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Wang YX, Deng ZH, Li YY, Bai K, Ma J, Liu Y, Chen Q. Function of hematopoiesis and bone marrow niche in inflammation and non-hematopoietic diseases. LIFE MEDICINE 2025; 4:lnaf015. [PMID: 40376111 PMCID: PMC12076419 DOI: 10.1093/lifemedi/lnaf015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 03/24/2025] [Indexed: 05/18/2025]
Abstract
Hematopoiesis and the behavior of hematopoietic stem and progenitor cells (HSPCs) are regulated by the bone marrow niche. Here, we introduce the major niche cell types in bone marrow and their response to stress condition. We highlight the hematopoietic response and bone marrow niche adaptation to inflammatory condition and non-hematopoietic diseases, which are not systematically summarized. These emerging data suggest targeting hematopoiesis and bone marrow niche may provide novel therapeutic target to precisely control the progression of the diseases.
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Affiliation(s)
- Yu-xiang Wang
- Center for Cell Lineage Atlas, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
- University of Chinese Academy of Sciences, Beijing 101408, China
- China-New Zealand Belt and Road Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory for Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
| | - Zhao-hua Deng
- Center for Cell Lineage Atlas, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
- University of Chinese Academy of Sciences, Beijing 101408, China
- China-New Zealand Belt and Road Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory for Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
| | - Yu-yan Li
- Center for Cell Lineage Atlas, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
- University of Chinese Academy of Sciences, Beijing 101408, China
- China-New Zealand Belt and Road Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory for Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
| | - Ke Bai
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou 510006, China
| | - Jinjin Ma
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou 510006, China
- The Institute of Future Health, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, China
| | - Yang Liu
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou 510006, China
| | - Qi Chen
- Center for Cell Lineage Atlas, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
- China-New Zealand Belt and Road Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory for Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
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Narayan AB, Hariom SK, Mukherjee AP, Das D, Nair A, Nelson EJR. 'Nomadic' Hematopoietic Stem Cells Navigate the Embryonic Landscape. Stem Cell Rev Rep 2025; 21:605-628. [PMID: 39786676 DOI: 10.1007/s12015-025-10843-6] [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] [Accepted: 01/03/2025] [Indexed: 01/12/2025]
Abstract
Hematopoietic stem cells are a unique population of tissue-resident multipotent cells with an extensive ability to self-renew and regenerate the entire lineage of differentiated blood cells. Stem cells reside in a highly specialized microenvironment with surrounding supporting cells, forming a complex and dynamic network to preserve and maintain their function. The survival, activation, and quiescence of stem cells are largely influenced by niche-derived signals, with aging niche contributing to a decline in stem cell function. Although the role of niche in regulating hematopoiesis has long been established by transplantation studies, limited methods in observing the process in vivo have eluded a detailed understanding of the various niche components. Danio rerio (zebrafish) has emerged as a solution in the past few decades, enabling discovery of cellular interactions, in addition to chemical and genetic factors regulating HSCs. This review reiterates zebrafish as a suitable model for studies on vertebrate embryonic and adult hematopoiesis, delving into this temporally and spatially dissected multi-step process. The critical role played by epigenetic regulators are discussed, along with contributions of the various physiological processes in sustaining the stem cell population. Stem cell niche transcends mere knowledge acquisition, assuring scope in cell therapy, organoid cultures, aging research, and clinical applications including bone marrow transplantation and cancer. A better understanding of the various niche components could also leverage therapeutic efforts to drive differentiation of HSCs from pluripotent progenitors, sustain stemness in laboratory cultures, and improve stem cell transplantation outcomes.
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Affiliation(s)
- Anand Badhri Narayan
- Department of Integrative Biology, Gene Therapy Laboratory, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, TN, 632 014, India
| | - Senthil Kumar Hariom
- Department of Integrative Biology, Gene Therapy Laboratory, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, TN, 632 014, India
| | - Ayan Prasad Mukherjee
- Department of Integrative Biology, Gene Therapy Laboratory, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, TN, 632 014, India
| | - Deotima Das
- Department of Integrative Biology, Gene Therapy Laboratory, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, TN, 632 014, India
| | - Aadhira Nair
- Department of Integrative Biology, Gene Therapy Laboratory, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, TN, 632 014, India
| | - Everette Jacob Remington Nelson
- Department of Integrative Biology, Gene Therapy Laboratory, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, TN, 632 014, India.
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Hemati H, Blanton MB, Koura J, Khadka R, Grant KA, Messaoudi I. Chronic alcohol consumption enhances the differentiation capacity of hematopoietic stem and progenitor cells into osteoclast precursors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.05.636743. [PMID: 39975302 PMCID: PMC11839057 DOI: 10.1101/2025.02.05.636743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Chronic alcohol consumption (CAC) is associated with an enhanced risk of bone fracture, reduced bone density, and osteoporosis. We have previously shown using a rhesus macaque model of voluntary ethanol consumption that CAC induces functional, transcriptomic, and epigenomic changes in hematopoietic stem and progenitor cells (HSPCs) and their resultant monocytes/macrophages, skewing them towards a hyper-inflammatory response. Here, we extended those studies and investigated alterations in osteoclasts, which, in postnatal life, are differentiated from HSPCs and play a critical role in maintaining bone homeostasis. Analysis using spectral flow cytometry revealed a skewing of HSPCs towards granulocyte-monocyte progenitors (GMPs) with the CAC group that was in concordance with an increased number of colony-forming unit-granulocyte/macrophage (CFU-GM). Additionally, HSPCs from animals in the CAC group incubated with M-CSF and RANKL were more likely to differentiate into osteoclasts, as evidenced by increased Tartrate-Resistant Acid Phosphatase (TRAP) staining and bone resorption activity. Moreover, single-cell RNA sequencing of differentiated HSPCs identified three clusters of osteoclast precursors in the CAC group with enhanced gene expression in pathways associated with cellular response to stimuli, membrane trafficking, and vesicle-mediated transport. Collectively, these data show that CAC-derived hematopoietic progenitor cells exhibit a higher capacity to differentiate into osteoclast precursors. These findings provide critical insights for future research on the mechanisms by which CAC disrupts monopoiesis homeostasis and enhances osteoclast precursors, thereby contributing to reduced bone density.
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Affiliation(s)
- Hami Hemati
- Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Madison B Blanton
- Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, United States
| | - Jude Koura
- Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Rupak Khadka
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, OR, United States
| | - Kathleen A Grant
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, OR, United States
| | - Ilhem Messaoudi
- Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY, United States
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Prchal-Murphy M, Zehenter J, Fischer M, Pirabe A, Themanns M, Afrashteh B, Putz EM, Kollmann K, Basílio J, Salzmann M, Strohmaier W, Krumpl G, Farr A, Sexl V, Freissmuth M, Zebedin-Brandl E. Repurposing the prostaglandin analogue treprostinil and the calcium-sensing receptor modulator cinacalcet to revive cord blood as an alternate source of hematopoietic stem and progenitor cells for transplantation. Front Pharmacol 2025; 15:1444311. [PMID: 39850556 PMCID: PMC11755040 DOI: 10.3389/fphar.2024.1444311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 12/05/2024] [Indexed: 01/25/2025] Open
Abstract
Objective The expanding field of hematopoietic cell transplantation (HCT) for non-malignant diseases, including those amenable to gene therapy or gene editing, faces challenges due to limited donor availability and the toxicity associated with cell collection methods. Umbilical cord blood (CB) represents a readily accessible source of hematopoietic stem and progenitor cells (HSPCs); however, the cell dose obtainable from a single cord blood unit is frequently insufficient. This limitation can be addressed by enhancing the potency of HSPCs, specifically their capacity to reconstitute hematopoiesis. In our study, we investigated the combined effects of treprostinil, a prostaglandin analog, and cinacalcet, a calcium-sensing receptor modulator, on the reconstitution of hematopoiesis. Methods A Lineage Cell Depletion Kit was employed to isolate lineage-negative (lin-) HSPCs from mouse bone marrow. A Human CB CD34 Positive Selection Kit was utilized to isolate CD34+ cells from the CB of healthy donors. In vitro, the effects of treprostinil, cinacalcet, and their combination on the migration, adhesion, and differentiation of HSPCs were assessed. In vivo, homing and engraftment were examined. Eight-week-old female and male C57BL/6J, BALB/c, or female NSG mice served as recipient models. Results When administered concomitantly, treprostinil and cinacalcet exhibited mutual antagonism: the survival of recipient animals was lower when both drugs were administered together compared to either agent alone. Conversely, a sequential regimen involving priming with treprostinil/forskolin followed by cinacalcet treatment in vivo enhanced survival, irrespective of whether hematopoiesis was reconstituted by human or murine HSPCs. In vitro assays demonstrated enhanced migration and adhesion in response to the presence of treprostinil and cinacalcet, suggesting potential synergistic effects. Colony formation confirmed synergism. Conclusion Augmenting the bone marrow reconstitution potential of HSPCs with treprostinil and cinacalcet shows promise for rescuing patients undergoing HCT. This approach is particularly beneficial for those patients at high risk of transplant failure due to limited numbers of available HSPCs. Furthermore, enhancing the potency of HSPCs has the potential to alleviate the burden and risks associated with HSPC donation, as it would reduce the number of cells needed for collection.
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Affiliation(s)
- Michaela Prchal-Murphy
- Department for Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - Julia Zehenter
- Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Marlene Fischer
- Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Anita Pirabe
- Department for Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna, Austria
| | - Madeleine Themanns
- Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Behnaz Afrashteh
- Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Eva Maria Putz
- Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Karoline Kollmann
- Department for Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - José Basílio
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
- Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria
| | - Manuel Salzmann
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | | | - Günther Krumpl
- AOP Health International Management AG, Ruggell, Liechtenstein
| | - Alex Farr
- Department of Obstetrics and Gynecology, Division of Obstetrics and Feto-Maternal Medicine, Medical University of Vienna, Vienna, Austria
| | - Veronika Sexl
- Department for Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - Michael Freissmuth
- Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Eva Zebedin-Brandl
- Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Cain TL, Derecka M, McKinney-Freeman S. The role of the haematopoietic stem cell niche in development and ageing. Nat Rev Mol Cell Biol 2025; 26:32-50. [PMID: 39256623 DOI: 10.1038/s41580-024-00770-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/23/2024] [Indexed: 09/12/2024]
Abstract
Blood production depends on rare haematopoietic stem cells (HSCs) and haematopoietic stem and progenitor cells (HSPCs) that ultimately take up residence in the bone marrow during development. HSPCs and HSCs are subject to extrinsic regulation by the bone marrow microenvironment, or niche. Studying the interactions between HSCs and their niche is critical for improving ex vivo culturing conditions and genetic manipulation of HSCs, which is pivotal for improving autologous HSC therapies and transplantations. Additionally, understanding how the complex molecular network in the bone marrow is altered during ageing is paramount for developing novel therapeutics for ageing-related haematopoietic disorders. HSCs are unique amongst stem and progenitor cell pools in that they engage with multiple physically distinct niches during their ontogeny. HSCs are specified from haemogenic endothelium in the aorta, migrate to the fetal liver and, ultimately, colonize their final niche in the bone marrow. Recent studies employing single-cell transcriptomics and microscopy have identified novel cellular interactions that govern HSC specification and engagement with their niches throughout ontogeny. New lineage-tracing models and microscopy tools have raised questions about the numbers of HSCs specified, as well as the functional consequences of HSCs interacting with each developmental niche. Advances have also been made in understanding how these niches are modified and perturbed during ageing, and the role of these altered interactions in haematopoietic diseases. In this Review, we discuss these new findings and highlight the questions that remain to be explored.
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Affiliation(s)
- Terri L Cain
- Department of Haematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Marta Derecka
- Department of Haematology, St. Jude Children's Research Hospital, Memphis, TN, USA
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Weng W, Li Y, Lin Y, Wang J, Chen X, Zhou T. Cinacalcet Improves Erythropoietin Resistance in Patients with Secondary Hyperparathyroidism Receiving Dialysis Treatment. Curr Pharm Des 2025; 31:1299-1306. [PMID: 39817391 DOI: 10.2174/0113816128321721241118171041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 09/25/2024] [Accepted: 09/30/2024] [Indexed: 01/18/2025]
Abstract
INTRODUCTION Chronic Kidney Disease (CKD) is recognized as a major global public health problem. Dialysis is the mainstay of treatment for patients with end-stage renal disease and can prolong survival in patients with CKD. As patient survival increases, the treatment of complications becomes more important. CKD-mineral and bone disorders (CKD-MBD) and renal anemia are common complications in patients with CKD. Cinacalcet is a calcimimetic for the treatment of secondary hyperparathyroidism (SHPT) in adult dialysis patients, which regulates the synthesis and secretion of parathyroid hormone by increasing the sensitivity of calcium-sensitive receptors. This retrospective study evaluated the efficacy of cinacalcet in dialysis patients. METHODS Forty-six patients on dialysis with elevated parathyroid hormone were included. The selected patients have regular follow-up visits in our outpatient clinic and regular use of cinacalcet for no less than 6 months. RESULTS During the 6-month efficacy evaluation phase, cinacalcet not only reduced the levels of the intact parathyroid hormone (iPTH, P ≤ 0.05), serum calcium (P ≤ 0.01), and Ca×P (P ≤ 0.05) but also reduced weekly erythropoietin (EPO) dosage (P ≤ 0.01) and erythropoietin resistance index (ERI, P ≤ 0.05). CONCLUSION While controlling SHPT in patients with CKD, cinacalcet reduced EPO resistance and improved renal anemia. In conclusion, cinacalcet not only decreased the levels of the iPTH, serum calcium, and Ca×P but also reduced weekly EPO dosage and ERI levels. Controlling SHPT in patients with CKD, cinacalcet also reduced ERI and improved renal anemia.
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Affiliation(s)
- Wenjuan Weng
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Yingjuan Li
- Department of Nephrology, Chang'an Hospital, Dongguan, China
| | - Yongda Lin
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Jiali Wang
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Xiutian Chen
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Tianbiao Zhou
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
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Afkhami H, Yarahmadi A, Bostani S, Yarian N, Haddad MS, Lesani SS, Aghaei SS, Zolfaghari MR. Converging frontiers in cancer treatment: the role of nanomaterials, mesenchymal stem cells, and microbial agents-challenges and limitations. Discov Oncol 2024; 15:818. [PMID: 39707033 DOI: 10.1007/s12672-024-01590-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/14/2024] [Indexed: 12/23/2024] Open
Abstract
Globally, people widely recognize cancer as one of the most lethal diseases due to its high mortality rates and lack of effective treatment options. Ongoing research into cancer therapies remains a critical area of inquiry, holding significant social relevance. Currently used treatment, such as chemotherapy, radiation, or surgery, often suffers from other problems like damaging side effects, inaccuracy, and the lack of ability to clear tumors. Conventional cancer therapies are usually imprecise and ineffective and usually develop resistance to treatments and cancer recurs. Cancer patients need fresh and innovative treatment that can reduce side effects while maximizing effectiveness. In recent decades several breakthroughs in these, and other areas of medical research, have paved the way for new avenues of fighting cancer including more focused and more effective alternatives. This study reviews exciting possibilities for mesenchymal stem cells (MSCs), nanomaterials, and microbial agents in the modern realm of cancer treatment. Nanoparticles (NPs) have demonstrated surprisingly high potential. They improve drug delivery systems (DDS) significantly, enhance imaging techniques remarkably, and target cancer cells selectively while protecting healthy tissues. MSCs play a double role in tissue repair and are a vehicle for novel cancer treatments such as gene treatments or NPs loaded with therapeutic agents. Additionally, therapies utilizing microbial agents, particularly those involving bacteria, offer an inventive approach to cancer treatment. This review investigates the potential of nanomaterials, MSCs, and microbial agents in addressing the shortcomings of conventional cancer therapies. We will also discuss the challenges and limitations of using these therapeutic approaches.
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Affiliation(s)
- Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
| | - Shoroq Bostani
- Department of Microbiology, Qom Branch, Islamic Azad University, Qom, Iran
| | - Nahid Yarian
- Department of Microbiology, Qom Branch, Islamic Azad University, Qom, Iran
| | | | - Shima Sadat Lesani
- Department of Microbiology, Qom Branch, Islamic Azad University, Qom, Iran
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Xinyi Y, Vladimirovich RI, Beeraka NM, Satyavathi A, Kamble D, Nikolenko VN, Lakshmi AN, Basappa B, Reddy Y P, Fan R, Liu J. Emerging insights into epigenetics and hematopoietic stem cell trafficking in age-related hematological malignancies. Stem Cell Res Ther 2024; 15:401. [PMID: 39506818 PMCID: PMC11539620 DOI: 10.1186/s13287-024-04008-4] [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: 07/31/2024] [Accepted: 10/22/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Hematopoiesis within the bone marrow (BM) is a complex and tightly regulated process predominantly influenced by immune factors. Aging, diabetes, and obesity are significant contributors to BM niche damage, which can alter hematopoiesis and lead to the development of clonal hematopoiesis of intermediate potential (CHIP). Genetic/epigenetic alterations during aging could influence BM niche reorganization for hematopoiesis or clonal hematopoiesis. CHIP is driven by mutations in genes such as Tet2, Dnmt3a, Asxl1, and Jak2, which are associated with age-related hematological malignancies. OBJECTIVE This literature review aims to provide an updated exploration of the functional aspects of BM niche cells within the hematopoietic microenvironment in the context of age-related hematological malignancies. The review specifically focuses on how immunological stressors modulate different signaling pathways that impact hematopoiesis. METHODS An extensive review of recent studies was conducted, examining the roles of various BM niche cells in hematopoietic stem cell (HSC) trafficking and the development of age-related hematological malignancies. Emphasis was placed on understanding the influence of immunological stressors on these processes. RESULTS Recent findings reveal a significant microheterogeneity and temporal stochasticity of niche cells across the BM during hematopoiesis. These studies demonstrate that niche cells, including mesenchymal stem cells, osteoblasts, and endothelial cells, exhibit dynamic interactions with HSCs, significantly influenced by the BM microenvironment as the age increases. Immunosurveillance plays a crucial role in maintaining hematopoietic homeostasis, with alterations in immune signaling pathways contributing to the onset of hematological malignancies. Novel insights into the interaction between niche cells and HSCs under stress/aging conditions highlight the importance of niche plasticity and adaptability. CONCLUSION The involvement of age-induced genetic/epigenetic alterations in BM niche cells and immunological stressors in hematopoiesis is crucial for understanding the development of age-related hematological malignancies. This comprehensive review provides new insights into the complex interplay between niche cells and HSCs, emphasizing the potential for novel therapeutic approaches that target niche cell functionality and resilience to improve hematopoietic outcomes in the context of aging and metabolic disorders. NOVELTY STATEMENT This review introduces novel concepts regarding the plasticity and adaptability of BM niche cells in response to immunological stressors and epigenetics. It proposes that targeted therapeutic strategies aimed at enhancing niche cell resilience could mitigate the adverse effects of aging, diabetes, and obesity on hematopoiesis and clonal hematopoiesis. Additionally, the review suggests that understanding the precise temporal and spatial dynamics of niche-HSC interactions and epigenetics influence may lead to innovative treatments for age-related hematological malignancies.
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Affiliation(s)
- Yang Xinyi
- Department of Oncology, 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
| | - Reshetov Igor Vladimirovich
- Department of Oncology, 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
| | - Narasimha M Beeraka
- 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.
- 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 Studies in Molecular Biology, Faculty of Science and Technology, University of Mysore, Mysore, Karnataka, 570006, India.
| | - Allaka Satyavathi
- Department of Chemistry, Faculty of science, Dr B R Ambedkar Open University, Wanaparthy, Telangana, 509103, India
| | - Dinisha Kamble
- 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
| | - 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
| | - Allaka Naga Lakshmi
- Department of Computer Science, St Philomena's College (Autonomous), Bangalore - Mysore Rd, Bannimantap, Mysuru, Karnataka, 570015, India
| | - Basappa Basappa
- Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore, Karnataka, 570006, India
| | - Padmanabha Reddy Y
- Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapuramu, Chiyyedu, Andhra Pradesh, 515721, India
| | - Ruitai Fan
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450000, China.
| | - Junqi Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450000, China
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Quarato ER, Salama NA, Calvi LM. Interplay Between Skeletal and Hematopoietic Cells in the Bone Marrow Microenvironment in Homeostasis and Aging. Curr Osteoporos Rep 2024; 22:416-432. [PMID: 38782850 DOI: 10.1007/s11914-024-00874-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/05/2024] [Indexed: 05/25/2024]
Abstract
PURPOSE OF THE REVIEW In this review, we discuss the most recent scientific advances on the reciprocal regulatory interactions between the skeletal and hematopoietic stem cell niche, focusing on immunomodulation and its interplay with the cell's mitochondrial function, and how this impacts osteoimmune health during aging and disease. RECENT FINDINGS Osteoimmunology investigates interactions between cells that make up the skeletal stem cell niche and immune system. Much work has investigated the complexity of the bone marrow microenvironment with respect to the skeletal and hematopoietic stem cells that regulate skeletal formation and immune health respectively. It has now become clear that these cellular components cooperate to maintain homeostasis and that dysfunction in their interaction can lead to aging and disease. Having a deeper, mechanistic appreciation for osteoimmune regulation will lead to better research perspective and therapeutics with the potential to improve the aging process, skeletal and hematologic regeneration, and disease targeting.
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Affiliation(s)
- Emily R Quarato
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, USA.
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
| | - Noah A Salama
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.
| | - Laura M Calvi
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
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10
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Okamoto K. Crosstalk between bone and the immune system. J Bone Miner Metab 2024; 42:470-480. [PMID: 39060500 DOI: 10.1007/s00774-024-01539-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024]
Abstract
Bone functions not only as a critical element of the musculoskeletal system but also serves as the primary lymphoid organ harboring hematopoietic stem cells (HSCs) and immune progenitor cells. The interdisciplinary field of osteoimmunology has illuminated the dynamic interactions between the skeletal and immune systems, vital for the maintenance of skeletal tissue homeostasis and the pathogenesis of immune and skeletal diseases. Aberrant immune activation stimulates bone cells such as osteoclasts and osteoblasts, disturbing the bone remodeling and leading to skeletal disorders as seen in autoimmune diseases like rheumatoid arthritis. On the other hand, intricate multicellular network within the bone marrow creates a specialized microenvironment essential for the maintenance and differentiation of HSCs and the progeny. Dysregulation of immune-bone crosstalk in the bone marrow environment can trigger tumorigenesis and exacerbated inflammation. A comprehensive deciphering of the complex "immune-bone crosstalk" leads to a deeper understanding of the pathogenesis of immune diseases as well as skeletal diseases, and might provide insight into potential therapeutic approaches.
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Affiliation(s)
- Kazuo Okamoto
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
- Division of Immune Environment Dynamics, Cancer Research Institute, Kanazawa University, Kakuma-Machi, Kanazawa, 920-1192, Japan.
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11
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Martinez LM, Guzman ML. Understanding the interaction between leukaemia stem cells and their microenvironment to improve therapeutic approaches. Br J Pharmacol 2024; 181:273-282. [PMID: 37309573 DOI: 10.1111/bph.16162] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/21/2023] [Accepted: 06/02/2023] [Indexed: 06/14/2023] Open
Abstract
Although chemotherapeutic regimens can eliminate blasts in leukaemia patients, such therapies are associated with toxicity and often fail to eliminate all malignant cells resulting in disease relapse. Disease relapse has been attributed to the persistence of leukaemia cells in the bone marrow (BM) with the capacity to recapitulate disease; these cells are often referred to as leukaemia stem cells (LSCs). Although LSCs have distinct characteristics in terms of pathobiology and immunophenotype, they are still regulated by their interactions with the surrounding microenvironment. Thus, understanding the interaction between LSCs and their microenvironment is critical to identify effective therapies. To this end, there are numerous efforts to develop models to study such interactions. In this review, we will focus on the reciprocal interactions between LSCs and their milieu in the BM. Furthermore, we will highlight relevant therapies targeting these interactions and discuss some of the promising in vitro models designed to mimic such relationship. LINKED ARTICLES: This article is part of a themed issue on Cancer Microenvironment and Pharmacological Interventions. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.2/issuetoc.
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Affiliation(s)
- Leandro M Martinez
- Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York, USA
| | - Monica L Guzman
- Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York, USA
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12
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Sarachakov A, Varlamova A, Svekolkin V, Polyakova M, Valencia I, Unkenholz C, Pannellini T, Galkin I, Ovcharov P, Tabakov D, Postovalova E, Shin N, Sethi I, Bagaev A, Itkin T, Crane G, Kluk M, Geyer J, Inghirami G, Patel S. Spatial mapping of human hematopoiesis at single-cell resolution reveals aging-associated topographic remodeling. Blood 2023; 142:2282-2295. [PMID: 37774374 DOI: 10.1182/blood.2023021280] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 09/26/2023] [Accepted: 09/27/2023] [Indexed: 10/01/2023] Open
Abstract
ABSTRACT The spatial anatomy of hematopoiesis in the bone marrow (BM) has been extensively studied in mice and other preclinical models, but technical challenges have precluded a commensurate exploration in humans. Institutional pathology archives contain thousands of paraffinized BM core biopsy tissue specimens, providing a rich resource for studying the intact human BM topography in a variety of physiologic states. Thus, we developed an end-to-end pipeline involving multiparameter whole tissue staining, in situ imaging at single-cell resolution, and artificial intelligence-based digital whole slide image analysis and then applied it to a cohort of disease-free samples to survey alterations in the hematopoietic topography associated with aging. Our data indicate heterogeneity in marrow adipose tissue (MAT) content within each age group and an inverse correlation between MAT content and proportions of early myeloid and erythroid precursors, irrespective of age. We identify consistent endosteal and perivascular positioning of hematopoietic stem and progenitor cells (HSPCs) with medullary localization of more differentiated elements and, importantly, uncover new evidence of aging-associated changes in cellular and vascular morphologies, microarchitectural alterations suggestive of foci with increased lymphocytes, and diminution of a potentially active megakaryocytic niche. Overall, our findings suggest that there is topographic remodeling of human hematopoiesis associated with aging. More generally, we demonstrate the potential to deeply unravel the spatial biology of normal and pathologic human BM states using intact archival tissue specimens.
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Affiliation(s)
| | | | | | | | - Itzel Valencia
- Multiparametric In Situ Imaging Laboratory, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
| | - Caitlin Unkenholz
- Multiparametric In Situ Imaging Laboratory, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
| | - Tania Pannellini
- Multiparametric In Situ Imaging Laboratory, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
| | | | | | | | | | | | | | | | - Tomer Itkin
- Division of Regenerative Medicine, Department of Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Weill Cornell Medicine, New York, NY
| | - Genevieve Crane
- Department of Laboratory Medicine, Cleveland Clinic, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland, OH
| | - Michael Kluk
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine/NewYork-Presbyterian Hospital, New York, NY
| | - Julia Geyer
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine/NewYork-Presbyterian Hospital, New York, NY
| | - Giorgio Inghirami
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine/NewYork-Presbyterian Hospital, New York, NY
| | - Sanjay Patel
- Multiparametric In Situ Imaging Laboratory, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine/NewYork-Presbyterian Hospital, New York, NY
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13
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Ussishkin N, Nachmani D. A Bloody Feast-Nutritional Regulation of Hematopoiesis. Exp Hematol 2023; 127:1-7. [PMID: 37582454 DOI: 10.1016/j.exphem.2023.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 07/31/2023] [Accepted: 08/07/2023] [Indexed: 08/17/2023]
Abstract
Hematopoietic stem cells provide us with a lifelong supply of blood cells. Hence, their proper function is absolutely essential for life, and their dysfunction can lead to infectious and malignant diseases. These cells have specific metabolic requirements to enable their lifelong function and blood-producing capacity. With the words of the Roman poet Juvenal "a healthy mind in a healthy body" in mind, it is intriguing to understand the connection between our daily diet and the quality of our blood, with the hope that through specific dietary adjustments we can improve our hematopoietic stem cell function and prevent disease. Nowadays, dietary supplements are an expanding market filled with potential and promises for better health. However, the link between many of those supplements and human physiology is obscure. Several groups have begun to shed light on this by investigating the metabolic regulation of hematopoiesis by specific nutrients. Beyond the link to dietary supplementation, these studies have also significantly improved our understanding of basic hematopoietic stem cell biology. Herein we summarize recent knowledge on the effect of specific vitamins and amino acids, which might be considered as dietary supplements, on normal hematopoiesis and hematopoietic stem cell function. We propose that improving our understanding of the link between nutrition in general and blood physiology can ultimately lead to the optimization of health-care policies, protocols, and standards of care.
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Affiliation(s)
- Noga Ussishkin
- Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, Israel
| | - Daphna Nachmani
- Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, Israel.
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14
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Pereira RS, Kumar R, Cais A, Paulini L, Kahler A, Bravo J, Minciacchi VR, Krack T, Kowarz E, Zanetti C, Godavarthy PS, Hoeller F, Llavona P, Stark T, Tascher G, Nowak D, Meduri E, Huntly BJP, Münch C, Pampaloni F, Marschalek R, Krause DS. Distinct and targetable role of calcium-sensing receptor in leukaemia. Nat Commun 2023; 14:6242. [PMID: 37802982 PMCID: PMC10558580 DOI: 10.1038/s41467-023-41770-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 09/12/2023] [Indexed: 10/08/2023] Open
Abstract
Haematopoietic stem cells (HSC) reside in the bone marrow microenvironment (BMM), where they respond to extracellular calcium [eCa2+] via the G-protein coupled calcium-sensing receptor (CaSR). Here we show that a calcium gradient exists in this BMM, and that [eCa2+] and response to [eCa2+] differ between leukaemias. CaSR influences the location of MLL-AF9+ acute myeloid leukaemia (AML) cells within this niche and differentially impacts MLL-AF9+ AML versus BCR-ABL1+ leukaemias. Deficiency of CaSR reduces AML leukaemic stem cells (LSC) 6.5-fold. CaSR interacts with filamin A, a crosslinker of actin filaments, affects stemness-associated factors and modulates pERK, β-catenin and c-MYC signaling and intracellular levels of [Ca2+] in MLL-AF9+ AML cells. Combination treatment of cytarabine plus CaSR-inhibition in various models may be superior to cytarabine alone. Our studies suggest CaSR to be a differential and targetable factor in leukaemia progression influencing self-renewal of AML LSC via [eCa2+] cues from the BMM.
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Affiliation(s)
- Raquel S Pereira
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany
| | - Rahul Kumar
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany
| | - Alessia Cais
- Pediatric Neurooncology, Hopp Children's Cancer Center Heidelberg (KiTZ) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Lara Paulini
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany
| | - Alisa Kahler
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany
| | - Jimena Bravo
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany
| | - Valentina R Minciacchi
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany
| | - Theresa Krack
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany
| | - Eric Kowarz
- Institute of Pharmaceutical Biology, Goethe University, Frankfurt am Main, Germany
| | - Costanza Zanetti
- University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | | | - Fabian Hoeller
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany
| | - Pablo Llavona
- Institute of Molecular Biology gGmbH (IMB), Mainz, Germany
| | - Tabea Stark
- Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany
| | - Georg Tascher
- Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany
| | - Daniel Nowak
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Eshwar Meduri
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Brian J P Huntly
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Christian Münch
- Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany
| | - Francesco Pampaloni
- Buchmann Institute for Molecular Life Sciences (BMLS, CEF-MC), Goethe University, Frankfurt am Main, Germany
| | - Rolf Marschalek
- Institute of Pharmaceutical Biology, Goethe University, Frankfurt am Main, Germany
| | - Daniela S Krause
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
- Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany.
- Institute of General Pharmacology and Toxicology, Goethe-University, Frankfurt am Main, Germany.
- German Cancer Research Center (DKFZ), Heidelberg, Germany.
- German Cancer Consortium (DKTK), Heidelberg, Germany.
- Frankfurt Cancer Institute, Frankfurt, Germany.
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15
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Mass E, Nimmerjahn F, Kierdorf K, Schlitzer A. Tissue-specific macrophages: how they develop and choreograph tissue biology. Nat Rev Immunol 2023; 23:563-579. [PMID: 36922638 PMCID: PMC10017071 DOI: 10.1038/s41577-023-00848-y] [Citation(s) in RCA: 229] [Impact Index Per Article: 114.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2023] [Indexed: 03/17/2023]
Abstract
Macrophages are innate immune cells that form a 3D network in all our tissues, where they phagocytose dying cells and cell debris, immune complexes, bacteria and other waste products. Simultaneously, they produce growth factors and signalling molecules - such activities not only promote host protection in response to invading microorganisms but are also crucial for organ development and homeostasis. There is mounting evidence of macrophages orchestrating fundamental physiological processes, such as blood vessel formation, adipogenesis, metabolism and central and peripheral neuronal function. In parallel, novel methodologies have led to the characterization of tissue-specific macrophages, with distinct subpopulations of these cells showing different developmental trajectories, transcriptional programmes and life cycles. Here, we summarize our growing knowledge of macrophage diversity and how macrophage subsets orchestrate tissue development and function. We further interrelate macrophage ontogeny with their core functions across tissues, that is, the signalling events within the macrophage niche that may control organ functionality during development, homeostasis and ageing. Finally, we highlight the open questions that will need to be addressed by future studies to better understand the tissue-specific functions of distinct macrophage subsets.
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Affiliation(s)
- Elvira Mass
- Developmental Biology of the Immune System, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
| | - Falk Nimmerjahn
- Division of Genetics, Department of Biology, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Katrin Kierdorf
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
- Centre for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Andreas Schlitzer
- Quantitative Systems Biology, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
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16
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Grockowiak E, Korn C, Rak J, Lysenko V, Hallou A, Panvini FM, Williams M, Fielding C, Fang Z, Khatib-Massalha E, García-García A, Li J, Khorshed RA, González-Antón S, Baxter EJ, Kusumbe A, Wilkins BS, Green A, Simons BD, Harrison CN, Green AR, Lo Celso C, Theocharides APA, Méndez-Ferrer S. Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms. NATURE CANCER 2023; 4:1193-1209. [PMID: 37550517 PMCID: PMC10447237 DOI: 10.1038/s43018-023-00607-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 06/27/2023] [Indexed: 08/09/2023]
Abstract
Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver.
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Affiliation(s)
- Elodie Grockowiak
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Claudia Korn
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Justyna Rak
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Veronika Lysenko
- Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland
| | - Adrien Hallou
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
- Wellcome Trust-CRUK Gurdon Institute, University of Cambridge, Cambridge, UK
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
- Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK
| | - Francesca M Panvini
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Matthew Williams
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Claire Fielding
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Zijian Fang
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Eman Khatib-Massalha
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Andrés García-García
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Juan Li
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Reema A Khorshed
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, UK
- The Sir Francis Crick Institute, London, UK
| | - Sara González-Antón
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, UK
- The Sir Francis Crick Institute, London, UK
| | - E Joanna Baxter
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
| | - Anjali Kusumbe
- The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | | | - Anna Green
- Guy's and Saint Thomas' NHS Foundation Trust, London, UK
| | - Benjamin D Simons
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
- Wellcome Trust-CRUK Gurdon Institute, University of Cambridge, Cambridge, UK
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
- Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK
| | | | - Anthony R Green
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Cristina Lo Celso
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, UK
- The Sir Francis Crick Institute, London, UK
| | - Alexandre P A Theocharides
- Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland
| | - Simón Méndez-Ferrer
- National Health Service Blood and Transplant, Cambridge, UK.
- Department of Haematology, University of Cambridge, Cambridge, UK.
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
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17
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Feng J, Liu J, Wang Y, Diao J, Kuang Y, Zhao N. Beta-TCP scaffolds with rationally designed macro-micro hierarchical structure improved angio/osteo-genesis capability for bone regeneration. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2023; 34:36. [PMID: 37486393 PMCID: PMC10366319 DOI: 10.1007/s10856-023-06733-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 05/08/2023] [Indexed: 07/25/2023]
Abstract
The design of hierarchical porous structure in scaffolds is crucial for bone defect regenerative repair. However, bioceramic materials present a challenge in precisely constructing designed micropores owing to the limitation of forming process. To investigate micropore shape influences bone regeneration in bioceramic scaffolds with macropores, hierarchical porous scaffolds with interconnective macropores (~400 μm) and two types of micropores (spherical and fibrous) were prepared using a combination of direct ink writing (DIW) and template sacrifice methods. Compared to the scaffold with spherical micropores, the scaffold with highly interconnected fibrous micropores significantly improved cell adhesion and upregulated osteogenic and angiogenetic-related gene expression in mBMSCs and HUVECs, respectively. Furthermore, in vivo implantation experiments showed that hierarchical scaffolds with fibrous micropores accelerated the bone repair process significantly. This result can be attributed to the high interconnectivity of fibrous micropores, which promotes the transportation of nutrients and waste during bone regeneration. Our work demonstrates that hierarchical porous scaffold design, especially one with a fibrous micropore structure, is a promising strategy for improving the bone regeneration performance of bioceramic scaffolds.
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Affiliation(s)
- Jianlang Feng
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510641, PR China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, PR China
- NMPA Key Laboratory for Research and Evaluation of Innovative Biomaterials for Medical Devices, Guangzhou, 510006, PR China
| | - Junjie Liu
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510641, PR China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, PR China
- NMPA Key Laboratory for Research and Evaluation of Innovative Biomaterials for Medical Devices, Guangzhou, 510006, PR China
| | - Yingqu Wang
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, PR China
| | - Jingjing Diao
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, PR China
- Medical Devices Research & Testing Center of SCUT, Guangzhou, 510006, PR China
| | - Yudi Kuang
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, PR China.
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 511442, PR China.
- Guangdong Institute of Advanced Biomaterials and Medical Devices, Guangzhou, 510535, PR China.
| | - Naru Zhao
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510641, PR China.
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, PR China.
- NMPA Key Laboratory for Research and Evaluation of Innovative Biomaterials for Medical Devices, Guangzhou, 510006, PR China.
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18
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Herd CL, Mellet J, Mashingaidze T, Durandt C, Pepper MS. Consequences of HIV infection in the bone marrow niche. Front Immunol 2023; 14:1163012. [PMID: 37497228 PMCID: PMC10366613 DOI: 10.3389/fimmu.2023.1163012] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 06/21/2023] [Indexed: 07/28/2023] Open
Abstract
Dysregulation of the bone marrow niche resulting from the direct and indirect effects of HIV infection contributes to haematological abnormalities observed in HIV patients. The bone marrow niche is a complex, multicellular environment which functions primarily in the maintenance of haematopoietic stem/progenitor cells (HSPCs). These adult stem cells are responsible for replacing blood and immune cells over the course of a lifetime. Cells of the bone marrow niche support HSPCs and help to orchestrate the quiescence, self-renewal and differentiation of HSPCs through chemical and molecular signals and cell-cell interactions. This narrative review discusses the HIV-associated dysregulation of the bone marrow niche, as well as the susceptibility of HSPCs to infection by HIV.
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19
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Rothzerg E, Erber WN, Gibbons CLMH, Wood D, Xu J. Osteohematology: To be or Notch to be. J Cell Physiol 2023. [PMID: 37269472 DOI: 10.1002/jcp.31042] [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: 02/23/2023] [Revised: 04/08/2023] [Accepted: 05/06/2023] [Indexed: 06/05/2023]
Abstract
Osteohematology is an emerging research field that studies the crosstalk between hematopoietic and bone stromal cells, to elucidate the mechanisms of hematological and skeletal malignancies and diseases. The Notch is an evolutionary conserved developmental signaling pathway, with critical roles in embryonic development by controlling cell proliferation and differentiation. However, the Notch pathway is also critically involved in cancer initiation and progression, such as osteosarcoma, leukemia, and multiple myeloma. The Notch-mediated malignant cells dysregulate bone and bone marrow cells in the tumour microenvironment, resulting in disorders ranging from osteoporosis to bone marrow dysfunction. To date, the complex interplay of Notch signaling molecules in hematopoietic and bone stromal cells is still poorly understood. In this mini-review, we summarize the crosstalk between cells in bone and bone marrow and their influence under the Notch signaling pathway in physiological conditions and in tumour microenvironment.
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Affiliation(s)
- Emel Rothzerg
- School of Biomedical Sciences, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Wendy N Erber
- School of Biomedical Sciences, The University of Western Australia, Nedlands, Western Australia, Australia
- PathWest Laboratory Medicine, Nedlands, Western Australia, Australia
| | - Christopher L M H Gibbons
- Orthopaedics Oncology, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Trust, Oxford, UK
| | - David Wood
- Medical School, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Jiake Xu
- School of Biomedical Sciences, The University of Western Australia, Nedlands, Western Australia, Australia
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20
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Xu S, Hu A, Chen J, Shuai Z, Liu T, Deng J, Li L, Gong Q, He Z, Yu L. The role of calcium-sensing receptor in ginsenoside Rg1 promoting reendothelialization to inhibit intimal hyperplasia after balloon injury. Biomed Pharmacother 2023; 163:114843. [PMID: 37201261 DOI: 10.1016/j.biopha.2023.114843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/25/2023] [Accepted: 05/04/2023] [Indexed: 05/20/2023] Open
Abstract
Calcium-sensing receptor (CaSR) is a G protein-coupled receptor, widely distributed in various tissues, including vascular endothelial cells and smooth muscle cells, which plays an important role in the migration and homing of stem/progenitor cells and the proliferation of tissue cells. Restenosis after Percutaneous coronary intervention (PCI) seriously affects its prognosis and application. Our previous research has found that ginsenoside Rg1 (GS-Rg1) can inhibit the occurrence of restenosis after balloon injury of the common carotid artery in rats, but the mechanism is still unclear. In this study, it was found that GS-Rg1 (4, 8, 16 mg/kg) inhibited vascular restenosis caused by balloon injury, and mobilize endothelial progenitor cells (EPCs) to promote reendothelialization and inhibit intimal hyperplasia, which significantly reduced after administration of CaSR antagonist NPS 2143. Interestingly, CaSR and its downstream JNK, P38 were highly expressed in the proliferative intima and participated in the abnormal proliferation of vascular smooth muscle cells mediated by smooth muscle progenitor cells (SMPCs). GS-Rg1 inhibited intimal hyperplasia, while it decreased the expression of CaSR, JNK, and P38. This might relate to the distribution of CaSR and the facilitation of GS-Rg1 on the vascular endothelial repair. It is concluded that CaSR plays a key role in GS-Rg1 promoting reendothelialization to inhibit intimal hyperplasia after balloon Injury.
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Affiliation(s)
- Shangfu Xu
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China; Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China; Collaborative Innovation Center of Chinese Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China.
| | - Anling Hu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou 550014, China
| | - Jiameng Chen
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China; Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Zhiqin Shuai
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China; Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Taotao Liu
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China; Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Jiang Deng
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Lisheng Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Qihai Gong
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Zhixu He
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China; Collaborative Innovation Center of Chinese Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China.
| | - Limei Yu
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China; Collaborative Innovation Center of Chinese Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China.
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21
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Zhan Q, Wang J, Zhang H, Zhang L. E3 ubiquitin ligase on the biological properties of hematopoietic stem cell. J Mol Med (Berl) 2023; 101:543-556. [PMID: 37081103 PMCID: PMC10163092 DOI: 10.1007/s00109-023-02315-6] [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: 11/08/2022] [Revised: 02/25/2023] [Accepted: 03/30/2023] [Indexed: 04/22/2023]
Abstract
Hematopoietic stem cells are a group of heterogeneity cells with the potential to differentiate into various types of mature blood cells. Their basic biological properties include quiescence, self-renewal, multilineage differentiation, and homing ability, with the homing of exogenous hematopoietic stem cells after transplantation becoming a new focus, while the first three properties share some similarity in mechanism due to connectivity. In various complex mechanisms, the role of E3 ubiquitin ligases in hematopoietic homeostasis and malignant transformation is receiving increasing attention. As a unique part, E3 ubiquitin ligases play an important role in physiological regulation mechanism of posttranslational modification. In this review, we focus on the recent progress of the crucial role of E3 ubiquitin ligases that target specific proteins for ubiquitination to regulate biological properties of hematopoietic stem cells. Additionally, this paper deals with E3 ubiquitin ligases that affect the biological properties through aging and summarizes the relevant applications of targeting E3 ligases in hematopoietic malignancies. We present some ideas on the clinical application of E3 ubiquitin ligase to regulate hematopoietic stem cells and also believe that it is meaningful to study the upstream signal of these E3 ubiquitin ligases because hematopoietic stem cell dysfunction is caused by deficiency of some E3 ligases.
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Affiliation(s)
- Qianru Zhan
- Department of Hematology, The First Hospital of China Medical University, No. 155, Nanjing North Street, Shenyang, Liaoning, People's Republic of China
| | - Jing Wang
- Department of Hematology, The First Hospital of China Medical University, No. 155, Nanjing North Street, Shenyang, Liaoning, People's Republic of China
| | - Heyang Zhang
- Department of Hematology, The First Hospital of China Medical University, No. 155, Nanjing North Street, Shenyang, Liaoning, People's Republic of China.
| | - Lijun Zhang
- Department of Hematology, The First Hospital of China Medical University, No. 155, Nanjing North Street, Shenyang, Liaoning, People's Republic of China.
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22
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Dausinas Ni P, Hartman M, Slack J, Basile C, Liu S, Wan J, O'Leary HA. Novel differential calcium regulation of hematopoietic stem and progenitor cells under physiological low oxygen conditions. J Cell Physiol 2023. [PMID: 37051890 DOI: 10.1002/jcp.30942] [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: 03/14/2022] [Revised: 11/28/2022] [Accepted: 12/23/2022] [Indexed: 04/14/2023]
Abstract
Low oxygen bone marrow (BM) niches (~1%-4% low O2 ) provide critical signals for hematopoietic stem/progenitor cells (HSC/HSPCs). Our presented data are the first to investigate live, sorted HSC/HSPCs in their native low O2 conditions. Transcriptional and proteomic analysis uncovered differential Ca2+ regulation that correlated with overlapping phenotypic populations consisting of robust increases of cytosolic and mitochondrial Ca2+ , ABC transporter (ABCG2) expression and sodium/hydrogen exchanger (NHE1) expression in live, HSC/HSPCs remaining in constant low O2. We identified a novel Ca2+ high population in HSPCs predominantly detected in low O2 that displayed enhanced frequency of phenotypic LSK/LSKCD150 in low O2 replating assays compared to Ca2+ low populations. Inhibition of the Ca2+ regulator NHE1 (Cariporide) resulted in attenuation of both the low O2 induced Ca2+ high population and subsequent enhanced maintenance of phenotypic LSK and LSKCD150 during low O2 replating. These data reveal multiple levels of differential Ca2+ regulation in low O2 resulting in phenotypic, signaling, and functional consequences in HSC/HSPCs.
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Affiliation(s)
- Paige Dausinas Ni
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Melissa Hartman
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jacob Slack
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Christopher Basile
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Sheng Liu
- Department of Medical and Molecular Genetics, Center of Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jun Wan
- Department of Medical and Molecular Genetics, Center of Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Heather A O'Leary
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
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23
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Zhang H, Liesveld JL, Calvi LM, Lipe BC, Xing L, Becker MW, Schwarz EM, Yeh SCA. The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies. Bone Res 2023; 11:15. [PMID: 36918531 PMCID: PMC10014945 DOI: 10.1038/s41413-023-00249-w] [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: 08/01/2022] [Revised: 12/24/2022] [Accepted: 01/26/2023] [Indexed: 03/16/2023] Open
Abstract
Prior research establishing that bone interacts in coordination with the bone marrow microenvironment (BMME) to regulate hematopoietic homeostasis was largely based on analyses of individual bone-associated cell populations. Recent advances in intravital imaging has suggested that the expansion of hematopoietic stem cells (HSCs) and acute myeloid leukemia cells is restricted to bone marrow microdomains during a distinct stage of bone remodeling. These findings indicate that dynamic bone remodeling likely imposes additional heterogeneity within the BMME to yield differential clonal responses. A holistic understanding of the role of bone remodeling in regulating the stem cell niche and how these interactions are altered in age-related hematological malignancies will be critical to the development of novel interventions. To advance this understanding, herein, we provide a synopsis of the cellular and molecular constituents that participate in bone turnover and their known connections to the hematopoietic compartment. Specifically, we elaborate on the coupling between bone remodeling and the BMME in homeostasis and age-related hematological malignancies and after treatment with bone-targeting approaches. We then discuss unresolved questions and ambiguities that remain in the field.
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Affiliation(s)
- Hengwei Zhang
- Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Ave, Box 665, Rochester, NY, 14642, USA.
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
| | - Jane L Liesveld
- Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine, Division of Hematology/Oncology and Bone Marrow Transplantation Program, University of Rochester Medical Center, Rochester, NY, USA
| | - Laura M Calvi
- Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine, Division of Endocrinology/Metabolism, University of Rochester Medical Center, Rochester, NY, USA
| | - Brea C Lipe
- Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine, Division of Hematology/Oncology and Bone Marrow Transplantation Program, University of Rochester Medical Center, Rochester, NY, USA
| | - Lianping Xing
- Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Ave, Box 665, Rochester, NY, 14642, USA
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Michael W Becker
- Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine, Division of Hematology/Oncology and Bone Marrow Transplantation Program, University of Rochester Medical Center, Rochester, NY, USA
| | - Edward M Schwarz
- Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Ave, Box 665, Rochester, NY, 14642, USA
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine, Division of Allergy/Immunology/Rheumatology, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
| | - Shu-Chi A Yeh
- Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Ave, Box 665, Rochester, NY, 14642, USA.
- Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA.
- Department of Physiology/Pharmacology, University of Rochester Medical Center, Rochester, NY, USA.
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24
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Hao D, Liu R, Fernandez TG, Pivetti C, Jackson JE, Kulubya ES, Jiang HJ, Ju HY, Liu WL, Panitch A, Lam KS, Leach JK, Farmer DL, Wang A. A bioactive material with dual integrin-targeting ligands regulates specific endogenous cell adhesion and promotes vascularized bone regeneration in adult and fetal bone defects. Bioact Mater 2023; 20:179-193. [PMID: 35663336 PMCID: PMC9160290 DOI: 10.1016/j.bioactmat.2022.05.027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 05/19/2022] [Accepted: 05/19/2022] [Indexed: 12/18/2022] Open
Abstract
Significant progress has been made in designing bone materials capable of directing endogenous cells to promote vascularized bone regeneration. However, current strategies lack regulation of the specific endogenous cell populations for vascularized bone regeneration, thus leading to adverse tissue formation and decreased regenerative efficiency. Here, we engineered a biomaterial to regulate endogenous cell adhesion and promote vascularized bone regeneration. The biomaterial works by presenting two synthetic ligands, LLP2A and LXW7, explicitly targeting integrins α4β1 and αvβ3, respectively, expressed on the surfaces of the cells related to bone formation and vascularization, such as mesenchymal stem cells (MSCs), osteoblasts, endothelial progenitor cells (EPCs), and endothelial cells (ECs). In vitro, the LLP2A/LXW7 modified biomaterial improved the adhesion of MSCs, osteoblasts, EPCs, and ECs via integrin α4β1 and αvβ3, respectively. In an adult rat calvarial bone defect model, the LLP2A/LXW7 modified biomaterial enhanced bone formation and vascularization by synergistically regulating endogenous cells with osteogenic and angiogenic potentials, such as DLX5+ cells, osteocalcin+ cells, CD34+/CD45- cells and CD31+ cells. In a fetal sheep spinal bone defect model, the LLP2A/LXW7 modified biomaterial augmented bone formation and vascularization without any adverse effects. This innovative biomaterial offers an off-the-shelf, easy-to-use, and biologically safe product suitable for vascularized bone regeneration in both fetal and adult disease environments.
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Affiliation(s)
- Dake Hao
- Department of Surgery, School of Medicine, University of California Davis, Sacramento, CA, 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA, 95817, United States
| | - Ruiwu Liu
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA, 95817, United States
| | - Tomas Gonzalez Fernandez
- Department of Biomedical Engineering, University of California Davis, Davis, CA, 95616, United States
| | - Christopher Pivetti
- Department of Surgery, School of Medicine, University of California Davis, Sacramento, CA, 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA, 95817, United States
| | - Jordan Elizabeth Jackson
- Department of Surgery, School of Medicine, University of California Davis, Sacramento, CA, 95817, United States
| | - Edwin Samuel Kulubya
- Department of Surgery, School of Medicine, University of California Davis, Sacramento, CA, 95817, United States
| | - Hong-Jiang Jiang
- Wendeng Orthopaedic Hospital, No. 1 Fengshan Road, Wendeng, 264400, Shandong, China
| | - Hai-Yang Ju
- Wendeng Orthopaedic Hospital, No. 1 Fengshan Road, Wendeng, 264400, Shandong, China
| | - Wen-Liang Liu
- Wendeng Orthopaedic Hospital, No. 1 Fengshan Road, Wendeng, 264400, Shandong, China
| | - Alyssa Panitch
- Department of Surgery, School of Medicine, University of California Davis, Sacramento, CA, 95817, United States
- Department of Biomedical Engineering, University of California Davis, Davis, CA, 95616, United States
| | - Kit S. Lam
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA, 95817, United States
| | - J. Kent Leach
- Department of Orthopaedic Surgery, School of Medicine, University of California Davis, Sacramento, CA, 95817, United States
| | - Diana L. Farmer
- Department of Surgery, School of Medicine, University of California Davis, Sacramento, CA, 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA, 95817, United States
| | - Aijun Wang
- Department of Surgery, School of Medicine, University of California Davis, Sacramento, CA, 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA, 95817, United States
- Department of Biomedical Engineering, University of California Davis, Davis, CA, 95616, United States
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25
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Guo B, Huang X, Chen Y, Broxmeyer HE. Ex Vivo Expansion and Homing of Human Cord Blood Hematopoietic Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1442:85-104. [PMID: 38228960 DOI: 10.1007/978-981-99-7471-9_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
Cord blood (CB) has been proven to be an alternative source of haematopoietic stem cells (HSCs) for clinical transplantation and has multiple advantages, including but not limited to greater HLA compatibility, lower incidence of graft-versus-host disease (GvHD), higher survival rates and lower relapse rates among patients with minimal residual disease. However, the limited number of HSCs in a single CB unit limits the wider use of CB in clinical treatment. Many efforts have been made to enhance the efficacy of CB HSC transplantation, particularly by ex vivo expansion or enhancing the homing efficiency of HSCs. In this chapter, we will document the major advances regarding human HSC ex vivo expansion and homing and will also discuss the possibility of clinical translation of such laboratory work.
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Affiliation(s)
- Bin Guo
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Xinxin Huang
- Xuhui Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
| | - Yandan Chen
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hal E Broxmeyer
- Department of Microbiology and Immunology, School of Medicine, Indiana University, Indianapolis, IN, USA.
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26
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Zhang W, Wang Y, Zhong F, Wang X, Sucher R, Lin CH, Brandacher G, Solari MG, Gorantla VS, Zheng XX. Donor derived hematopoietic stem cell niche transplantation facilitates mixed chimerism mediated donor specific tolerance. Front Immunol 2023; 14:1093302. [PMID: 36875068 PMCID: PMC9978155 DOI: 10.3389/fimmu.2023.1093302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 02/08/2023] [Indexed: 02/18/2023] Open
Abstract
Compelling experimental evidence confirms that the robustness and longevity of mixed chimerism (MC) relies on the persistence and availability of donor-derived hematopoietic stem cell (HSC) niches in recipients. Based on our prior work in rodent vascularized composite allotransplantation (VCA) models, we hypothesize that the vascularized bone components in VCA bearing donor HSC niches, thus may provide a unique biologic opportunity to facilitate stable MC and transplant tolerance. In this study, by utilizing a series of rodent VCA models we demonstrated that donor HSC niches in the vascularized bone facilitate persistent multilineage hematopoietic chimerism in transplant recipients and promote donor-specific tolerance without harsh myeloablation. In addition, the transplanted donor HSC niches in VCA facilitated the donor HSC niches seeding to the recipient bone marrow compartment and contributed to the maintenance and homeostasis of stable MC. Moreover, this study provided evidences that chimeric thymus plays a role in MC-mediated transplant tolerance through a mechanism of thymic central deletion. Mechanistic insights from our study could lead to the use of vascularized donor bone with pre-engrafted HSC niches as a safe, complementary strategy to induce robust and stable MC-mediated tolerance in VCA or solid organ transplantation recipients.
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Affiliation(s)
- Wensheng Zhang
- Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Yong Wang
- Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Fushun Zhong
- Transplantation Medical Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xinghuan Wang
- Transplantation Medical Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Robert Sucher
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Cheng-Hung Lin
- Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan, Taiwan
| | - Gerald Brandacher
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Mario G Solari
- Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Vijay S Gorantla
- Departments of Surgery, Ophthalmology and Bioengineering, Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Xin Xiao Zheng
- Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Transplantation Medical Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
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27
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Bharti S, Anant PS, Kumar A. Nanotechnology in stem cell research and therapy. JOURNAL OF NANOPARTICLE RESEARCH 2023; 25:6. [DOI: 10.1007/s11051-022-05654-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 12/14/2022] [Indexed: 01/04/2025]
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28
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Jing P, Song X, Xiong L, Wang B, Wang Y, Wang L. Angelica sinensis polysaccharides prevents hematopoietic regression in D-Galactose-Induced aging model via attenuation of oxidative stress in hematopoietic microenvironment. Mol Biol Rep 2023; 50:121-132. [PMID: 36315330 DOI: 10.1007/s11033-022-07898-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 01/29/2023]
Abstract
BACKGROUND Extrinsic molecular mechanisms that regulate hematopoietic stem/progenitor cell (HSPC) aging are still poorly understood, and a potential protective medication needs to be explored. MATERIALS AND METHODS The senescent parameters of hematopoietic cells and bone marrow stromal cells (BMSCs) including cell cycle analysis, senescence-associated SA-β-gal staining and signals, hematopoietic factors and cellular junction were analyzed in femur and tibia of rats. Furthermore, Sca-1+ HSPCs and BMSCs co-culture system was established to evaluate the direct effects of BMSC feeder layer to HSPCs. Oxidative DNA damage indicators in Sca-1+ HSCs and senescence-associated secretory phenotype (SASP) of BMSCs, gap junction intercellular communication between BMSCs, osteogenesis/adipogenisis differentiation balance of BMSCs were detected. RESULTS In the D-gal pre-administrated rats, ASP treatment rescued senescence of hematopoietic cells and BMSCs, reserved CFU-GEMM; also, ASP treatment attenuated stromal oxidative load, ameliorated SCF, CXCL12, and GM-CSF production, increased Connexin-43 (Cx43) expression. BMSCs and Sca-1+ HSPCs co-cultivation demonstrated that ASP treatment prevented oxidative DNA damage response in co-cultured Sca-1+ HSPCs induced by D-gal pre-administration of feeder layer and the underlying mechanism may be related to ASP ameliorating feeder layer dysfunction due to D-gal induced senescence via inhibiting secretion of IL-1, IL-6, TNF-α, and RANTES, enhancing Cx43-mediated intercellular communication, improving Runx2 expression whereas decreasing PPARγ expression in BMSCs. CONCLUSION The antioxidant property of ASP may provide a stroma-mediated potential therapeutic strategy for HSPC aging.
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Affiliation(s)
- Pengwei Jing
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, 400016, Chongqing, China
| | - Xiaoying Song
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, 400016, Chongqing, China.,The People's Hospital of Jiajiang, 614100, Leshan, China
| | - Lirong Xiong
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, 400016, Chongqing, China
| | - Biyao Wang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, 400016, Chongqing, China
| | - Yaping Wang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, 400016, Chongqing, China.,Department of Histology and Embryology, Chongqing Medical University, 1# Yixueyuan Road, Yuzhong District, 400016, Chongqing, China
| | - Lu Wang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, 400016, Chongqing, China. .,Department of Histology and Embryology, Chongqing Medical University, 1# Yixueyuan Road, Yuzhong District, 400016, Chongqing, China.
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29
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Skelding KA, Barry DL, Theron DZ, Lincz LF. Bone Marrow Microenvironment as a Source of New Drug Targets for the Treatment of Acute Myeloid Leukaemia. Int J Mol Sci 2022; 24:563. [PMID: 36614005 PMCID: PMC9820412 DOI: 10.3390/ijms24010563] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/05/2022] [Accepted: 12/22/2022] [Indexed: 12/30/2022] Open
Abstract
Acute myeloid leukaemia (AML) is a heterogeneous disease with one of the worst survival rates of all cancers. The bone marrow microenvironment is increasingly being recognised as an important mediator of AML chemoresistance and relapse, supporting leukaemia stem cell survival through interactions among stromal, haematopoietic progenitor and leukaemic cells. Traditional therapies targeting leukaemic cells have failed to improve long term survival rates, and as such, the bone marrow niche has become a promising new source of potential therapeutic targets, particularly for relapsed and refractory AML. This review briefly discusses the role of the bone marrow microenvironment in AML development and progression, and as a source of novel therapeutic targets for AML. The main focus of this review is on drugs that modulate/target this bone marrow microenvironment and have been examined in in vivo models or clinically.
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Affiliation(s)
- Kathryn A. Skelding
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW 2308, Australia
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Daniel L. Barry
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW 2308, Australia
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Danielle Z. Theron
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW 2308, Australia
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Lisa F. Lincz
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- Hunter Hematology Research Group, Calvary Mater Newcastle Hospital, Waratah, NSW 2298, Australia
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Abstract
Osteoclasts are the only cells that can efficiently resorb bone. They do so by sealing themselves on to bone and removing the mineral and organic components. Osteoclasts are essential for bone homeostasis and are involved in the development of diseases associated with decreased bone mass, like osteoporosis, or abnormal bone turnover, like Paget's disease of bone. In addition, compromise of their development or resorbing machinery is pathogenic in multiple types of osteopetrosis. However, osteoclasts also have functions other than bone resorption. Like cells of the innate immune system, they are derived from myeloid precursors and retain multiple immune cell properties. In addition, there is now strong evidence that osteoclasts regulate osteoblasts through a process known as coupling, which coordinates rates of bone resorption and bone formation during bone remodeling. In this article we review the non-resorbing functions of osteoclasts and highlight their importance in health and disease.
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Affiliation(s)
- Kyung-Hyun Park-Min
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
| | - Joseph Lorenzo
- The Departments of Medicine and Orthopaedics, UConn Health, Farmington, CT 06030, USA.
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31
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Urao N, Liu J, Takahashi K, Ganesh G. Hematopoietic Stem Cells in Wound Healing Response. Adv Wound Care (New Rochelle) 2022; 11:598-621. [PMID: 34353116 PMCID: PMC9419985 DOI: 10.1089/wound.2021.0065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Significance: Emerging evidence has shown a link between the status of hematopoietic stem cells (HSCs) and wound healing responses. Thus, better understanding HSCs will contribute to further advances in wound healing research. Recent Advances: Myeloid cells such as neutrophils and monocyte-derived macrophages are critical players in the process of wound healing. HSCs actively respond to wound injury and other tissue insults, including infection and produce the effector myeloid cells, and a failing of the HSC response can result in impaired wound healing. Technological advances such as transcriptome at single-cell resolution, epigenetics, three-dimensional imaging, transgenic animals, and animal models, have provided novel concepts of myeloid generation (myelopoiesis) from HSCs, and have revealed cell-intrinsic and -extrinsic mechanisms that can impact HSC functions in the context of health conditions. Critical Issues: The newer concepts include-the programmed cellular fate at a differentiation stage that is used to be considered as the multilineage, the signaling pathways that can activate HSCs directly and indirectly, the mechanisms that can deteriorate HSCs, the roles and remodeling of the surrounding environment for HSCs and their progenitors (the niche). Future Directions: The researches on HSCs, which produce blood cells, should contribute to the development of blood biomarkers predicting a risk of chronic wounds, which may transform clinical practice of wound care with precision medicine for patients at high risk of poor healing.
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Affiliation(s)
- Norifumi Urao
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA.,Correspondence: Department of Pharmacology, State University of New York Upstate Medical University, 766 Irving Avenue, Weiskotten Hall Room 5322, Syracuse, NY 13210, USA.
| | - Jinghua Liu
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA
| | - Kentaro Takahashi
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA
| | - Gayathri Ganesh
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA
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Immanuel T, Li J, Green TN, Bogdanova A, Kalev-Zylinska ML. Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential. Front Oncol 2022; 12:1010506. [PMID: 36330491 PMCID: PMC9623116 DOI: 10.3389/fonc.2022.1010506] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/21/2022] [Indexed: 02/05/2023] Open
Abstract
Intracellular calcium signaling regulates diverse physiological and pathological processes. In solid tumors, changes to calcium channels and effectors via mutations or changes in expression affect all cancer hallmarks. Such changes often disrupt transport of calcium ions (Ca2+) in the endoplasmic reticulum (ER) or mitochondria, impacting apoptosis. Evidence rapidly accumulates that this is similar in blood cancer. Principles of intracellular Ca2+ signaling are outlined in the introduction. We describe different Ca2+-toolkit components and summarize the unique relationship between extracellular Ca2+ in the endosteal niche and hematopoietic stem cells. The foundational data on Ca2+ homeostasis in red blood cells is discussed, with the demonstration of changes in red blood cell disorders. This leads to the role of Ca2+ in neoplastic erythropoiesis. Then we expand onto the neoplastic impact of deregulated plasma membrane Ca2+ channels, ER Ca2+ channels, Ca2+ pumps and exchangers, as well as Ca2+ sensor and effector proteins across all types of hematologic neoplasms. This includes an overview of genetic variants in the Ca2+-toolkit encoding genes in lymphoid and myeloid cancers as recorded in publically available cancer databases. The data we compiled demonstrate that multiple Ca2+ homeostatic mechanisms and Ca2+ responsive pathways are altered in hematologic cancers. Some of these alterations may have genetic basis but this requires further investigation. Most changes in the Ca2+-toolkit do not appear to define/associate with specific disease entities but may influence disease grade, prognosis, treatment response, and certain complications. Further elucidation of the underlying mechanisms may lead to novel treatments, with the aim to tailor drugs to different patterns of deregulation. To our knowledge this is the first review of its type in the published literature. We hope that the evidence we compiled increases awareness of the calcium signaling deregulation in hematologic neoplasms and triggers more clinical studies to help advance this field.
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Affiliation(s)
- Tracey Immanuel
- Blood and Cancer Biology Laboratory, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Jixia Li
- Blood and Cancer Biology Laboratory, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
- Department of Laboratory Medicine, School of Medicine, Foshan University, Foshan City, China
| | - Taryn N. Green
- Blood and Cancer Biology Laboratory, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Anna Bogdanova
- Red Blood Cell Research Group, Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zürich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zürich, Switzerland
| | - Maggie L. Kalev-Zylinska
- Blood and Cancer Biology Laboratory, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
- Haematology Laboratory, Department of Pathology and Laboratory Medicine, Auckland City Hospital, Auckland, New Zealand
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Kim MJ, Valderrábano RJ, Wu JY. Osteoblast Lineage Support of Hematopoiesis in Health and Disease. J Bone Miner Res 2022; 37:1823-1842. [PMID: 35983701 PMCID: PMC11346465 DOI: 10.1002/jbmr.4678] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/21/2022] [Accepted: 08/13/2022] [Indexed: 11/06/2022]
Abstract
In mammals, hematopoiesis migrates to the bone marrow during embryogenesis coincident with the appearance of mineralized bone, where hematopoietic stem cells (HSCs) and their progeny are maintained by the surrounding microenvironment or niche, and sustain the entirety of the hematopoietic system. Genetic manipulation of niche factors and advances in cell lineage tracing techniques have implicated cells of both hematopoietic and nonhematopoietic origin as important regulators of hematopoiesis in health and disease. Among them, cells of the osteoblast lineage, from stromal skeletal stem cells to matrix-embedded osteocytes, are vital niche residents with varying capacities for hematopoietic support depending on stage of differentiation. Here, we review populations of osteoblasts at differing stages of differentiation and summarize the current understanding of the role of the osteoblast lineage in supporting hematopoiesis. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Matthew J Kim
- Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Rodrigo J Valderrábano
- Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Joy Y Wu
- Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
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Bohner M, Maazouz Y, Ginebra MP, Habibovic P, Schoenecker JG, Seeherman H, van den Beucken JJ, Witte F. Sustained local ionic homeostatic imbalance caused by calcification modulates inflammation to trigger heterotopic ossification. Acta Biomater 2022; 145:1-24. [PMID: 35398267 DOI: 10.1016/j.actbio.2022.03.057] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 12/15/2022]
Abstract
Heterotopic ossification (HO) is a condition triggered by an injury leading to the formation of mature lamellar bone in extraskeletal soft tissues. Despite being a frequent complication of orthopedic and trauma surgery, brain and spinal injury, the etiology of HO is poorly understood. The aim of this study is to evaluate the hypothesis that a sustained local ionic homeostatic imbalance (SLIHI) created by mineral formation during tissue calcification modulates inflammation to trigger HO. This evaluation also considers the role SLIHI could play for the design of cell-free, drug-free osteoinductive bone graft substitutes. The evaluation contains five main sections. The first section defines relevant concepts in the context of HO and provides a summary of proposed causes of HO. The second section starts with a detailed analysis of the occurrence and involvement of calcification in HO. It is followed by an explanation of the causes of calcification and its consequences. This allows to speculate on the potential chemical modulators of inflammation and triggers of HO. The end of this second section is devoted to in vitro mineralization tests used to predict the ectopic potential of materials. The third section reviews the biological cascade of events occurring during pathological and material-induced HO, and attempts to propose a quantitative timeline of HO formation. The fourth section looks at potential ways to control HO formation, either acting on SLIHI or on inflammation. Chemical, physical, and drug-based approaches are considered. Finally, the evaluation finishes with a critical assessment of the definition of osteoinduction. STATEMENT OF SIGNIFICANCE: The ability to regenerate bone in a spatially controlled and reproducible manner is an essential prerequisite for the treatment of large bone defects. As such, understanding the mechanism leading to heterotopic ossification (HO), a condition triggered by an injury leading to the formation of mature lamellar bone in extraskeletal soft tissues, would be very useful. Unfortunately, the mechanism(s) behind HO is(are) poorly understood. The present study reviews the literature on HO and based on it, proposes that HO can be caused by a combination of inflammation and calcification. This mechanism helps to better understand current strategies to prevent and treat HO. It also shows new opportunities to improve the treatment of bone defects in orthopedic and dental procedures.
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35
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Afsar B, Kanbay M, Afsar RE. Interconnections of fibroblast growth factor 23 and klotho with erythropoietin and hypoxia-inducible factor. Mol Cell Biochem 2022; 477:1973-1985. [PMID: 35381946 DOI: 10.1007/s11010-022-04422-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/22/2022] [Indexed: 12/01/2022]
Abstract
Bone marrow (BM) hematopoiesis is tightly regulated process and bone components such as osteoblasts, extracellular matrix, and minerals influence hematopoiesis via regulation of hematopoietic stem cell function. Erythropoietin (EPO) secreted mostly by renal EPO producing (REP) cells which employ the hypoxia-inducible factor (HIF) pathway. When tissue hypoxia occurs, HIFs bind to hypoxia response element in the EPO promoter and induce EPO production. EPO binds to the EPO receptor on red cell progenitors in the BM and triggers expansion of red cell mass. Fibroblast growth factor-23 (FGF23) which is secreted mostly by osteoblasts and less by BM impacts hematopoiesis by influencing EPO production. Reciprocally, increases of EPO (acute or chronic) influence both FG23 production and cleavage resulting in variation of c fragment FGF23 (cFGF23) and intact FGF23 (iFGF23) ratios. As HIFs stimulate EPO production, they indirectly affect FGF23. Direct stimulation of FGF23 synthesis by binding of HIF on FGF23 promoter is also suggested. FGF23 cleavage by furin is another potential mechanism affecting FGF23 levels. Klotho is present in membrane-bound (transmembrane) and free (circulating) forms. Transmembrane klotho is the co-receptor of FGF23 and forms complexes with FGF23 receptors in the membrane surface and required for FGF23 actions. Recent evidence showed that klotho is also associated with EPO and HIF production suggesting a complex relationship between FGF23, klotho, EPO, and HIF. In this review, we have summarized the connections between FGF23, klotho, HIF, and EPO and their reflections to hematopoiesis.
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Affiliation(s)
- Baris Afsar
- Department of Nephrology, School of Medicine, Suleyman Demirel University, Isparta, Turkey.
| | - Mehmet Kanbay
- Department of Nephrology, School of Medicine, Koc University, Istanbul, Turkey
| | - Rengin Elsurer Afsar
- Department of Nephrology, School of Medicine, Suleyman Demirel University, Isparta, Turkey
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36
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Bonora M, Kahsay A, Pinton P. Mitochondrial calcium homeostasis in hematopoietic stem cell: Molecular regulation of quiescence, function, and differentiation. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 362:111-140. [PMID: 34253293 DOI: 10.1016/bs.ircmb.2021.05.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Hematopoiesis is based on the existence of hematopoietic stem cells (HSC) with the capacity to self-proliferate and self-renew or to differentiate into specialized cells. The hematopoietic niche is the essential microenvironment where stem cells reside and integrate various stimuli to determine their fate. Recent studies have identified niche containing high level of calcium (Ca2+) suggesting that HSCs are sensitive to Ca2+. This is a highly versatile and ubiquitous second messenger that regulates a wide variety of cellular functions. Advanced methods for measuring its concentrations, genetic experiments, cell fate tracing data, single-cell imaging, and transcriptomics studies provide information into its specific roles to integrate signaling into an array of mechanisms that determine HSC identity, lineage potential, maintenance, and self-renewal. Accumulating and contrasting evidence, are revealing Ca2+ as a previously unacknowledged feature of HSC, involved in functional maintenance, by regulating multiple actors including transcription and epigenetic factors, Ca2+-dependent kinases and mitochondrial physiology. Mitochondria are significant participants in HSC functions and their responsiveness to cellular demands is controlled to a significant extent via Ca2+ signals. Recent reports indicate that mitochondrial Ca2+ uptake also controls HSC fate. These observations reveal a physiological feature of hematopoietic stem cells that can be harnessed to improve HSC-related disease. In this review, we discuss the current knowledge Ca2+ in hematopoietic stem cell focusing on its potential involvement in proliferation, self-renewal and maintenance of HSC and discuss future research directions.
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Affiliation(s)
- Massimo Bonora
- Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
| | - Asrat Kahsay
- Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Paolo Pinton
- Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
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37
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Lewuillon C, Laguillaumie MO, Quesnel B, Idziorek T, Touil Y, Lemonnier L. Put in a “Ca2+ll” to Acute Myeloid Leukemia. Cells 2022; 11:cells11030543. [PMID: 35159351 PMCID: PMC8834247 DOI: 10.3390/cells11030543] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/28/2022] [Accepted: 02/01/2022] [Indexed: 02/05/2023] Open
Abstract
Acute myeloid leukemia (AML) is a clonal disorder characterized by genetic aberrations in myeloid primitive cells (blasts) which lead to their defective maturation/function and their proliferation in the bone marrow (BM) and blood of affected individuals. Current intensive chemotherapy protocols result in complete remission in 50% to 80% of AML patients depending on their age and the AML type involved. While alterations in calcium signaling have been extensively studied in solid tumors, little is known about the role of calcium in most hematologic malignancies, including AML. Our purpose with this review is to raise awareness about this issue and to present (i) the role of calcium signaling in AML cell proliferation and differentiation and in the quiescence of hematopoietic stem cells; (ii) the interplay between mitochondria, metabolism, and oxidative stress; (iii) the effect of the BM microenvironment on AML cell fate; and finally (iv) the mechanism by which chemotherapeutic treatments modify calcium homeostasis in AML cells.
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Affiliation(s)
- Clara Lewuillon
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (C.L.); (M.-O.L.); (B.Q.); (T.I.); (Y.T.)
| | - Marie-Océane Laguillaumie
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (C.L.); (M.-O.L.); (B.Q.); (T.I.); (Y.T.)
| | - Bruno Quesnel
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (C.L.); (M.-O.L.); (B.Q.); (T.I.); (Y.T.)
| | - Thierry Idziorek
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (C.L.); (M.-O.L.); (B.Q.); (T.I.); (Y.T.)
| | - Yasmine Touil
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (C.L.); (M.-O.L.); (B.Q.); (T.I.); (Y.T.)
| | - Loïc Lemonnier
- Univ. Lille, Inserm, U1003—PHYCEL—Physiologie Cellulaire, F-59000 Lille, France
- Laboratory of Excellence, Ion Channels Science and Therapeutics, F-59655 Villeneuve d’Ascq, France
- Correspondence:
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38
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Satcher RL, Zhang XHF. Evolving cancer-niche interactions and therapeutic targets during bone metastasis. Nat Rev Cancer 2022; 22:85-101. [PMID: 34611349 DOI: 10.1038/s41568-021-00406-5] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 12/14/2022]
Abstract
Many cancer types metastasize to bone. This propensity may be a product of genetic traits of the primary tumour in some cancers. Upon arrival, cancer cells establish interactions with various bone-resident cells during the process of colonization. These interactions, to a large degree, dictate cancer cell fates at multiple steps of the metastatic cascade, from single cells to overt metastases. The bone microenvironment may even influence cancer cells to subsequently spread to multiple other organs. Therefore, it is imperative to spatiotemporally delineate the evolving cancer-bone crosstalk during bone colonization. In this Review, we provide a summary of the bone microenvironment and its impact on bone metastasis. On the basis of the microscopic anatomy, we tentatively define a roadmap of the journey of cancer cells through bone relative to various microenvironment components, including the potential of bone to function as a launch pad for secondary metastasis. Finally, we examine common and distinct features of bone metastasis from various cancer types. Our goal is to stimulate future studies leading to the development of a broader scope of potent therapies.
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Affiliation(s)
- Robert L Satcher
- Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiang H-F Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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39
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Dausinas Ni P, Basile C, Junge C, Hartman M, O’Leary HA. Hypoxia and Hematopoiesis. CURRENT STEM CELL REPORTS 2022. [DOI: 10.1007/s40778-021-00203-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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40
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Yeh SCA, Hou J, Wu JW, Yu S, Zhang Y, Belfield KD, Camargo FD, Lin CP. Quantification of bone marrow interstitial pH and calcium concentration by intravital ratiometric imaging. Nat Commun 2022; 13:393. [PMID: 35046411 PMCID: PMC8770570 DOI: 10.1038/s41467-022-27973-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 12/22/2021] [Indexed: 12/23/2022] Open
Abstract
The fate of hematopoietic stem cells (HSCs) can be directed by microenvironmental factors including extracellular calcium ion concentration ([Ca2+]e), but the local [Ca2+]e around individual HSCs in vivo remains unknown. Here we develop intravital ratiometric analyses to quantify the absolute pH and [Ca2+]e in the mouse calvarial bone marrow, taking into account the pH sensitivity of the calcium probe and the wavelength-dependent optical loss through bone. Unexpectedly, the mean [Ca2+]e in the bone marrow (1.0 ± 0.54 mM) is not significantly different from the blood serum, but the HSCs are found in locations with elevated local [Ca2+]e (1.5 ± 0.57 mM). With aging, a significant increase in [Ca2+]e is found in M-type cavities that exclusively support clonal expansion of activated HSCs. This work thus establishes a tool to investigate [Ca2+]e and pH in the HSC niche with high spatial resolution and can be broadly applied to other tissue types.
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Affiliation(s)
- S-C A Yeh
- Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - J Hou
- Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - J W Wu
- Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - S Yu
- Department of Chemistry and Environmental Science, New Jersey Institute of Technology, 323 Martin Luther King Jr. Blvd., Newark, NJ, 07102, USA
| | - Y Zhang
- Department of Chemistry and Environmental Science, New Jersey Institute of Technology, 323 Martin Luther King Jr. Blvd., Newark, NJ, 07102, USA
| | - K D Belfield
- Department of Chemistry and Environmental Science, New Jersey Institute of Technology, 323 Martin Luther King Jr. Blvd., Newark, NJ, 07102, USA
| | - F D Camargo
- Stem Cell Program, Boston Children's Hospital, Boston, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - C P Lin
- Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, 02138, USA.
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41
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Zhu W, Guo S, Homilius M, Nsubuga C, Wright SH, Quan D, Kc A, Eddy SS, Victorio RA, Beerens M, Flaumenhaft R, Deo RC, MacRae CA. PIEZO1 mediates a mechanothrombotic pathway in diabetes. Sci Transl Med 2022; 14:eabk1707. [PMID: 34985971 DOI: 10.1126/scitranslmed.abk1707] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Wandi Zhu
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.,Harvard Medical School, Boston, MA 02115, USA
| | - Shihui Guo
- Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
| | - Max Homilius
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.,Harvard Medical School, Boston, MA 02115, USA
| | - Cissy Nsubuga
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Shane H Wright
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.,Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA
| | - Dajun Quan
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Ashmita Kc
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Samuel S Eddy
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | | | - Manu Beerens
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.,Harvard Medical School, Boston, MA 02115, USA
| | - Robert Flaumenhaft
- Harvard Medical School, Boston, MA 02115, USA.,Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
| | - Rahul C Deo
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.,Harvard Medical School, Boston, MA 02115, USA
| | - Calum A MacRae
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.,Harvard Medical School, Boston, MA 02115, USA
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Zeytin IC, Alkan B, Ozdemir C, Cetinkaya DU, Okur FV. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:310-321. [PMID: 35356978 PMCID: PMC8969067 DOI: 10.1093/stcltm/szab019] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 11/07/2021] [Indexed: 11/22/2022] Open
Abstract
Osteopetrosis is a rare inherited disease characterized by impaired osteoclast activity causing defective bone resorption and bone marrow aplasia. It is fatal in early childhood unless hematopoietic stem cell transplantation is performed. But, the transplant course is complicated with engraftment failure. Recently, osteoclasts have been described as the potential regulators of hematopoietic stem cell (HSC) niche. Here we investigated the alterations in the HSC and mesenchymal stromal cell (MSC) components of osteopetrotic niche and their interactions to mimic the stem cell dynamics/trafficking in the BM niche after HSC transplantation. Induced pluripotent stem cells were generated from peripheral blood mononuclear cells of patients with osteopetrosis carrying TCIRG1 mutation. iPSC lines were differentiated into hematopoietic and myeloid progenitors, then into osteoclasts using a step-wise protocol. We first demonstrated a shift toward monocyte-macrophages lineage regarding hematopoietic differentiation potential of osteopetrotic iPSC-derived hematopoietic progenitors (HPCs) and phenotypically normal and functionally defective osteoclast formation. The expression of the genes involved in HSC homing and maintenance (Sdf-1, Jagged-1, Kit-L, and Opn) in osteopetrotic MSCs recovered significantly after coculture with healthy HPCs. Similarly, the restoration of phenotype, impaired differentiation, and migratory potential of osteopetrotic iHPCs were observed upon interaction with healthy MSCs. Our results establish significant alterations in both MSC and HPC compartments of the osteopetrotic niche, and support the impact of functionally impaired osteoclasts in defective niche formation.
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Affiliation(s)
- Inci Cevher Zeytin
- Center for Stem Cell Research and Development PEDI-STEM, Hacettepe University, Ankara, Turkey
- Department of Stem Cell Sciences, Institute of Health Sciences, Hacettepe University, Ankara, Turkey
| | - Berna Alkan
- Center for Stem Cell Research and Development PEDI-STEM, Hacettepe University, Ankara, Turkey
- Department of Stem Cell Sciences, Institute of Health Sciences, Hacettepe University, Ankara, Turkey
| | - Cansu Ozdemir
- Center for Stem Cell Research and Development PEDI-STEM, Hacettepe University, Ankara, Turkey
| | - Duygu Uckan Cetinkaya
- Center for Stem Cell Research and Development PEDI-STEM, Hacettepe University, Ankara, Turkey
- Department of Stem Cell Sciences, Institute of Health Sciences, Hacettepe University, Ankara, Turkey
- Department of Pediatrics, Division of Pediatric Hematology and Bone Marrow Transplantation Unit, Faculty of Medicine, Hacettepe University, Ankara, Turkey
- Corresponding authors: Duygu Uckan Cetinkaya and Fatma Visal Okur, Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, Ankara, Turkey, (F.V.O.), (D.U.C.)
| | - Fatma Visal Okur
- Center for Stem Cell Research and Development PEDI-STEM, Hacettepe University, Ankara, Turkey
- Department of Stem Cell Sciences, Institute of Health Sciences, Hacettepe University, Ankara, Turkey
- Department of Pediatrics, Division of Pediatric Hematology and Bone Marrow Transplantation Unit, Faculty of Medicine, Hacettepe University, Ankara, Turkey
- Corresponding authors: Duygu Uckan Cetinkaya and Fatma Visal Okur, Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, Ankara, Turkey, (F.V.O.), (D.U.C.)
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Sun Y, Li J, Xie X, Gu F, Sui Z, Zhang K, Yu T. Recent Advances in Osteoclast Biological Behavior. Front Cell Dev Biol 2021; 9:788680. [PMID: 34957116 PMCID: PMC8694526 DOI: 10.3389/fcell.2021.788680] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 11/15/2021] [Indexed: 12/19/2022] Open
Abstract
With the progress of the aging population, bone-related diseases such as osteoporosis and osteoarthritis have become urgent problems. Recent studies have demonstrated the importance of osteoclasts in bone homeostasis, implying these will be an important mediator in the treatment of bone-related diseases. Up to now, several reviews have been performed on part of osteoclast biological behaviors such as differentiation, function, or apoptosis. However, few reviews have shown the complete osteoclast biology and research advances in recent years. Therefore, in this review, we focus on the origin, differentiation, apoptosis, behavior changes and coupling signals with osteoblasts, providing a simple but comprehensive overview of osteoclasts for subsequent studies.
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Affiliation(s)
- Yang Sun
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
| | - Jiangbi Li
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
| | - Xiaoping Xie
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
| | - Feng Gu
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
| | - Zhenjiang Sui
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
| | - Ke Zhang
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
| | - Tiecheng Yu
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
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Kan C, Lu X, Zhang R. Effects of hypoxia on bone metabolism and anemia in patients with chronic kidney disease. World J Clin Cases 2021; 9:10616-10625. [PMID: 35004993 PMCID: PMC8686129 DOI: 10.12998/wjcc.v9.i34.10616] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 08/12/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Abnormal bone metabolism and renal anemia seriously affect the prognosis of patients with chronic kidney disease (CKD). Existing studies have mostly addressed the pathogenesis and treatment of bone metabolism abnormality and anemia in patients with CKD, but few have evaluated their mutual connection. Administration of exogenous erythropoietin to CKD patients with anemia used to be the mainstay of therapeutic approaches; however, with the availability of hypoxia-inducible factor (HIF) stabilizers such as roxadustat, more therapeutic choices for renal anemia are expected in the future. However, the effects posed by the hypoxic environment on both CKD complications remain incompletely understood. AIM To summarize the relationship between renal anemia and abnormal bone metabolism, and to discuss the influence of hypoxia on bone metabolism. METHODS CNKI and PubMed searches were performed using the key words "chronic kidney disease," "abnormal bone metabolism," "anemia," "hypoxia," and "HIF" to identify relevant articles published in multiple languages and fields. Reference lists from identified articles were reviewed to extract additional pertinent articles. Then we retrieved the Abstract and Introduction and searched the results from the literature, classified the extracted information, and summarized important information. Finally, we made our own conclusions. RESULTS There is a bidirectional relationship between renal anemia and abnormal bone metabolism. Abnormal vitamin D metabolism and hyperparathyroidism can affect bone metabolism, blood cell production, and survival rates through multiple pathways. Anemia will further attenuate the normal bone growth. The hypoxic environment regulates bone morphogenetic protein, vascular endothelial growth factor, and neuropilin-1, and affects osteoblast/osteoclast maturation and differentiation through bone metabolic changes. Hypoxia preconditioning of mesenchymal stem cells (MSCs) can enhance their paracrine effects and promote fracture healing. Concurrently, hypoxia reduces the inhibitory effect on osteocyte differentiation by inhibiting the expression of fibroblast growth factor 23. Hypoxia potentially improves bone metabolism, but it still carries potential risks. The optimal concentration and duration of hypoxia remain unclear. CONCLUSION There is a bidirectional relationship between renal anemia and abnormal bone metabolism. Hypoxia may improve bone metabolism but the concentration and duration of hypoxia remain unclear and need further study.
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Affiliation(s)
- Chao Kan
- Department of Clinical Medicine, Changchun University of Chinese Medicine, Changchun 130000, Jilin Province, China
| | - Xu Lu
- Department of Clinical Medicine, Changchun University of Chinese Medicine, Changchun 130000, Jilin Province, China
| | - Rui Zhang
- Department of Nephrology, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519070, Guangdong Province, China
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Tosato G, Feng JX, Ohnuki H, Sim M. Bone marrow niches in myelodysplastic syndromes. JOURNAL OF CANCER METASTASIS AND TREATMENT 2021; 7. [PMID: 34746416 PMCID: PMC8570581 DOI: 10.20517/2394-4722.2021.120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Genetic and epigenetic lesions within hematopoietic cell populations drive diverse hematological malignancies. Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms affecting the hematopoietic stem cells characterized by recurrent genetic abnormalities, myelodysplasia (a pathological definition of abnormal bone marrow structure), ineffective hematopoiesis resulting in blood cytopenia, and a propensity to evolve into acute myelogenous leukemia. Although there is evidence that the accumulation of a set of genetic mutations is an essential event in MDS, there is an increased appreciation of the contribution of specific microenvironments, niches, in the pathogenesis of MDS and response to treatment. In physiologic hematopoiesis, niches are critical functional units that maintain hematopoietic stem and progenitor cells and regulate their maturation into mature blood cells. In MDS and other hematological malignancies, altered bone marrow niches can promote the survival and expansion of mutant hematopoietic clones and provide a shield from therapy. In this review, we focus on our understanding of the composition and function of hematopoietic niches and their role in the evolution of myeloid malignancies, with an emphasis on MDS.
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Affiliation(s)
- Giovanna Tosato
- Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Jing-Xin Feng
- Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Hidetaka Ohnuki
- Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Minji Sim
- Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
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Hsieh CC, Chan MJ, Su YJ, Fu JF, Wang IK, Chen CY, Weng CH, Huang WH, Hsu CW, Yen TH. Bone Marrow Hypocellularity in Patients with End-Stage Kidney Disease. Healthcare (Basel) 2021; 9:1452. [PMID: 34828498 PMCID: PMC8621268 DOI: 10.3390/healthcare9111452] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 10/12/2021] [Accepted: 10/22/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Anemia and pancytopenia are not uncommon in patients with chronic kidney disease (CKD). Nevertheless, there is insufficient literature analyzing bone marrow pathology in patients with CKD or end-stage kidney disease (ESKD) receiving dialysis. METHODS This observational cohort study included 22 patients with ESKD and 23 patients with CKD that received bone marrow biopsy and aspiration at Chang Gung Memorial Hospital. Demographic, hematological, and biochemical data were collected at the time of bone marrow study for analysis. RESULTS Bone marrow aspiration demonstrated that patients with ESKD had a lower percentage of blasts than patients with CKD (0.52 ± 0.84 versus 1.06 ± 0.78 %, p = 0.033). Bone marrow biopsy revealed that the overall incidence of hypocellular bone marrow was 55.6%. Furthermore, patients with ESKD had higher proportion of hypocellular bone marrow than patients with CKD (72.7% versus 39.1%, p = 0.023). In a multivariate logistic regression model, it was revealed that ESKD status (odds ratio 9.43, 95% confidence interval 1.66-53.63, p = 0.011) and megakaryocyte count within bone marrow (odds ratio 0.48, 95% confidence interval 0.29-0.79, p = 0.004) were significant predictors for bone marrow hypocellularity. CONCLUSION Bone marrow hypocellularity is common in patients with kidney dysfunction. Hypocellular marrow occurs more frequently in patients with ESKD than patients with CKD.
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Affiliation(s)
- Chia-Chen Hsieh
- Clinical Poison Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou 333, Taiwan; (C.-C.H.); (M.-J.C.); (C.-Y.C.); (C.-H.W.); (W.-H.H.); (C.-W.H.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Ming-Jen Chan
- Clinical Poison Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou 333, Taiwan; (C.-C.H.); (M.-J.C.); (C.-Y.C.); (C.-H.W.); (W.-H.H.); (C.-W.H.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Yi-Jiun Su
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou 333, Taiwan;
| | - Jen-Fen Fu
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
- Department of Medical Research, Chang Gung Memorial Hospital, Linkou 333, Taiwan
| | - I-Kuan Wang
- Department of Nephrology, China Medical University Hospital, Taichung 404, Taiwan;
- College of Medicine, China Medical University, Taichung 406, Taiwan
| | - Chao-Yu Chen
- Clinical Poison Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou 333, Taiwan; (C.-C.H.); (M.-J.C.); (C.-Y.C.); (C.-H.W.); (W.-H.H.); (C.-W.H.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Cheng-Hao Weng
- Clinical Poison Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou 333, Taiwan; (C.-C.H.); (M.-J.C.); (C.-Y.C.); (C.-H.W.); (W.-H.H.); (C.-W.H.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Wen-Hung Huang
- Clinical Poison Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou 333, Taiwan; (C.-C.H.); (M.-J.C.); (C.-Y.C.); (C.-H.W.); (W.-H.H.); (C.-W.H.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Ching-Wei Hsu
- Clinical Poison Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou 333, Taiwan; (C.-C.H.); (M.-J.C.); (C.-Y.C.); (C.-H.W.); (W.-H.H.); (C.-W.H.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Tzung-Hai Yen
- Clinical Poison Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou 333, Taiwan; (C.-C.H.); (M.-J.C.); (C.-Y.C.); (C.-H.W.); (W.-H.H.); (C.-W.H.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
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Rebuilding the hematopoietic stem cell niche: Recent developments and future prospects. Acta Biomater 2021; 132:129-148. [PMID: 33813090 DOI: 10.1016/j.actbio.2021.03.061] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 03/25/2021] [Accepted: 03/25/2021] [Indexed: 12/20/2022]
Abstract
Hematopoietic stem cells (HSCs) have proven their clinical relevance in stem cell transplantation to cure patients with hematological disorders. Key to their regenerative potential is their natural microenvironment - their niche - in the bone marrow (BM). Developments in the field of biomaterials enable the recreation of such environments with increasing preciseness in the laboratory. Such artificial niches help to gain a fundamental understanding of the biophysical and biochemical processes underlying the interaction of HSCs with the materials in their environment and the disturbance of this interplay during diseases affecting the BM. Artificial niches also have the potential to multiply HSCs in vitro, to enable the targeted differentiation of HSCs into mature blood cells or to serve as drug-testing platforms. In this review, we will introduce the importance of artificial niches followed by the biology and biophysics of the natural archetype. We will outline how 2D biomaterials can be used to dissect the complexity of the natural niche into individual parameters for fundamental research and how 3D systems evolved from them. We will present commonly used biomaterials for HSC research and their applications. Finally, we will highlight two areas in the field of HSC research, which just started to unlock the possibilities provided by novel biomaterials, in vitro blood production and studying the pathophysiology of the niche in vitro. With these contents, the review aims to give a broad overview of the different biomaterials applied for HSC research and to discuss their potentials, challenges and future directions in the field. STATEMENT OF SIGNIFICANCE: Hematopoietic stem cells (HSCs) are multipotent cells responsible for maintaining the turnover of all blood cells. They are routinely applied to treat patients with hematological diseases. This high clinical relevance explains the necessity of multiplication or differentiation of HSCs in the laboratory, which is hampered by the missing natural microenvironment - the so called niche. Biomaterials offer the possibility to mimic the niche and thus overcome this hurdle. The review introduces the HSC niche in the bone marrow and discusses the utility of biomaterials in creating artificial niches. It outlines how 2D systems evolved into sophisticated 3D platforms, which opened the gateway to applications such as, expansion of clinically relevant HSCs, in vitro blood production, studying niche pathologies and drug testing.
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The relationship between FGF23 and anemia in HD and renal transplant patients. Int Urol Nephrol 2021; 54:1117-1122. [PMID: 34482498 DOI: 10.1007/s11255-021-02982-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 08/21/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Recent studies claim that FGF23 is also associated with anemia and inflammation. In this study, the relationship between FGF23 and anemia in hemodialysis (HD) and renal transplantation patients (RTx patients) patients was investigated. METHODS This was a cross-sectional study involving 40 RTx patients (13 females, 27 males; mean age, 45.93 ± 12.49 years) who had transplantation at least 6 months before, 25 HD patients (12 females, 13 males; mean age, 54.72 ± 15.5 years), and 20 healthy control subjects (13 females, 7 males; mean age, 36.7 ± 9.38 years). FGF23 was studied using Elisa method. Parameters such as iron, ferritin, total iron binding capacity, and transferrin saturation were assessed. RESULTS FGF23 level was significantly higher in HD patients when compared with the RTx patients and control groups. In the bivariate correlation analysis, hemoglobin was positively correlated with albumin (r = 0.681, p = 0.000), ferritin (r = 0.446, p = 0.043), and negatively correlated with CRP (r = - 0.476, p = 0.016) and FGF23 (r = 0.493, p = 0.043). FGF23 was found to be an independent predictor of decreased hemoglobin in HD patients. In addition, this association was observed to disappear after transplantation. CONCLUSION While FGF23 is closely related to hemoglobin levels in HD patients, we have shown that this relationship disappears after transplantation.
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Zheng J, Liu G, Wu C, Jia G, Zhao H, Chen X, Wang J. Effect of calcium-sensing receptor on the migration and proliferation of porcine intestinal epithelial cells. Anim Biotechnol 2021; 34:365-374. [PMID: 34459707 DOI: 10.1080/10495398.2021.1968885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The rapid healing of impaired intestinal surface plays a role in maintaining intestinal homeostasis. This study investigated the effect of calcium-sensing receptor (CaSR) on the migration and proliferation of intestinal porcine epithelial cells (IPEC-J2). Results showed that cell migration area and width were increased by R568 (CaSR activator) and decreased by NPS2143 (CaSR inhibitor). The protein level of GTP-rac1 and the phosphorylation of phospholipase C gamma 1 (PLCγ1) were increased by 2 µM R568. Furthermore, R568 + 120 µM NSC23766 (Rac1 inhibitor) and R568 + 1 µM U73122 (PLCγ1 inhibitor) decreased the protein level of GTP-rac1 and the phosphorylated PLCγ1, respectively, and both inhibited cell migration compared with R568. In addition, spermine increased the protein expression levels of CaSR and the levels of GTP-rac1 and the phosphorylated PLCγ1 and thereby promoted the migration of IPEC-J2 cells. Moreover, R568 improved the proliferation of the IPEC-J2 cells. Spermine increased cell proliferation, but NPS2143 incubated with spermine decreased cell proliferation compared with the spermine group. This study suggests that CaSR activation increased cell migration by activating Rac1 and PLCγ1 signaling and improved cell proliferation, and both effects were regulated by spermine by activating CaSR.
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Affiliation(s)
- Jie Zheng
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Chengdu, Sichuan, China.,Key laboratory of Animal Disease-resistant Nutrition and Feed, Ministry of Agriculture and Rural Affairs, Chengdu, Sichuan, China
| | - Guangmang Liu
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Chengdu, Sichuan, China.,Key laboratory of Animal Disease-resistant Nutrition and Feed, Ministry of Agriculture and Rural Affairs, Chengdu, Sichuan, China
| | - Caimei Wu
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Chengdu, Sichuan, China.,Key laboratory of Animal Disease-resistant Nutrition and Feed, Ministry of Agriculture and Rural Affairs, Chengdu, Sichuan, China
| | - Gang Jia
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Chengdu, Sichuan, China.,Key laboratory of Animal Disease-resistant Nutrition and Feed, Ministry of Agriculture and Rural Affairs, Chengdu, Sichuan, China
| | - Hua Zhao
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Chengdu, Sichuan, China.,Key laboratory of Animal Disease-resistant Nutrition and Feed, Ministry of Agriculture and Rural Affairs, Chengdu, Sichuan, China
| | - Xiaoling Chen
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Chengdu, Sichuan, China.,Key laboratory of Animal Disease-resistant Nutrition and Feed, Ministry of Agriculture and Rural Affairs, Chengdu, Sichuan, China
| | - Jing Wang
- Maize Research Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
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Jalali S, Ansell SM. Role of the Bone Marrow Niche in Supporting the Pathogenesis of Lymphoid Malignancies. Front Cell Dev Biol 2021; 9:692320. [PMID: 34395425 PMCID: PMC8355623 DOI: 10.3389/fcell.2021.692320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/07/2021] [Indexed: 11/24/2022] Open
Abstract
While the bone marrow (BM) microenvironment is the primary location for nurturing the multipotent hematopoietic stem cells and developing the blood cells of either myeloid or lymphoid origin under normal physiological conditions, it could provide a supportive milieu for the proliferation of blood cancer cells. In fact, the multiple and complex direct cell-to-cell or indirect soluble factors-mediated interactions taking place among the BM cells of different origins are shown to play a significant role in tumorigenesis of hematological cancers. In the current review, we focus on lymphoid malignancies and highlight the novel insights surrounding the role of both cellular as well as non-cellular BM compartments in modulating hematopoiesis and promoting growth and proliferation of cancer cells across a variety of aggressive and indolent lymphoid malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia. We also discuss the mechanisms of potential intervention and discuss their therapeutic impact in clinical settings.
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Affiliation(s)
- Shahrzad Jalali
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, United States
| | - Stephen M Ansell
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, United States
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