prov. le Valenzano-Casamassima Km 3 , Valenzano, Italy . ; Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali (DiSTeBA), Università del Salento , Lecce-Monteroni, Lecce, Italy
| | - Grazia Serino
- Department of Emergency and Organ Transplantation, University of Bari , Bari, Italy
| | - Francesco Paolo Schena
- C.A.R.S.O. Consortium, Strada Prov. le Valenzano-Casamassima Km 3 , Valenzano, Italy . ; Schena Foundation, Research Center of Renal Diseases , Bari, Italy
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48
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Pineault N, Abu-Khader A. Advances in umbilical cord blood stem cell expansion and clinical translation. Exp Hematol 2015; 43:498-513. [DOI: 10.1016/j.exphem.2015.04.011] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2015] [Revised: 04/23/2015] [Accepted: 04/24/2015] [Indexed: 11/24/2022]
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Kang H, Kim KH, Lim J, Kim YS, Heo J, Choi J, Jeong J, Kim Y, Kim SW, Oh YM, Choo MS, Son J, Kim SJ, Yoo HJ, Oh W, Choi SJ, Lee SW, Shin DM. The Therapeutic Effects of Human Mesenchymal Stem Cells Primed with Sphingosine-1 Phosphate on Pulmonary Artery Hypertension. Stem Cells Dev 2015; 24:1658-71. [PMID: 25761906 DOI: 10.1089/scd.2014.0496] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Stem cell (SC) therapy has become a potential treatment modality for pulmonary artery hypertension (PAH), but the efficacy of human SC and priming effects have not yet been established. The mobilization and homing of hematopoietic stem cells (HSCs) are modulated by priming factors that include a bioactive lipid, sphingosine-1-phosphate (S1P), which stimulates CXCR4 receptor kinase signaling. Here, we show that priming human mesenchymal stem cells (MSCs) with S1P enhances their therapeutic efficacy in PAH. Human MSCs, similar to HSCs, showed stronger chemoattraction to S1P in transwell assays. Concomitantly, MSCs treated with 0.2 μM S1P showed increased phosphorylation of both MAPKp42/44 and AKT protein compared with nonprimed MSCs. Furthermore, S1P-primed MSCs potentiated colony forming unit-fibroblast, anti-inflammatory, and angiogenic activities of MSCs in culture. In a PAH animal model induced by subcutaneously injected monocrotaline, administration of human cord blood-derived MSCs (hCB-MSCs) or S1P-primed cells significantly attenuated the elevated right ventricular systolic pressure. Notably, S1P-primed CB-MSCs, but not unprimed hCB-MSCs, also elicited a significant reduction in the right ventricular weight ratio and pulmonary vascular wall thickness. S1P-primed MSCs enhanced the expression of several genes responsible for stem cell trafficking and angiogenesis, increasing the density of blood vessels in the damaged lungs. Thus, this study demonstrates that human MSCs have potential utility for the treatment of PAH, and that S1P priming increases the effects of SC therapy by enhancing cardiac and vascular remodeling. By optimizing this protocol in future studies, SC therapy might form a basis for clinical trials to treat human PAH.
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Affiliation(s)
- Hyunsook Kang
- 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.,2 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Kang-Hyun Kim
- 3 Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Jisun Lim
- 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.,2 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - You-Sun Kim
- 3 Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Jinbeom Heo
- 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.,2 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Jongjin Choi
- 3 Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Jaeho Jeong
- 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.,2 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - YongHwan Kim
- 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.,2 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Seong Who Kim
- 4 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Yeon-Mok Oh
- 3 Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Myung-Soo Choo
- 5 Department of Urology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Jaekyoung Son
- 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Su Jung Kim
- 6 Department of Biomedical Research Center, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Hyun Ju Yoo
- 6 Department of Biomedical Research Center, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Wonil Oh
- 7 Biomedical Research Institute , Medipost Co., Ltd., Seoul, Korea
| | - Soo Jin Choi
- 7 Biomedical Research Institute , Medipost Co., Ltd., Seoul, Korea
| | - Sei Won Lee
- 3 Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Dong-Myung Shin
- 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.,2 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
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Regal JF, Gilbert JS, Burwick RM. The complement system and adverse pregnancy outcomes. Mol Immunol 2015; 67:56-70. [PMID: 25802092 DOI: 10.1016/j.molimm.2015.02.030] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 02/20/2015] [Accepted: 02/24/2015] [Indexed: 02/08/2023]
Abstract
Adverse pregnancy outcomes significantly contribute to morbidity and mortality for mother and child, with lifelong health consequences for both. The innate and adaptive immune system must be regulated to insure survival of the fetal allograft, and the complement system is no exception. An intact complement system optimizes placental development and function and is essential to maintain host defense and fetal survival. Complement regulation is apparent at the placental interface from early pregnancy with some degree of complement activation occurring normally throughout gestation. However, a number of pregnancy complications including early pregnancy loss, fetal growth restriction, hypertensive disorders of pregnancy and preterm birth are associated with excessive or misdirected complement activation, and are more frequent in women with inherited or acquired complement system disorders or complement gene mutations. Clinical studies employing complement biomarkers in plasma and urine implicate dysregulated complement activation in components of each of the adverse pregnancy outcomes. In addition, mechanistic studies in rat and mouse models of adverse pregnancy outcomes address the complement pathways or activation products of importance and allow critical analysis of the pathophysiology. Targeted complement therapeutics are already in use to control adverse pregnancy outcomes in select situations. A clearer understanding of the role of the complement system in both normal pregnancy and complicated or failed pregnancy will allow a rational approach to future therapeutic strategies for manipulating complement with the goal of mitigating adverse pregnancy outcomes, preserving host defense, and improving long term outcomes for both mother and child.
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Affiliation(s)
- Jean F Regal
- Department of Biomedical Sciences, University of Minnesota Medical School, 1035 University Drive, Duluth, MN 55812, USA.
| | - Jeffrey S Gilbert
- Department of Biomedical Sciences, University of Minnesota Medical School, 1035 University Drive, Duluth, MN 55812, USA.
| | - Richard M Burwick
- Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Oregon Health & Science University, Mail Code: L-458, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
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