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Sajjad U, Ahmed M, Iqbal MZ, Riaz M, Mustafa M, Biedermann T, Klar AS. Exploring mesenchymal stem cells homing mechanisms and improvement strategies. Stem Cells Transl Med 2024; 13:1161-1177. [PMID: 39550211 PMCID: PMC11631218 DOI: 10.1093/stcltm/szae045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 05/16/2024] [Indexed: 11/18/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells with high self-renewal and multilineage differentiation abilities, playing an important role in tissue healing. Recent advancements in stem cell-based technologies have offered new and promising therapeutic options in regenerative medicine. Upon tissue damage, MSCs are immediately mobilized from the bone marrow and move to the injury site via blood circulation. Notably, allogenically transplanted MSCs can also home to the damaged tissue site. Therefore, MSCs hold great therapeutic potential for curing various diseases. However, one major obstacle to this approach is attracting MSCs specifically to the injury site following systemic administration. In this review, we describe the molecular pathways governing the homing mechanism of MSCs and various strategies for improving this process, including targeted stem cell administration, target tissue modification, in vitro priming, cell surface engineering, genetic modifications, and magnetic guidance. These strategies are crucial for directing MSCs precisely to the injury site and, consequently, enhancing their migration and local tissue repair properties. Specifically, our review provides a guide to improving the therapeutic efficacy of clinical applications of MSCs through optimized in vivo administration and homing capacities.
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Affiliation(s)
- Umar Sajjad
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Muhammad Ahmed
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - M Zohaib Iqbal
- Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, CH-8952, Zurich, Switzerland
- Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Mahrukh Riaz
- Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, CH-8952, Zurich, Switzerland
- Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Muhammad Mustafa
- KAM School of Life Sciences, Forman Christian College University, Lahore, Pakistan
| | - Thomas Biedermann
- Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, CH-8952, Zurich, Switzerland
- Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Agnes S Klar
- Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, CH-8952, Zurich, Switzerland
- Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
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Cai H, Han XJ, Luo ZR, Wang QL, Lu PP, Mou FF, Zhao ZN, Hu D, Guo HD. Pretreatment with Notoginsenoside R1 enhances the efficacy of neonatal rat mesenchymal stem cell transplantation in model of myocardial infarction through regulating PI3K/Akt/FoxO1 signaling pathways. Stem Cell Res Ther 2024; 15:419. [PMID: 39533348 PMCID: PMC11558819 DOI: 10.1186/s13287-024-04039-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 11/03/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Although stem cell transplantation is a promising approach for the treatment of myocardial infarction (MI), there are still some problems faced such as the low survival rate of stem cells. Here, we investigated the role of Notoginsenoside R1 (NGR1) pretreatment in improving the effects of neonatal rat bone marrow mesenchymal stem cell (MSC) transplantation for treatment of MI. METHODS Cardiac functions were detected by echocardiography and the myocardial infarct size was determined by Masson's trichrome staining in a rat model of MI. The cardioprotective effects of NGR1/LY294002 co-pretreated MSCs was evaluated to explore the underlying mechanism. The angiogenesis was determined by vWF and α-SMA immunofluorescence staining and cell apoptosis was detected by TUNEL. In vitro, the effects of NGR1 on stem cell proliferation was examined by CCK-8 and levels of P-Akt, P-CREB, P-FoxO1 were detected by western blot. Apoptosis, ROS content, and cytokine levels were examined by DAPI and TUNEL staining, a ROS assay kit, and ELISA, respectively. RESULTS NGR1 elevated the therapeutic effect of MSC transplantation on infarction by preserving cardiac function, increasing angiogenesis and expressions of IGF-1, VEGF, and SDF-1, and reducing cell apoptosis, whereas the addition of LY294002 prior to NGR1 treatment significantly counteracted the foregoing effects of NGR1. NGR1 pretreatment and SC79 pretreatment were similar in that both significantly increased P-Akt and P-FoxO1 levels in MSC and did not affect P-CREB levels. Besides, both NGR1 and SC79 promoted VEGF, SCF and bFGF levels in MSC cultures, and significantly reduced ROS accumulation and the attenuated cell apoptosis in MSC triggered by H2O2. Similarly, addition of LY294002 before NGR1 treatment significantly counteracted the aforementioned effects of NGR1 in vitro. CONCLUSIONS NGR1 pretreatment enhances the effect of MSC transplantation for treatment of MI through paracrine signaling, and the mechanism underlying this effect may be associated with PI3K/Akt/FoxO1 signaling pathways.
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Affiliation(s)
- Hao Cai
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiao-Jing Han
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhi-Rong Luo
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qiang-Li Wang
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ping-Ping Lu
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Fang-Fang Mou
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhi-Nan Zhao
- Development and Planning Division (Department of Discipline Development）, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Dan Hu
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China.
| | - Hai-Dong Guo
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Wang Y, Xiao Y, Yang X, He F, Hu J, Yang G, Wang W. Bone marrow mesenchymal stem cells overexpressing stromal cell- derived factor 1 aid in bone formation in osteoporotic mice. BMC Musculoskelet Disord 2024; 25:878. [PMID: 39497150 PMCID: PMC11536944 DOI: 10.1186/s12891-024-07957-2] [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] [Received: 04/10/2024] [Accepted: 10/14/2024] [Indexed: 11/06/2024] Open
Abstract
BACKGROUND Osteoporosis is characterized by low systemic bone mineral content and destruction of bone microarchitecture. Promoting bone regeneration and reversing its loss by infusion of exogenous bone marrow mesenchymal stem cells (BMSCs) is a potentially effective treatment for osteoporosis. However, their limited migration to target organs reduces the therapeutic effect of the cells. Stromal cell-derived factor 1 (SDF1) is a chemokine that induces targeted cell migration through the SDF1/CXCR4 (C-X-C chemokine receptor 4) axis and can induce migration of exogenous mesenchymal stem cells to sites of high SDF1 concentration. There are no studies on BMSCs overexpressing SDF1 (SDF1-BMSCs) in osteoporotic mice in vivo. We aimed to investigate if the increased SDF1 concentration facilitated cell migration to the bone. METHODS We used lentivirus to construct BMSCs overexpressing SDF1 or knocking down CXCR4. We verified the proliferation ability of the cells in vitro using Cell Counting Kit-8 (CCK8) and 5-Bromodeoxyuridinc (BrdU), the migration ability of the cells using Transwell, and the osteogenic and lipogenic ability of the cells using osteogenic and lipogenic induction solutions. In in vivo experiments, we induced osteoporosis in 72 female mice by ovariectomy and injected different groups of cells via the tail vein. Femoral tissue samples were collected for a fixed time, and the osteogenic and homing abilities of the cells were verified by MicroCT and tissue section staining. RESULTS We successfully demonstrated that high expression of SDF1 promoted cell proliferation and migration in vitro, without affecting their cell differentiation ability. In an ovariectomized mouse model, SDF1-BMSCs were more likely to be home to the femur than the BMSCs, had a better pro-osteogenic ability, and had higher expression of Wnt-1. Blocking the SDF1/CXCR4 axis reduced the homing of exogenous mesenchymal stem cells (MSCs) to the femur and their osteogenic capacity. CONCLUSIONS SDF1-BMSCs can further promote bone formation by increasing the number of cells homing to the femur in osteoporotic mice. Our study shows that stem cells can promote their proliferation and home to the femur via the SDF1/CXCR4 axis and further help bone formation via Wnt-1 signaling.
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Affiliation(s)
- Yanghao Wang
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Ya Xiao
- First Clinical College, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - XinYu Yang
- Clinical Oncology College, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Fei He
- Department of Orthopedic, Qujing Affiliated Hospital of Kunming Medical University, Qujing, Yunnan, China
| | - Jun Hu
- Department of Orthopedic, The First People's Hospital of Kunming, Kunming, Yunnan, China
| | - Guang Yang
- Trauma Center, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
| | - Weizhou Wang
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
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Li Y, Ren M, Li H, Zhang Z, Yuan K, Huang Y, Yuan S, Ju W, He Y, Xu K, Zeng L. Silencing endomucin in bone marrow sinusoids improves hematopoietic stem and progenitor cell homing during transplantation. Stem Cells 2024; 42:889-901. [PMID: 38995653 DOI: 10.1093/stmcls/sxae046] [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: 12/11/2023] [Accepted: 06/13/2024] [Indexed: 07/13/2024]
Abstract
Efficient homing of infused hematopoietic stem and progenitor cells (HSPCs) into the bone marrow (BM) is the prerequisite for successful hematopoietic stem cell transplantation. However, only a small part of infused HSPCs find their way to the BM niche. A better understanding of the mechanisms that facilitate HSPC homing will help to develop strategies to improve the initial HSPC engraftment and subsequent hematopoietic regeneration. Here, we show that irradiation upregulates the endomucin expression of endothelial cells in vivo and in vitro. Furthermore, depletion of endomucin in irradiated endothelial cells with short-interfering RNA (siRNA) increases the HSPC-endothelial cell adhesion in vitro. To abrogate the endomucin of BM sinusoidal endothelial cells (BM-SECs) in vivo, we develop a siRNA-loaded bovine serum albumin nanoparticle for targeted delivery. Nanoparticle-mediated siRNA delivery successfully silences endomucin expression in BM-SECs and improves HSPC homing during transplantation. These results reveal that endomucin plays a critical role in HSPC homing during transplantation and that gene-based manipulation of BM-SEC endomucin in vivo can be exploited to improve the efficacy of HSPC transplantation.
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Affiliation(s)
- Yue Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- School of Medical Technology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, People's Republic of China
| | - Miao Ren
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
| | - Hu Li
- School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, People's Republic of China
| | - Zuo Zhang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- School of Medical Technology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, People's Republic of China
| | - Ke Yuan
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
| | - Yujin Huang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
| | - Shengnan Yuan
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- School of Medical Technology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, People's Republic of China
| | - Wen Ju
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
| | - Yuan He
- School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, People's Republic of China
| | - Kailin Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
| | - Lingyu Zeng
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
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Cuevas D, Amigo R, Agurto A, Heredia AA, Guzmán C, Recabal-Beyer A, González-Pecchi V, Caprile T, Haigh JJ, Farkas C. The Role of Epithelial-to-Mesenchymal Transition Transcription Factors (EMT-TFs) in Acute Myeloid Leukemia Progression. Biomedicines 2024; 12:1915. [PMID: 39200378 PMCID: PMC11351244 DOI: 10.3390/biomedicines12081915] [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: 07/12/2024] [Revised: 07/31/2024] [Accepted: 08/02/2024] [Indexed: 09/02/2024] Open
Abstract
Acute myeloid leukemia (AML) is a diverse malignancy originating from myeloid progenitor cells, with significant genetic and clinical variability. Modern classification systems like those from the World Health Organization (WHO) and European LeukemiaNet use immunophenotyping, molecular genetics, and clinical features to categorize AML subtypes. This classification highlights crucial genetic markers such as FLT3, NPM1 mutations, and MLL-AF9 fusion, which are essential for prognosis and directing targeted therapies. The MLL-AF9 fusion protein is often linked with therapy-resistant AML, highlighting the risk of relapse due to standard chemotherapeutic regimes. In this sense, factors like the ZEB, SNAI, and TWIST gene families, known for their roles in epithelial-mesenchymal transition (EMT) and cancer metastasis, also regulate hematopoiesis and may serve as effective therapeutic targets in AML. These genes contribute to cell proliferation, differentiation, and extramedullary hematopoiesis, suggesting new possibilities for treatment. Advancing our understanding of the molecular mechanisms that promote AML, especially how the bone marrow microenvironment affects invasion and drug resistance, is crucial. This comprehensive insight into the molecular and environmental interactions in AML emphasizes the need for ongoing research and more effective treatments.
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Affiliation(s)
- Diego Cuevas
- Laboratorio de Investigación en Ciencias Biomédicas, Departamento de Ciencias Básicas y Morfología, Facultad de Medicina, Universidad Católica de la Santísima Concepción, Concepción 4030000, Chile; (D.C.); (A.A.); (A.A.H.); (C.G.); (V.G.-P.)
| | - Roberto Amigo
- Laboratorio de Regulación Transcripcional, Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción 4030000, Chile;
| | - Adolfo Agurto
- Laboratorio de Investigación en Ciencias Biomédicas, Departamento de Ciencias Básicas y Morfología, Facultad de Medicina, Universidad Católica de la Santísima Concepción, Concepción 4030000, Chile; (D.C.); (A.A.); (A.A.H.); (C.G.); (V.G.-P.)
| | - Adan Andreu Heredia
- Laboratorio de Investigación en Ciencias Biomédicas, Departamento de Ciencias Básicas y Morfología, Facultad de Medicina, Universidad Católica de la Santísima Concepción, Concepción 4030000, Chile; (D.C.); (A.A.); (A.A.H.); (C.G.); (V.G.-P.)
| | - Catherine Guzmán
- Laboratorio de Investigación en Ciencias Biomédicas, Departamento de Ciencias Básicas y Morfología, Facultad de Medicina, Universidad Católica de la Santísima Concepción, Concepción 4030000, Chile; (D.C.); (A.A.); (A.A.H.); (C.G.); (V.G.-P.)
| | - Antonia Recabal-Beyer
- Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción 4030000, Chile;
| | - Valentina González-Pecchi
- Laboratorio de Investigación en Ciencias Biomédicas, Departamento de Ciencias Básicas y Morfología, Facultad de Medicina, Universidad Católica de la Santísima Concepción, Concepción 4030000, Chile; (D.C.); (A.A.); (A.A.H.); (C.G.); (V.G.-P.)
| | - Teresa Caprile
- Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción 4030000, Chile;
| | - Jody J. Haigh
- Paul Albrechtsen Research Institute, CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada
- Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Carlos Farkas
- Laboratorio de Investigación en Ciencias Biomédicas, Departamento de Ciencias Básicas y Morfología, Facultad de Medicina, Universidad Católica de la Santísima Concepción, Concepción 4030000, Chile; (D.C.); (A.A.); (A.A.H.); (C.G.); (V.G.-P.)
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Niu Y, Xiao H, Wang B, Wang Z, Du K, Wang Y, Wang L. Angelica sinensis polysaccharides alleviate the oxidative burden on hematopoietic cells by restoring 5-fluorouracil-induced oxidative damage in perivascular mesenchymal progenitor cells. PHARMACEUTICAL BIOLOGY 2023; 61:768-778. [PMID: 37148130 PMCID: PMC10167876 DOI: 10.1080/13880209.2023.2207592] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
CONTEXT 5-Fluorouracil (5-FU)-injured stromal cells may cause chronic bone marrow suppression; however, the underlying mechanism remains unclear. Angelica sinensis polysaccharide (ASP), the main biologically active ingredient of the Chinese herb, Angelica sinensis (Oliv.) Diels (Apiaceae), may enrich the blood and promote antioxidation. OBJECTIVE This study investigated the protective antioxidative effects of ASP on perivascular mesenchymal progenitors (PMPs) and their interactions with hematopoietic cells. MATERIALS AND METHODS PMPs were dissociated from C57BL/6 mouse femur and tibia and were subsequently divided into the control, ASP (0.1 g/L), 5-FU (0.025 g/L), and 5-FU + ASP (pre-treatment with 0.1 g/L ASP for 6 h, together with 0.025 g/L 5-FU) then cultured for 48 h. Hematopoietic cells were co-cultured on these feeder layers for 24 h. Cell proliferation, senescence, apoptosis, and oxidative indices were detected, along with stromal osteogenic and adipogenic differentiation potentials. Intercellular and intracellular signaling was analyzed by real-time quantitative reverse transcription polymerase chain reaction and Western blotting. RESULTS ASP ameliorated the reactive oxygen species production/scavenge balance in PMPs; improved osteogenic differentiation; increased SCF, CXCL12, VLA-4/VCAM-1, ICAM-1/LFA1, and TPO/MPL, Ang-1/Tie-2 gene expression. Further, the ASP-treated feeder layer alleviated hematopoietic cells senescence (from 21.9 ± 1.47 to 12.1 ± 1.13); decreased P53, P21, p-GSK-3β, β-catenin and cyclin-D1 protein expression, and increased glycogen synthase kinase (GSK)-3β protein expression in co-cultured hematopoietic cells. DISCUSSION AND CONCLUSIONS ASP delayed oxidative stress-induced premature senescence of 5-FU-treated feeder co-cultured hematopoietic cells via down-regulation of overactivated Wnt/β-catenin signaling. These findings provide a new strategy for alleviating myelosuppressive stress.
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Affiliation(s)
- Yilin Niu
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, China
| | - Hanxianzhi Xiao
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, China
| | - Biyao Wang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, China
| | - Ziling Wang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, China
| | - Kunhang Du
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, China
| | - Yaping Wang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, China
- Department of Histology and Embryology, Chongqing Medical University, Chongqing, China
| | - Lu Wang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, China
- Department of Histology and Embryology, Chongqing Medical University, Chongqing, China
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Gao JL, Owusu-Ansah A, Yang A, Yim E, McDermott DH, Jacobs P, Majumdar S, Choi U, Sweeney CL, Malech HL, Murphy PM. CRISPR/Cas9-mediated Cxcr4 disease allele inactivation for gene therapy in a mouse model of WHIM syndrome. Blood 2023; 142:23-32. [PMID: 36928087 PMCID: PMC10356574 DOI: 10.1182/blood.2022019142] [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: 11/21/2022] [Revised: 02/07/2023] [Accepted: 03/10/2023] [Indexed: 03/18/2023] Open
Abstract
WHIM syndrome is an autosomal dominant immunodeficiency disorder caused by gain-of-function mutations in chemokine receptor CXCR4 that promote severe panleukopenia because of retention of mature leukocytes in the bone marrow (BM). We previously reported that Cxcr4-haploinsufficient (Cxcr4+/o) hematopoietic stem cells (HSCs) have a strong selective advantage for durable hematopoietic reconstitution over wild-type (Cxcr4+/+) and WHIM (Cxcr4+/w) HSCs and that a patient with WHIM was spontaneously cured by chromothriptic deletion of the disease allele in an HSC, suggesting that WHIM allele inactivation through gene editing may be a safe genetic cure strategy for the disease. We have developed a 2-step preclinical protocol of autologous hematopoietic stem and progenitor cell (HSPC) transplantation to achieve this goal. First, 1 copy of Cxcr4 in HSPCs was inactivated in vitro by CRISPR/Cas9 editing with a single guide RNA (sgRNA) that does not discriminate between Cxcr4+/w and Cxcr4+/+ alleles. Then, through in vivo natural selection, WHIM allele-inactivated cells were enriched over wild-type allele-inactivated cells. The WHIM allele-inactivated HSCs retained long-term pluripotency and selective hematopoietic reconstitution advantages. To our knowledge, this is the first example of gene therapy for an autosomal dominant gain-of-function disease using a disease allele inactivation strategy in place of the less efficient disease allele repair approach.
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Affiliation(s)
- Ji-Liang Gao
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Albert Owusu-Ansah
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Alexander Yang
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Erin Yim
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - David H. McDermott
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Paejonette Jacobs
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Shamik Majumdar
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Uimook Choi
- Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Colin L. Sweeney
- Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Harry L. Malech
- Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Philip M. Murphy
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
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Tanaka M, Thoma J, Poisa-Beiro L, Wuchter P, Eckstein V, Dietrich S, Pabst C, Müller-Tidow C, Ohta T, Ho AD. Physical biomarkers for human hematopoietic stem and progenitor cells. Cells Dev 2023; 174:203845. [PMID: 37116713 DOI: 10.1016/j.cdev.2023.203845] [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: 02/13/2023] [Revised: 04/18/2023] [Accepted: 04/21/2023] [Indexed: 04/30/2023]
Abstract
Adhesion of hematopoietic stem and progenitor cells (HSPCs) to the bone marrow niche plays critical roles in the maintenance of the most primitive HSPCs. The interactions of HSPC-niche interactions are clinically relevant in acute myeloid leukemia (AML), because (i) leukemia-initiating cells adhered to the marrow niche are protected from the cytotoxic effect by chemotherapy and (ii) mobilization of HSPCs from healthy donors' bone marrow is crucial for the effective stem cell transplantation. However, although many clinical agents have been developed for the HSPC mobilization, the effects caused by the extrinsic molecular cues were traditionally evaluated based on phenomenological observations. This review highlights the recent interdisciplinary challenges of hematologists, biophysicists and cell biologists towards the design of defined in vitro niche models and the development of physical biomarkers for quantitative indexing of differential effects of clinical agents on human HSPCs.
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Affiliation(s)
- Motomu Tanaka
- Physical Chemistry of Biosystems, Institute of Physical Chemistry, INF253, Heidelberg University, 69120 Heidelberg, Germany; Center for Integrative Medicine and Physics, Institute for Advanced Study, Kyoto University, 606-8501 Kyoto, Japan.
| | - Judith Thoma
- Physical Chemistry of Biosystems, Institute of Physical Chemistry, INF253, Heidelberg University, 69120 Heidelberg, Germany
| | - Laura Poisa-Beiro
- Department of Medicine V, Heidelberg University, INF410, 69120 Heidelberg, Germany
| | - Patrick Wuchter
- Department of Medicine V, Heidelberg University, INF410, 69120 Heidelberg, Germany
| | - Volker Eckstein
- Department of Medicine V, Heidelberg University, INF410, 69120 Heidelberg, Germany
| | - Sascha Dietrich
- Department of Medicine V, Heidelberg University, INF410, 69120 Heidelberg, Germany
| | - Caroline Pabst
- Department of Medicine V, Heidelberg University, INF410, 69120 Heidelberg, Germany
| | - Carsten Müller-Tidow
- Department of Medicine V, Heidelberg University, INF410, 69120 Heidelberg, Germany
| | - Takao Ohta
- Center for Integrative Medicine and Physics, Institute for Advanced Study, Kyoto University, 606-8501 Kyoto, Japan
| | - Anthony D Ho
- Center for Integrative Medicine and Physics, Institute for Advanced Study, Kyoto University, 606-8501 Kyoto, Japan; Department of Medicine V, Heidelberg University, INF410, 69120 Heidelberg, Germany; Molecular Medicine Partnership Unit Heidelberg, European Molecular Biology Laboratory (EMBL), Heidelberg University, 69120 Heidelberg, Germany.
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9
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Research progress of stem cell therapy for endometrial injury. Mater Today Bio 2022; 16:100389. [PMID: 36033375 PMCID: PMC9403503 DOI: 10.1016/j.mtbio.2022.100389] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 07/27/2022] [Accepted: 07/27/2022] [Indexed: 11/24/2022] Open
Abstract
Endometrial damage is an important factor leading to infertility and traditional conventional treatments have limited efficacy. As an emerging technology in recent years, stem cell therapy has provided new hope for the treatment of this disease. By comparing the advantages of stem cells from different sources, it is believed that menstrual blood endometrial stem cells have a good application prospect as a new source of stem cells. However, the clinical utility of stem cells is still limited by issues such as colonization rates, long-term efficacy, tumor formation, and storage and transportation. This paper summarizes the mechanism by which stem cells repair endometrial damage and clarifies the material basis of their effects from four aspects: replacement of damaged sites, paracrine effects, interaction with growth factors, and other new targets. According to the pathological characteristics and treatment requirements of intrauterine adhesion (IUA), the research work to solve the above problems from the aspects of functional bioscaffold preparation and multi-functional platform construction is also summarized. From the perspective of scaffold materials and component functions, this review will provide a reference for comprehensively optimizing the clinical application of stem cells.
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10
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Roy IM, Anu P, Zaunz S, Reddi S, Giri AM, Sankar RS, Schouteden S, Huelsken J, Verfaillie CM, Khurana S. Inhibition of SRC-mediated integrin signaling in bone marrow niche enhances hematopoietic stem cell function. iScience 2022; 25:105171. [PMID: 36204266 PMCID: PMC9530850 DOI: 10.1016/j.isci.2022.105171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 07/13/2022] [Accepted: 09/16/2022] [Indexed: 11/20/2022] Open
Abstract
Interaction with microenvironmental factors is crucial for the regulation of hematopoietic stem cell (HSC) function. Stroma derived factor (SDF)-1α supports HSCs in the quiescent state and is central to the homing of transplanted HSCs. Here, we show that integrin signaling regulates Sdf-1α expression transcriptionally. Systemic deletion of Periostin, an Integrin-αv ligand, showed increased expression of Sdf-1α in bone marrow (BM) niche. Pharmacological inhibition or CRISPR-Cas9-mediated deletion of SRC, resulted in a similar increase in the chemokine expression in vitro. Importantly, systemic SRC-inhibition led to increase in SDF-1α levels in BM plasma. This resulted in a robust increase (14.05 ± 1.22% to 29.11 ± 0.69%) in the homing efficiency of transplanted HSCs. In addition, we observed enhancement in the recovery of blood cell counts following radiation injury, indicating an enhanced hematopoietic function. These results establish a role of SRC-mediated integrin signaling in the transcriptional regulation of Sdf-1α. This mechanism could be harnessed further to improve the hematopoietic function.
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Affiliation(s)
- Irene Mariam Roy
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Thiruvananthapuram, Kerala 695551, India
| | - P.V. Anu
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Thiruvananthapuram, Kerala 695551, India
| | | | - Srinu Reddi
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Thiruvananthapuram, Kerala 695551, India
| | - Aravind M. Giri
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Thiruvananthapuram, Kerala 695551, India
| | - Rithika Saroj Sankar
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Thiruvananthapuram, Kerala 695551, India
| | | | - Joerg Huelsken
- École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
| | | | - Satish Khurana
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Thiruvananthapuram, Kerala 695551, India
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11
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Hughes AM, Kuek V, Kotecha RS, Cheung LC. The Bone Marrow Microenvironment in B-Cell Development and Malignancy. Cancers (Basel) 2022; 14:2089. [PMID: 35565219 PMCID: PMC9102980 DOI: 10.3390/cancers14092089] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/11/2022] [Accepted: 04/20/2022] [Indexed: 11/16/2022] Open
Abstract
B lymphopoiesis is characterized by progressive loss of multipotent potential in hematopoietic stem cells, followed by commitment to differentiate into B cells, which mediate the humoral response of the adaptive immune system. This process is tightly regulated by spatially distinct bone marrow niches where cells, including mesenchymal stem and progenitor cells, endothelial cells, osteoblasts, osteoclasts, and adipocytes, interact with B-cell progenitors to direct their proliferation and differentiation. Recently, the B-cell niche has been implicated in initiating and facilitating B-cell precursor acute lymphoblastic leukemia. Leukemic cells are also capable of remodeling the B-cell niche to promote their growth and survival and evade treatment. Here, we discuss the major cellular components of bone marrow niches for B lymphopoiesis and the role of the malignant B-cell niche in disease development, treatment resistance and relapse. Further understanding of the crosstalk between leukemic cells and bone marrow niche cells will enable development of additional therapeutic strategies that target the niches in order to hinder leukemia progression.
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Affiliation(s)
- Anastasia M. Hughes
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
| | - Vincent Kuek
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia
| | - Rishi S. Kotecha
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- School of Medicine, University of Western Australia, Perth, WA 6009, Australia
- Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children’s Hospital, Perth, WA 6009, Australia
| | - Laurence C. Cheung
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia
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12
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Maric DM, Velikic G, Maric DL, Supic G, Vojvodic D, Petric V, Abazovic D. Stem Cell Homing in Intrathecal Applications and Inspirations for Improvement Paths. Int J Mol Sci 2022; 23:ijms23084290. [PMID: 35457107 PMCID: PMC9027729 DOI: 10.3390/ijms23084290] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/26/2022] [Accepted: 04/01/2022] [Indexed: 02/04/2023] Open
Abstract
A transplanted stem cell homing is a directed migration from the application site to the targeted tissue. Intrathecal application of stem cells is their direct delivery to cerebrospinal fluid, which defines the homing path from the point of injection to the brain. In the case of neurodegenerative diseases, this application method has the advantage of no blood–brain barrier restriction. However, the homing efficiency still needs improvement and homing mechanisms elucidation. Analysis of current research results on homing mechanisms in the light of intrathecal administration revealed a discrepancy between in vivo and in vitro results and a gap between preclinical and clinical research. Combining the existing research with novel insights from cutting-edge biochips, nano, and other technologies and computational models may bridge this gap faster.
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Affiliation(s)
- Dusan M. Maric
- Department for Research and Development, Clinic Orto MD-Parks Dr Dragi Hospital, 21000 Novi Sad, Serbia;
- Faculty of Dentistry Pancevo, University Business Academy, 26000 Pancevo, Serbia
- Vincula Biotech Group, 11000 Belgrade, Serbia;
| | - Gordana Velikic
- Department for Research and Development, Clinic Orto MD-Parks Dr Dragi Hospital, 21000 Novi Sad, Serbia;
- Vincula Biotech Group, 11000 Belgrade, Serbia;
- Correspondence: (G.V.); (D.L.M.)
| | - Dusica L. Maric
- Department of Anatomy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia
- Correspondence: (G.V.); (D.L.M.)
| | - Gordana Supic
- Institute for Medical Research, Military Medical Academy, 11000 Belgrade, Serbia; (G.S.); (D.V.)
- Medical Faculty of Military Medical Academy, University of Defense, 11000 Belgrade, Serbia
| | - Danilo Vojvodic
- Institute for Medical Research, Military Medical Academy, 11000 Belgrade, Serbia; (G.S.); (D.V.)
- Medical Faculty of Military Medical Academy, University of Defense, 11000 Belgrade, Serbia
| | - Vedrana Petric
- Infectious Diseases Clinic, Clinical Center of Vojvodina, 21000 Novi Sad, Serbia;
- Department of Infectious Diseases, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia
| | - Dzihan Abazovic
- Vincula Biotech Group, 11000 Belgrade, Serbia;
- Department for Regenerative Medicine, Biocell Hospital, 11000 Belgrade, Serbia
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13
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Cell-Based Transplantation versus Cell Homing Approaches for Pulp-Dentin Complex Regeneration. Stem Cells Int 2021; 2021:8483668. [PMID: 34646323 PMCID: PMC8505125 DOI: 10.1155/2021/8483668] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/01/2021] [Accepted: 08/19/2021] [Indexed: 12/19/2022] Open
Abstract
Regenerative dentistry has paved the way for a new era for the replacement of damaged dental tissues. Whether the causative factor is dental caries, trauma, or chemical insult, the loss of the pulp vitality constitutes one of the major health problems worldwide. Two regenerative therapies were introduced for a fully functional pulp-dentin complex regeneration, namely, cell-based (cell transplantation) and cell homing (through revascularization or homing by injection of stem cells in situ or intravenously) therapies, with each demonstrating advantages as well as drawbacks, especially in clinical application. The present review is aimed at elaborating on these two techniques in the treatment of irreversibly inflamed or necrotic pulp, which is aimed at regenerating a fully functional pulp-dentin complex.
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14
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Niches that regulate stem cells and hematopoiesis in adult bone marrow. Dev Cell 2021; 56:1848-1860. [PMID: 34146467 DOI: 10.1016/j.devcel.2021.05.018] [Citation(s) in RCA: 157] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/27/2021] [Accepted: 05/27/2021] [Indexed: 01/08/2023]
Abstract
In mammals, hematopoietic stem cells (HSCs) engage in hematopoiesis throughout adult life within the bone marrow, where they produce the mature cells necessary to maintain blood cell counts and immune function. In the bone marrow and spleen, HSCs are sustained in perivascular niches (microenvironments) associated with sinusoidal blood vessels-specialized veins found only in hematopoietic tissues. Endothelial cells and perivascular leptin receptor+ stromal cells produce the known factors required to maintain HSCs and many restricted progenitors in the bone marrow. Various other cells synthesize factors that maintain other restricted progenitors or modulate HSC or niche function. Recent studies identified new markers that resolve some of the heterogeneity among stromal cells and refine the localization of restricted progenitor niches. Other recent studies identified ways in which niches regulate HSC function and hematopoiesis beyond growth factors. We summarize the current understanding of hematopoietic niches, review recent progress, and identify important unresolved questions.
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15
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Low-dose decitabine for refractory prolonged isolated thrombocytopenia after HCT: a randomized multicenter trial. Blood Adv 2021; 5:1250-1258. [PMID: 33646303 DOI: 10.1182/bloodadvances.2020002790] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
Refractory prolonged isolated thrombocytopenia (RPIT) is an intractable complication after allogeneic hematopoietic cell transplantation (HCT), which often leads to poor prognosis. A clinical study was designed to validate the efficacy and safety of low-dose decitabine for RPIT after HCT and explore the related underlying mechanisms. Eligible patients were randomly allocated to receive 1 of 3 interventions: arm A, low-dose decitabine (15 mg/m2 daily IV for 3 consecutive days [days 1-3]) plus recombinant human thrombopoietin (300 U/kg daily); arm B, decitabine alone; or arm C, conventional treatment. The primary end point was the response rate of platelet recovery at day 28 after treatment. Secondary end points included megakaryocyte count 28 days after treatment and survival during additional follow-up of 24 weeks. Among the 91 evaluable patients, response rates were 66.7%, 73.3%, and 19.4% for the 3 arms, respectively (P < .001). One-year survival rates in arms A (64.4% ± 9.1%) and B (73.4% ± 8.8%) were similar (P = .662), and both were superior to that in arm C (41.0% ± 9.8%; P = .025). Megakaryocytes, endothelial cells (ECs), and cytokines relating to megakaryocyte migration and EC damage were improved in patients responding to decitabine. This study showed low-dose decitabine improved platelet recovery as well as overall survival in RPIT patients after transplantation. This trial was registered at www.clinicaltrials.gov as #NCT02487563.
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16
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Luker GD, Yang J, Richmond A, Scala S, Festuccia C, Schottelius M, Wester HJ, Zimmermann J. At the Bench: Pre-clinical evidence for multiple functions of CXCR4 in cancer. J Leukoc Biol 2021; 109:969-989. [PMID: 33104270 PMCID: PMC8254203 DOI: 10.1002/jlb.2bt1018-715rr] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 12/15/2022] Open
Abstract
Signaling through chemokine receptor, C-X-C chemokine receptor type 4 (CXCR4) regulates essential processes in normal physiology, including embryogenesis, tissue repair, angiogenesis, and trafficking of immune cells. Tumors co-opt many of these fundamental processes to directly stimulate proliferation, invasion, and metastasis of cancer cells. CXCR4 signaling contributes to critical functions of stromal cells in cancer, including angiogenesis and multiple cell types in the tumor immune environment. Studies in animal models of several different types of cancers consistently demonstrate essential functions of CXCR4 in tumor initiation, local invasion, and metastasis to lymph nodes and distant organs. Data from animal models support clinical observations showing that integrated effects of CXCR4 on cancer and stromal cells correlate with metastasis and overall poor prognosis in >20 different human malignancies. Small molecules, Abs, and peptidic agents have shown anticancer efficacy in animal models, sparking ongoing efforts at clinical translation for cancer therapy. Investigators also are developing companion CXCR4-targeted imaging agents with potential to stratify patients for CXCR4-targeted therapy and monitor treatment efficacy. Here, pre-clinical studies demonstrating functions of CXCR4 in cancer are reviewed.
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Affiliation(s)
- Gary D Luker
- Departments of Radiology, Biomedical Engineering, and Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA
| | - Jinming Yang
- School of Medicine, Vanderbilt University, Nashville, Tennessee, USA
| | - Ann Richmond
- School of Medicine, Vanderbilt University, Nashville, Tennessee, USA
| | - Stefania Scala
- Research Department, Microenvironment Molecular Targets, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, Italy
| | - Claudio Festuccia
- Department of Applied Clinical Science and Biotechnologies, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy
| | - Margret Schottelius
- Department of Nuclear Medicine, Centre Hospitalier Universitaire Vaudois, and Department of Oncology, University of Lausanne, Lausanne, Switzerland
| | - Hans-Jürgen Wester
- Department of Chemistry, Technical University of Munich, Garching, Germany
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17
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Andrzejewska A, Dabrowska S, Lukomska B, Janowski M. Mesenchymal Stem Cells for Neurological Disorders. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2002944. [PMID: 33854883 PMCID: PMC8024997 DOI: 10.1002/advs.202002944] [Citation(s) in RCA: 187] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 11/23/2020] [Indexed: 05/13/2023]
Abstract
Neurological disorders are becoming a growing burden as society ages, and there is a compelling need to address this spiraling problem. Stem cell-based regenerative medicine is becoming an increasingly attractive approach to designing therapies for such disorders. The unique characteristics of mesenchymal stem cells (MSCs) make them among the most sought after cell sources. Researchers have extensively studied the modulatory properties of MSCs and their engineering, labeling, and delivery methods to the brain. The first part of this review provides an overview of studies on the application of MSCs to various neurological diseases, including stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, and other less frequently studied clinical entities. In the second part, stem cell delivery to the brain is focused. This fundamental but still understudied problem needs to be overcome to apply stem cells to brain diseases successfully. Here the value of cell engineering is also emphasized to facilitate MSC diapedesis, migration, and homing to brain areas affected by the disease to implement precision medicine paradigms into stem cell-based therapies.
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Affiliation(s)
- Anna Andrzejewska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Sylwia Dabrowska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Barbara Lukomska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Miroslaw Janowski
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
- Center for Advanced Imaging ResearchDepartment of Diagnostic Radiology and Nuclear MedicineUniversity of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of MarylandBaltimoreMD21201‐1595USA
- Tumor Immunology and Immunotherapy ProgramUniversity of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of MarylandBaltimoreMD21201‐1595USA
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18
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Zorina T, Black L. Mesenchymal–Hematopoietic Stem Cell Axis: Applications for Induction of Hematopoietic Chimerism and Therapies for Malignancies. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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19
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Goto T, Murata M, Nishida T, Terakura S, Kamoshita S, Ishikawa Y, Ushijima Y, Adachi Y, Suzuki S, Kato K, Hirakawa A, Nishiwaki S, Nishio N, Takahashi Y, Kodera Y, Matsushita T, Kiyoi H. Phase I clinical trial of intra-bone marrow cotransplantation of mesenchymal stem cells in cord blood transplantation. Stem Cells Transl Med 2020; 10:542-553. [PMID: 33314650 PMCID: PMC7980216 DOI: 10.1002/sctm.20-0381] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/23/2020] [Accepted: 11/12/2020] [Indexed: 01/25/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have immunomodulatory properties and support hematopoiesis in the bone marrow (BM). To develop a new strategy to not only prevent graft‐vs‐host disease (GVHD) but also to enhance engraftment, a phase I trial of cord blood transplantation (CBT) combined with intra‐BM injection of MSCs (MSC‐CBT) was designed. Third‐party BM‐derived MSCs were injected intra‐BM on the day of CBT. The conditioning regimen varied according to patient characteristics. GVHD prophylaxis was tacrolimus and methotrexate. The primary endpoint was toxicity related to intra‐BM injection of MSCs. Clinical outcomes were compared with those of six controls who received CBT alone. Five adult patients received MSC‐CBT, and no adverse events related to intra‐BM injection of MSCs were observed. All patients achieved neutrophil, reticulocyte, and platelet recoveries, with median times to recoveries of 21, 35, and 38 days, respectively, comparable with controls. Grade II‐IV acute GVHD developed in three controls but not in MSC‐CBT patients. No patients developed chronic GVHD in both groups. At 1 year after transplantation, all MSC‐CBT patients survived without relapse. This study shows the safety of MSC‐CBT, and the findings also suggest that cotransplantation of MSCs may prevent GVHD with no inhibition of engraftment. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as number 000024291.
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Affiliation(s)
- Tatsunori Goto
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Makoto Murata
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tetsuya Nishida
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Seitaro Terakura
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Sonoko Kamoshita
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuichi Ishikawa
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoko Ushijima
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiya Adachi
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Satoshi Suzuki
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Katsuyoshi Kato
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Akihiro Hirakawa
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Satoshi Nishiwaki
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Nobuhiro Nishio
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Yoshiyuki Takahashi
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihisa Kodera
- Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Tadashi Matsushita
- Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Hitoshi Kiyoi
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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20
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Rafieemehr H, Maleki Behzad M, Azandeh S, Farshchi N, Ghasemi Dehcheshmeh M, Saki N. Chemo/radiotherapy-Induced Bone Marrow Niche Alterations. Cancer Invest 2020; 39:180-194. [PMID: 33225760 DOI: 10.1080/07357907.2020.1855353] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Bone marrow (BM) niche is a specific microenvironment for hematopoietic stem cells (HSCs) as well as non-hematopoietic cells. Evidence shows that chemo/radiotherapy can lead to the disruption of different properties of HSCs such as proliferation, differentiation, localization, self-renewa, and steady-state of cell populations. Investigations have shown that the deregulation of balance within the marrow cavity due to chemo/radiotherapy could lead to bone loss, abnormal hematopoiesis, and enhanced differentiation potential of mesenchymal stem cells towards the adipogenic lineage. Therefore, understanding the underlying mechanisms of chemo/radiotherapy induced BM niche changes may lead to the application of appropriate therapeutic agents to prevent BM niche defects. Highlights Chemo/radiotherapy disrupts the steady-state of bone marrow niche cells and result in deregulation of normal balance of stromal cell populations. Chemo/radiotherapy agents play a significant role in reducing of bone formation as well as fat accumulation in the bone marrow niche. Targeting molecular pathways may lead to recovery of bone marrow niches after chemo/radiotherapy.
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Affiliation(s)
- Hassan Rafieemehr
- Department of Medical Laboratory Sciences, School of Paramedicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Masumeh Maleki Behzad
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Blood Transfusion Research Center, High Institute for Research and Education in Transfusion, Hamadan, Iran
| | - Saeed Azandeh
- Cellular and Molecular Research Center (CMRC), Department of Anatomical Sciences, Faculty of Medicin, Ahvaz Jundishapur University of Medical Sciences (AJUMS), Ahvaz, Iran
| | - Niloofar Farshchi
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Najmaldin Saki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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21
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Zeissig MN, Zannettino ACW, Vandyke K. Tumour Dissemination in Multiple Myeloma Disease Progression and Relapse: A Potential Therapeutic Target in High-Risk Myeloma. Cancers (Basel) 2020; 12:cancers12123643. [PMID: 33291672 PMCID: PMC7761917 DOI: 10.3390/cancers12123643] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/02/2020] [Accepted: 12/02/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Like in solid cancers, the process of dissemination is a critical feature of disease progression in the blood cancer multiple myeloma. At diagnosis, myeloma patients have cancer that has spread throughout the bone marrow, with patients with more disseminatory myeloma having worse outcomes for their disease. In this review, we discuss the current understanding of the mechanisms that underpin the dissemination process in multiple myeloma. Furthermore, we discuss the potential for the use of therapies that target the dissemination process as a novel means of improving outcomes for multiple myeloma patients. Abstract Multiple myeloma (MM) is a plasma cell (PC) malignancy characterised by the presence of MM PCs at multiple sites throughout the bone marrow. Increased numbers of peripheral blood MM PCs are associated with rapid disease progression, shorter time to relapse and are a feature of advanced disease. In this review, the current understanding of the process of MM PC dissemination and the extrinsic and intrinsic factors potentially driving it are addressed through analysis of patient-derived MM PCs and MM cell lines as well as mouse models of homing and dissemination. In addition, we discuss how patient cytogenetic subgroups that present with highly disseminated disease, such as t(4;14), t(14;16) and t(14;20), suggest that intrinsic properties of MM PC influence their ability to disseminate. Finally, we discuss the possibility of using therapeutic targeting of tumour dissemination to slow disease progression and prevent overt relapse.
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Affiliation(s)
- Mara N. Zeissig
- Myeloma Research Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, The University of Australia, Adelaide 5005, Australia; (M.N.Z.); (A.C.W.Z.)
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide 5000, Australia
| | - Andrew C. W. Zannettino
- Myeloma Research Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, The University of Australia, Adelaide 5005, Australia; (M.N.Z.); (A.C.W.Z.)
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide 5000, Australia
- Central Adelaide Local Health Network, Adelaide 5000, Australia
- Centre for Cancer Biology, University of South Australia, Adelaide 5000, Australia
| | - Kate Vandyke
- Myeloma Research Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, The University of Australia, Adelaide 5005, Australia; (M.N.Z.); (A.C.W.Z.)
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide 5000, Australia
- Correspondence: ; Tel.: +61-8-8128-4694
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22
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Olson OC, Kang YA, Passegué E. Normal Hematopoiesis Is a Balancing Act of Self-Renewal and Regeneration. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a035519. [PMID: 31988205 DOI: 10.1101/cshperspect.a035519] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The hematopoietic system is highly organized to maintain its functional integrity and to meet lifelong organismal demands. Hematopoietic stem cells (HSCs) must balance self-renewal with differentiation and the regeneration of the blood system. It is a complex balancing act between these competing HSC functions. Although highly quiescent at steady state, HSCs become activated in response to inflammatory cytokines and regenerative challenges. This activation phase leads to many intrinsic stresses such as replicative, metabolic, and oxidative stress, which can cause functional decline, impaired self-renewal, and exhaustion of HSCs. To cope with these insults, HSCs use both built-in and emergency-triggered stress-response mechanisms to maintain homeostasis and to defend against disease development. In this review, we discuss how the hematopoietic system operates in steady state and stress conditions, what strategies are used to maintain functional integrity, and how deregulation in the balance between self-renewal and regeneration can drive malignant transformation.
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Affiliation(s)
- Oakley C Olson
- Columbia Stem Cell Initiative, Department of Genetics & Development, Columbia University Irving Medical Center, New York, New York 10032, USA
| | - Yoon-A Kang
- Columbia Stem Cell Initiative, Department of Genetics & Development, Columbia University Irving Medical Center, New York, New York 10032, USA
| | - Emmanuelle Passegué
- Columbia Stem Cell Initiative, Department of Genetics & Development, Columbia University Irving Medical Center, New York, New York 10032, USA
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23
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Rajan V, Melong N, Wong WH, King B, Tong RS, Mahajan N, Gaston D, Lund T, Rittenberg D, Dellaire G, Campbell CJ, Druley T, Berman JN. Humanized zebrafish enhance human hematopoietic stem cell survival and promote acute myeloid leukemia clonal diversity. Haematologica 2020; 105:2391-2399. [PMID: 33054079 PMCID: PMC7556680 DOI: 10.3324/haematol.2019.223040] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 12/05/2019] [Indexed: 11/25/2022] Open
Abstract
Xenograft models are invaluable tools in establishing the current paradigms of hematopoiesis and leukemogenesis. The zebrafish has emerged as a robust alternative xenograft model but, like mice, lack specific cytokines that mimic the microenvironment found in human patients. To address this critical gap, we generated the first humanized zebrafish that express human hematopoietic-specific cytokines (GM-CSF, SCF, and SDF1α). Termed GSS fish, these zebrafish promote survival, self-renewal and multilineage differentiation of human hematopoietic stem and progenitor cells and result in enhanced proliferation and hematopoietic niche-specific homing of primary human leukemia cells. Using error-corrected RNA sequencing, we determined that patient-derived leukemias transplanted into GSS zebrafish exhibit broader clonal representation compared to transplants into control hosts. GSS zebrafish incorporating error-corrected RNA sequencing establish a new standard for zebrafish xenotransplantation that more accurately recapitulates the human context, providing a more representative cost-effective preclinical model system for evaluating personalized response-based treatment in leukemia and therapies to expand human hematopoietic stem and progenitor cells in the transplant setting.
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Affiliation(s)
- Vinothkumar Rajan
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Nicole Melong
- Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada
| | - Wing Hing Wong
- Department of Pediatrics, Division of Hematology-Oncology, Washington University, St. Louis, MO, USA
| | - Benjamin King
- Department of Ocean Sciences, Memorial University, St. John’s, Newfoundland and Labrador, Canada
| | - R. Spencer Tong
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Nitin Mahajan
- Department of Pediatrics, Division of Hematology-Oncology, Washington University, St. Louis, MO, USA
| | - Daniel Gaston
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Troy Lund
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - David Rittenberg
- Department of Obstetrics and Gynecology, IWK Health Science Center, Halifax, Nova Scotia, Canada
| | - Graham Dellaire
- Departments of Pathology and Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Clinton J.V. Campbell
- Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada and
| | - Todd Druley
- Department of Pediatrics, Division of Hematology-Oncology, Washington University, St. Louis, MO, USA
| | - Jason N. Berman
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
- Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada
- CHEO Research Institute, Ottawa, Ontario, Canada
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24
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Cellular and Molecular Mechanisms of Environmental Pollutants on Hematopoiesis. Int J Mol Sci 2020; 21:ijms21196996. [PMID: 32977499 PMCID: PMC7583016 DOI: 10.3390/ijms21196996] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/20/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023] Open
Abstract
Hematopoiesis is a complex and intricate process that aims to replenish blood components in a constant fashion. It is orchestrated mostly by hematopoietic progenitor cells (hematopoietic stem cells (HSCs)) that are capable of self-renewal and differentiation. These cells can originate other cell subtypes that are responsible for maintaining vital functions, mediate innate and adaptive immune responses, provide tissues with oxygen, and control coagulation. Hematopoiesis in adults takes place in the bone marrow, which is endowed with an extensive vasculature conferring an intense flow of cells. A myriad of cell subtypes can be found in the bone marrow at different levels of activation, being also under constant action of an extensive amount of diverse chemical mediators and enzymatic systems. Bone marrow platelets, mature erythrocytes and leukocytes are delivered into the bloodstream readily available to meet body demands. Leukocytes circulate and reach different tissues, returning or not returning to the bloodstream. Senescent leukocytes, specially granulocytes, return to the bone marrow to be phagocytized by macrophages, restarting granulopoiesis. The constant high production and delivery of cells into the bloodstream, alongside the fact that blood cells can also circulate between tissues, makes the hematopoietic system a prime target for toxic agents to act upon, making the understanding of the bone marrow microenvironment vital for both toxicological sciences and risk assessment. Environmental and occupational pollutants, therapeutic molecules, drugs of abuse, and even nutritional status can directly affect progenitor cells at their differentiation and maturation stages, altering behavior and function of blood compounds and resulting in impaired immune responses, anemias, leukemias, and blood coagulation disturbances. This review aims to describe the most recently investigated molecular and cellular toxicity mechanisms of current major environmental pollutants on hematopoiesis in the bone marrow.
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25
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Abstract
A central feature of atherosclerosis, the most prevalent chronic vascular disease and root cause of myocardial infarction and stroke, is leukocyte accumulation in the arterial wall. These crucial immune cells are produced in specialized niches in the bone marrow, where a complex cell network orchestrates their production and release. A growing body of clinical studies has documented a correlation between leukocyte numbers and cardiovascular disease risk. Understanding how leukocytes are produced and how they contribute to atherosclerosis and its complications is, therefore, critical to understanding and treating the disease. In this review, we focus on the key cells and products that regulate hematopoiesis under homeostatic conditions, during atherosclerosis and after myocardial infarction.
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Affiliation(s)
- Wolfram C Poller
- From the Center for Systems Biology (W.C.P., M.N., F.K.S.), Massachusetts General Hospital and Harvard Medical School, Boston
| | - Matthias Nahrendorf
- From the Center for Systems Biology (W.C.P., M.N., F.K.S.), Massachusetts General Hospital and Harvard Medical School, Boston
- Department of Radiology (M.N., F.K.S.), Massachusetts General Hospital and Harvard Medical School, Boston
| | - Filip K Swirski
- From the Center for Systems Biology (W.C.P., M.N., F.K.S.), Massachusetts General Hospital and Harvard Medical School, Boston
- Department of Radiology (M.N., F.K.S.), Massachusetts General Hospital and Harvard Medical School, Boston
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26
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Analysis of a large single institution cohort of related donors fails to detect a relation between SDF1/CXCR4 or VCAM/VLA4 genetic polymorphisms and the level of hematopoietic progenitor cell mobilization in response to G-CSF. PLoS One 2020; 15:e0228878. [PMID: 32134938 PMCID: PMC7058310 DOI: 10.1371/journal.pone.0228878] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 01/24/2020] [Indexed: 02/07/2023] Open
Abstract
We studied a cohort of 367 healthy related donors who volunteered to donate their hematopoietic stem cells for allogeneic transplantation. All donors were homogeneously cared for at a single institution, and received rhG-CSF as a mobilization treatment prior to undergoing apheresis. Peripheral blood CD34+ cell counts were used as the main surrogate marker for rhG-CSF induced mobilization. We searched whether inter-individual variations in known genetic polymorphisms located in genes whose products are functionally important for mobilization, could affect the extent of CD34+ mobilization, either individually or in combination. We found little or no influence of individual SNPs or haplotypes for the SDF1, CXCR4, VCAM and VLA4 genes, whether using CD34+ cell counts as a continuous or a categorical variable. Simple clinical characteristics describing donors such as body mass index, age and possibly sex are more potent predictors of stem cell mobilization. The size of our cohort remains relatively small for genetic analyses, however compares favorably with cohorts analyzed in previously published reports suggesting associations of genetic traits to response to rhG-CSF; notwithstanding this limitation, our data do not support the use of genetic analyses when the choice exists of several potential donors for a given patient.
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27
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Zarrer J, Haider MT, Smit DJ, Taipaleenmäki H. Pathological Crosstalk between Metastatic Breast Cancer Cells and the Bone Microenvironment. Biomolecules 2020; 10:biom10020337. [PMID: 32092997 PMCID: PMC7072692 DOI: 10.3390/biom10020337] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 02/15/2020] [Accepted: 02/17/2020] [Indexed: 12/12/2022] Open
Abstract
Bone is the most common metastatic site in breast cancer. Upon arrival to the bone, disseminated tumor cells can undergo a period of dormancy but often eventually grow and hijack the bone microenvironment. The bone marrow microenvironment consists of multiple cell types including the bone cells, adipocytes, endothelial cells, and nerve cells that all have crucial functions in the maintenance of bone homeostasis. Tumor cells severely disturb the tightly controlled cellular and molecular interactions in the bone marrow fueling their own survival and growth. While the role of bone resorbing osteoclasts in breast cancer bone metastases is well established, the function of other bone cells, as well as adipocytes, endothelial cells, and nerve cells is less understood. In this review, we discuss the composition of the physiological bone microenvironment and how the presence of tumor cells influences the microenvironment, creating a pathological crosstalk between the cells. A better understanding of the cellular and molecular events that occur in the metastatic bone microenvironment could facilitate the identification of novel cellular targets to treat this devastating disease.
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Affiliation(s)
- Jennifer Zarrer
- Molecular Skeletal Biology Laboratory, Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Marie-Therese Haider
- Molecular Skeletal Biology Laboratory, Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Daniel J. Smit
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Hanna Taipaleenmäki
- Molecular Skeletal Biology Laboratory, Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Correspondence:
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28
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Black L, Zorina T. Cell-based immunomodulatory therapy approaches for type 1 diabetes mellitus. Drug Discov Today 2020; 25:380-391. [DOI: 10.1016/j.drudis.2019.11.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/11/2019] [Accepted: 11/30/2019] [Indexed: 12/14/2022]
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29
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Chen M, Li R, Yin W, Wang T, Kang YJ. Copper promotes migration of adipose-derived stem cells by enhancing vimentin-Ser39 phosphorylation. Exp Cell Res 2020; 388:111859. [PMID: 31972217 DOI: 10.1016/j.yexcr.2020.111859] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 01/16/2020] [Accepted: 01/19/2020] [Indexed: 02/05/2023]
Abstract
Mesenchymal stem cells (MSCs) are widely studied for their application in cell therapy. A noticed drawback of these cells in response to tissue injury is the low efficiency of homing. The present study was undertaken to explore a possible approach to promote the migration of MSCs. Primary cultures of rat adipose-derived stem cells (rADSCs) were cultured in standard L-DMEM media supplemented with or without copper (Cu) at its final concentration of 20 μM in cultures. The analyses of transwell and wound-healing assay revealed that Cu supplementation significantly promotes the migration of rADSCs in cultures. Further analysis found that Cu stimulated the phosphorylation of vimentin Ser39. Point mutation of vimentin Ser39 by substituting Ser with Ala prevented Cu-promoted migration of rADSCs. This study thus demonstrates that Cu promotes migration of rADSCs in cultures through at least in part Cu stimulation of vimentin Ser39 phosphorylation.
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Affiliation(s)
- Mengqi Chen
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan, 610041, China
| | - Rui Li
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan, 610041, China
| | - Wen Yin
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan, 610041, China
| | - Tao Wang
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan, 610041, China
| | - Y James Kang
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan, 610041, China.
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30
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Naudot M, Barre A, Caula A, Sevestre H, Dakpé S, Mueller AA, Devauchelle B, Testelin S, Marolleau JP, Le Ricousse S. Co-transplantation of Wharton's jelly mesenchymal stem cell-derived osteoblasts with differentiated endothelial cells does not stimulate blood vessel and osteoid formation in nude mice models. J Tissue Eng Regen Med 2020; 14:257-271. [PMID: 31713308 DOI: 10.1002/term.2989] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 09/23/2019] [Accepted: 10/11/2019] [Indexed: 12/30/2022]
Abstract
A major challenge in bone tissue engineering is the lack of post-implantation vascular growth into biomaterials. In the skeletal system, blood vessel growth appears to be coupled to osteogenesis-suggesting the existence of molecular crosstalk between endothelial cells (ECs) and osteoblastic cells. The present study (performed in two murine ectopic models) was designed to determine whether co-transplantation of human Wharton's jelly mesenchymal stem cell-derived osteoblasts (WJMSC-OBs) and human differentiated ECs enhances bone regeneration and stimulates angiogenesis, relative to the seeding of WJMSC-OBs alone. Human WJMSC-OBs and human ECs were loaded into a silicate-substituted calcium phosphate (SiCaP) scaffold and then ectopically implanted at subcutaneous or intramuscular sites in nude mice. At both subcutaneous and intramuscular implantation sites, we observed ectopic bone formation and osteoids composed of host cells when WJMSC-OBs were seeded into the scaffold. However, the addition of ECs was associated with a lower level of osteogenesis, and we did not observe stimulation of blood vessel ingrowth. in vitro studies demonstrated that WJMSC-OBs lost their ability to secrete vascular endothelial growth factor and stromal cell-derived factor 1-including when ECs were present. In these two murine ectopic models, our cell-matrix environment combination did not seem to be optimal for inducing vascularized bone reconstruction.
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Affiliation(s)
- Marie Naudot
- EA 7516, CHIMERE, University of Picardie Jules Verne, Amiens, France
| | - Anaïs Barre
- EA 7516, CHIMERE, University of Picardie Jules Verne, Amiens, France
| | - Alexandre Caula
- Service de chirurgie maxillo-faciale, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France
| | - Henri Sevestre
- Service d'anatomie et de cytology pathologique, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France
| | - Stéphanie Dakpé
- EA 7516, CHIMERE, University of Picardie Jules Verne, Amiens, France.,Service de chirurgie maxillo-faciale, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France.,Institut Faire Faces, Amiens, France
| | - Andreas Albert Mueller
- Department of Cranio-Maxillofacial Surgery, University and University Hospital Basel, Basel, Switzerland.,Department of Biomedical Engineering, Regenerative Medicine and Oral Health Technologies, University of Basel, Allschwil, Switzerland
| | - Bernard Devauchelle
- EA 7516, CHIMERE, University of Picardie Jules Verne, Amiens, France.,Service de chirurgie maxillo-faciale, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France.,Institut Faire Faces, Amiens, France
| | - Sylvie Testelin
- EA 7516, CHIMERE, University of Picardie Jules Verne, Amiens, France.,Service de chirurgie maxillo-faciale, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France.,Institut Faire Faces, Amiens, France
| | - Jean Pierre Marolleau
- Service d'Hématologie Clinique, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France.,EA 4666, HEMATIM, University of Picardie Jules Verne, Amiens, France
| | - Sophie Le Ricousse
- EA 7516, CHIMERE, University of Picardie Jules Verne, Amiens, France.,Institut Faire Faces, Amiens, France
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31
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Cardoso BA. The Bone Marrow Niche - The Tumor Microenvironment That Ensures Leukemia Progression. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1219:259-293. [PMID: 32130704 DOI: 10.1007/978-3-030-34025-4_14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The human body requires a constant delivery of fresh blood cells that are needed to maintain body homeostasis. Hematopoiesis is the process that drives the formation of new blood cells from a single stem cell. This is a complex, orchestrated and tightly regulated process that occurs within the bone marrow. When such process is faulty or deregulated, leukemia arises, develops and thrives by subverting normal hematopoiesis and availing the supplies of this rich milieu.In this book chapter we will describe and characterize the bone marrow microenvironment and its key importance for leukemia expansion. The several components of the bone marrow niche, their interaction with the leukemic cells and the cellular pathways activated within the malignant cells will be emphasized. Finally, novel therapeutic strategies to target this sibling interaction will also be discussed.
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Affiliation(s)
- Bruno António Cardoso
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
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32
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Mcheik S, Van Eeckhout N, De Poorter C, Galés C, Parmentier M, Springael JY. Coexpression of CCR7 and CXCR4 During B Cell Development Controls CXCR4 Responsiveness and Bone Marrow Homing. Front Immunol 2019; 10:2970. [PMID: 31921208 PMCID: PMC6930800 DOI: 10.3389/fimmu.2019.02970] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 12/03/2019] [Indexed: 12/11/2022] Open
Abstract
The CXCL12-CXCR4 axis plays a key role in the retention of stem cells and progenitors in dedicated bone marrow niches. It is well-known that CXCR4 responsiveness in B lymphocytes decreases dramatically during the final stages of their development in the bone marrow. However, the molecular mechanism underlying this regulation and whether it plays a role in B-cell homeostasis remain unknown. In the present study, we show that the differentiation of pre-B cells into immature and mature B cells is accompanied by modifications to the relative expression of chemokine receptors, with a two-fold downregulation of CXCR4 and upregulation of CCR7. We demonstrate that expression of CCR7 in B cells is involved in the selective inactivation of CXCR4, and that mature B cells from CCR7-/- mice display higher responsiveness to CXCL12 and improved retention in the bone marrow. We also provide molecular evidence supporting a model in which upregulation of CCR7 favors the formation of CXCR4-CCR7 heteromers, wherein CXCR4 is selectively impaired in its ability to activate certain G-protein complexes. Collectively, our results demonstrate that CCR7 behaves as a novel selective endogenous allosteric modulator of CXCR4.
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Affiliation(s)
- Saria Mcheik
- Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium
| | - Nils Van Eeckhout
- Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium
| | - Cédric De Poorter
- Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium
| | - Céline Galés
- Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, Université Toulouse III Paul Sabatier, Toulouse, France
| | - Marc Parmentier
- Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium
- Walloon Excellence in Life Sciences and Biotechnology, Brussels, Belgium
| | - Jean-Yves Springael
- Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium
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33
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Gilbert W, Bragg R, Elmansi AM, McGee-Lawrence ME, Isales CM, Hamrick MW, Hill WD, Fulzele S. Stromal cell-derived factor-1 (CXCL12) and its role in bone and muscle biology. Cytokine 2019; 123:154783. [PMID: 31336263 PMCID: PMC6948927 DOI: 10.1016/j.cyto.2019.154783] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 07/08/2019] [Accepted: 07/16/2019] [Indexed: 02/07/2023]
Abstract
Musculoskeletal disorders are the leading cause of disability worldwide; two of the most prevalent of which are osteoporosis and sarcopenia. Each affect millions in the aging population across the world and the associated morbidity and mortality contributes to billions of dollars in annual healthcare cost. Thus, it is important to better understand the underlying pathologic mechanisms of the disease process. Regulatory chemokine, CXCL12, and its receptor, CXCR4, are recognized to be essential in the recruitment, localization, maintenance, development and differentiation of progenitor stem cells of the musculoskeletal system. CXCL12 signaling results in the development and functional ability of osteoblasts, osteoclasts, satellite cells and myoblasts critical to maintaining musculoskeletal homeostasis. Interestingly, one suggested pathologic mechanism of osteoporosis and sarcopenia is a decline in the regenerative capacity of musculoskeletal progenitor stem cells. Thus, because CXCL12 is critical to progenitor function, a disruption in the CXCL12 signaling axis might play a distinct role in these pathological processes. Therefore, in this article, we perform a review of CXCL12, its physiologic and pathologic function in bone and muscle, and potential targets for therapeutic development.
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Affiliation(s)
- William Gilbert
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA 30912, United States
| | - Robert Bragg
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA 30912, United States
| | - Ahmed M Elmansi
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, United States
| | - Meghan E McGee-Lawrence
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA 30912, United States; Cell Biology and Anatomy, Augusta University, Augusta, GA 30912, United States
| | - Carlos M Isales
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA 30912, United States; Department of Medicine, Augusta University, Augusta, GA 30912, United States
| | - Mark W Hamrick
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA 30912, United States; Cell Biology and Anatomy, Augusta University, Augusta, GA 30912, United States
| | - William D Hill
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, United States; Ralph H Johnson Veterans Affairs Medical Center, Charleston, SC 29403, United States
| | - Sadanand Fulzele
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA 30912, United States; Cell Biology and Anatomy, Augusta University, Augusta, GA 30912, United States.
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34
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Metalloproteases: On the Watch in the Hematopoietic Niche. Trends Immunol 2019; 40:1053-1070. [DOI: 10.1016/j.it.2019.09.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 08/15/2019] [Accepted: 09/20/2019] [Indexed: 12/19/2022]
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35
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Brylka LJ, Schinke T. Chemokines in Physiological and Pathological Bone Remodeling. Front Immunol 2019; 10:2182. [PMID: 31572390 PMCID: PMC6753917 DOI: 10.3389/fimmu.2019.02182] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 08/29/2019] [Indexed: 12/21/2022] Open
Abstract
The bone matrix is constantly remodeled by bone-resorbing osteoclasts and bone-forming osteoblasts. These two cell types are fundamentally different in terms of progenitor cells, mode of action and regulation by specific molecules, acting either systemically or locally. Importantly, there is increasing evidence for an impact of cell types or molecules of the adaptive and innate immune system on bone remodeling. Understanding these influences is the major goal of a novel research area termed osteoimmunology, which is of key relevance in the context of inflammation-induced bone loss, skeletal metastases, and diseases of impaired bone remodeling, such as osteoporosis. This review article aims at summarizing the current knowledge on one particular aspect of osteoimmunology, namely the impact of chemokines on skeletal cells in order to regulate bone remodeling under physiological and pathological conditions. Chemokines have key roles in the adaptive immune system by controlling migration, localization, and function of immune cells during inflammation. The vast majority of chemokines are divided into two subgroups based on the pattern of cysteine residues. More specifically, there are 27 known C-C-chemokines, binding to 10 different C-C receptors, and 17 known C-X-C-chemokines binding to seven different C-X-C receptors. Three additional chemokines do not fall into this category, and only one of them, i.e., CX3CL1, has been shown to influence bone remodeling cell types. There is a large amount of published studies demonstrating specific effects of certain chemokines on differentiation and function of osteoclasts and/or osteoblasts. Chemokine signaling by skeletal cells or by other cells of the bone marrow niche regulates bone formation and resorption through autocrine and paracrine mechanisms. In vivo evidence from mouse deficiency models strongly supports the role of certain chemokine signaling pathways in bone remodeling. We will summarize these data in the present review with a special focus on the most established subsets of chemokines. In combination with the other review articles of this issue, the knowledge presented here confirms that there is a physiologically relevant crosstalk between the innate immune system and bone remodeling cell types, whose molecular understanding is of high clinical relevance.
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Affiliation(s)
- Laura J Brylka
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorsten Schinke
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Derakhshani M, Abbaszadeh H, Movassaghpour AA, Mehdizadeh A, Ebrahimi-Warkiani M, Yousefi M. Strategies for elevating hematopoietic stem cells expansion and engraftment capacity. Life Sci 2019; 232:116598. [PMID: 31247209 DOI: 10.1016/j.lfs.2019.116598] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 06/22/2019] [Accepted: 06/23/2019] [Indexed: 02/07/2023]
Abstract
Hematopoietic stem cells (HSCs) are a rare cell population in adult bone marrow, mobilized peripheral blood, and umbilical cord blood possessing self-renewal and differentiation capability into a full spectrum of blood cells. Bone marrow HSC transplantation has been considered as an ideal option for certain disorders treatment including hematologic diseases, leukemia, immunodeficiency, bone marrow failure syndrome, genetic defects such as thalassemia, sickle cell anemia, autoimmune disease, and certain solid cancers. Ex vivo proliferation of these cells prior to transplantation has been proposed as a potential solution against limited number of stem cells. In such culture process, MSCs have also been shown to exhibit high capacity for secretion of soluble mediators contributing to the principle biological and therapeutic activities of HSCs. In addition, endothelial cells have been introduced to bridge the blood and sub tissues in the bone marrow, as well as, HSCs regeneration induction and survival. Cell culture in the laboratory environment requires cell growth strict control to protect against contamination, symmetrical cell division and optimal conditions for maximum yield. In this regard, microfluidic systems provide culture and analysis capabilities in micro volume scales. Moreover, two-dimensional cultures cannot fully demonstrate extracellular matrix found in different tissues and organs as an abstract representation of three dimensional cell structure. Microfluidic systems can also strongly describe the effects of physical factors such as temperature and pressure on cell behavior.
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Affiliation(s)
- Mehdi Derakhshani
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Abbaszadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Akbar Movassaghpour
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Ebrahimi-Warkiani
- School of Biomedical Engineering, University Technology of Sydney, Sydney, New South Wales, 2007, Australia
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Lenkiewicz A, Bujko K, Brzezniakiewicz-Janus K, Xu B, Ratajczak MZ. The Complement Cascade as a Mediator of Human Malignant Hematopoietic Cell Trafficking. Front Immunol 2019; 10:1292. [PMID: 31231394 PMCID: PMC6567995 DOI: 10.3389/fimmu.2019.01292] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 05/21/2019] [Indexed: 12/13/2022] Open
Abstract
The complement cascade (ComC) cleavage fragments C3a and C5a regulate the trafficking of normal, differentiated hematopoietic cells, although they do not chemoattract more primitive hematopoietic stem/progenitor cells (HSPCs). By contrast, human myeloid and lymphoid leukemia cell lines and clonogenic blasts from chronic myelogenous leukemia (CML) and acute myelogenous leukemia (AML) patients respond to C3 and C5 cleavage fragments by chemotaxis and increased adhesion. Consistent with this finding, C3a and C5a receptors are expressed by leukemic cells at the mRNA (RT-PCR) and protein (FACS) levels, and these cells respond to C3a and C5a stimulation by phosphorylation of p44/42 MAPK and AKT. However, neither of these ComC cleavage fragments have an effect on cell proliferation or survival. In parallel, we found that inducible heme oxygenase 1 (HO-1)-an anti-inflammatory enzyme, is a negative regulator of ComC-mediated trafficking of malignant cells and that stimulation of these cells by C3 or C5 cleavage fragments downregulates HO-1 expression in a p38 MAPK-dependent manner, rendering cells exposed to C3a or C5a more mobile. We propose that, while the ComC is not directly involved in the proliferation of malignant hematopoietic cells, its activation in leukemia/lymphoma patients (e.g., as a result of accompanying infections or sterile inflammation after radio-chemotherapy) enhances the motility of malignant cells and contributes to their dissemination in a p38 MAPK-HO-1 axis-dependent manner. Based on this idea, we propose that inhibition of p38 MAPK or upregulation of HO-1 by available small-molecule modulators would have a beneficial effect on ameliorating expansion and dissemination of leukemia/lymphoma cells in clinical situations in which the ComC becomes activated. Finally, since we detected expression of C3 and C5 mRNA in human leukemic cell lines, further study of the potential role of the complosome in regulating the behavior of these cells is needed.
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Affiliation(s)
- Anna Lenkiewicz
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Warsaw Medical University, Warsaw, Poland
| | - Kamila Bujko
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States
| | | | - Bing Xu
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology of Xiamen University, Xiamen, China
| | - Mariusz Z. Ratajczak
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Warsaw Medical University, Warsaw, Poland
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States
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Ullah M, Liu DD, Thakor AS. Mesenchymal Stromal Cell Homing: Mechanisms and Strategies for Improvement. iScience 2019; 15:421-438. [PMID: 31121468 PMCID: PMC6529790 DOI: 10.1016/j.isci.2019.05.004] [Citation(s) in RCA: 355] [Impact Index Per Article: 59.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 03/30/2019] [Accepted: 05/02/2019] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) have been widely investigated for their therapeutic potential in regenerative medicine, owing to their ability to home damaged tissue and serve as a reservoir of growth factors and regenerative molecules. As such, clinical applications of MSCs are reliant on these cells successfully migrating to the desired tissue following their administration. Unfortunately, MSC homing is inefficient, with only a small percentage of cells reaching the target tissue following systemic administration. This attrition represents a major bottleneck in realizing the full therapeutic potential of MSC-based therapies. Accordingly, a variety of strategies have been employed in the hope of improving this process. Here, we review the molecular mechanisms underlying MSC homing, based on a multistep model involving (1) initial tethering by selectins, (2) activation by cytokines, (3) arrest by integrins, (4) diapedesis or transmigration using matrix remodelers, and (5) extravascular migration toward chemokine gradients. We then review the various strategies that have been investigated for improving MSC homing, including genetic modification, cell surface engineering, in vitro priming of MSCs, and in particular, ultrasound techniques, which have recently gained significant interest. Contextualizing these strategies within the multistep homing model emphasizes that our ability to optimize this process hinges on our understanding of its molecular mechanisms. Moving forward, it is only with a combined effort of basic biology and translational work that the potential of MSC-based therapies can be realized.
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Affiliation(s)
- Mujib Ullah
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, Department of Radiology, Palo Alto, CA 94304, USA
| | - Daniel D Liu
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, Department of Radiology, Palo Alto, CA 94304, USA
| | - Avnesh S Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, Department of Radiology, Palo Alto, CA 94304, USA.
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Koksal AC, Pennini ME, Marelli M, Xiao X, Dall'Acqua WF. Functional mimetic of the G-protein coupled receptor CXCR4 on a soluble antibody scaffold. MAbs 2019; 11:725-734. [PMID: 30900513 DOI: 10.1080/19420862.2019.1596703] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
G-protein coupled receptors (GPCRs) constitute major drug targets due to their involvement in critical biological functions and pathophysiological disorders. The leading challenge in their structural and functional characterization has been the need for a lipid environment to accommodate their hydrophobic cores. Here, we report an antibody scaffold mimetic (ASM) platform where we have recapitulated the extracellular functional domains of the GPCR, C-X-C chemokine receptor 4 (CXCR4) on a soluble antibody framework. The engineered ASM molecule can accommodate the N-terminal loop and all three extracellular loops of CXCR4. These extracellular features are important players in ligand recruitment and interaction for allostery and signal transduction. Our study shows that ASMCXCR4 can be recognized by the anti-CXCR4 antibodies, MEDI3185, 2B11, and 12G5, and that ASMCXCR4 can bind the HIV-1 glycoprotein ligand gp120, and the natural chemokine ligand SDF-1α. Further, we show that ASMCXCR4 can competitively inhibit the SDF-1α signaling pathway, and be used as an immunogen to generate CXCR4-specific antibodies. This platform will be useful in the study of GPCR biology in a soluble receptor context for evaluating its extracellular ligand interactions.
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Affiliation(s)
- Adem C Koksal
- a Department of Antibody Discovery and Protein Engineering , AstraZeneca , Gaithersburg , MD , USA
| | - Meghan E Pennini
- b Microbial Sciences , MedImmune, AstraZeneca , Gaithersburg , MD , USA
| | - Marcello Marelli
- a Department of Antibody Discovery and Protein Engineering , AstraZeneca , Gaithersburg , MD , USA
| | - Xiaodong Xiao
- a Department of Antibody Discovery and Protein Engineering , AstraZeneca , Gaithersburg , MD , USA
| | - William F Dall'Acqua
- a Department of Antibody Discovery and Protein Engineering , AstraZeneca , Gaithersburg , MD , USA
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Santamaria X, Mas A, Cervelló I, Taylor H, Simon C. Uterine stem cells: from basic research to advanced cell therapies. Hum Reprod Update 2019; 24:673-693. [PMID: 30239705 DOI: 10.1093/humupd/dmy028] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 08/04/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Stem cell research in the endometrium and myometrium from animal models and humans has led to the identification of endometrial/myometrial stem cells and their niches. This basic knowledge is beginning to be translated to clinical use for incurable uterine pathologies. Additionally, the implication of bone marrow-derived stem cells (BMDSCs) in uterine physiology has opened the field for the exploration of an exogenous and autologous source of stem cells. OBJECTIVE AND RATIONALE In this review, we outline the progress of endometrial and myometrial stem/progenitor cells in both human and mouse models from their characterization to their clinical application, indicating roles in Asherman syndrome, atrophic endometrium and tissue engineering, among others. SEARCH METHODS A comprehensive search of PubMed and Google Scholar up to December 2017 was conducted to identify peer-reviewed literature related to the contribution of bone marrow, endometrial and myometrial stem cells to potential physiological regeneration as well as their implications in pathologies of the human uterus. OUTCOMES The discovery and main characteristics of stem cells in the murine and human endometrium and myometrium are presented together with the relevance of their niches and cross-regulation. The current state of advanced stem cell therapy using BMDSCs in the treatment of Asherman syndrome and atrophic endometrium is analyzed. In the myometrium, the understanding of genetic and epigenetic defects that result in the development of tumor-initiating cells in the myometrial stem niche and thus contribute to the growth of uterine leiomyoma is also presented. Finally, recent advances in tissue engineering based on the creation of novel three-dimensional scaffolds or decellularisation open up new perspectives for the field of uterine transplantation. WIDER IMPLICATIONS More than a decade after their discovery, the knowledge of uterine stem cells and their niches is crystalising into novel therapeutic approaches aiming to treat with cells those conditions that cannot be cured with drugs, particularly the currently incurable uterine pathologies. Additional work and improvements are needed, but the basis has been formed for this therapeutic application of uterine cells.
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Affiliation(s)
- Xavier Santamaria
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Reproductive Medicine Department, IVI Barcelona, Barcelona, Spain.,Department of Obstetrics and Gynecology, Biomedical Research Group in Gynecology, Vall Hebron Institut de Recerca, Barcelona, Spain
| | - Aymara Mas
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Department of Obstetrics and Gynecology, Reproductive Medicine Research Group, La Fe Health Research Institute, Valencia, Spain
| | - Irene Cervelló
- Department of Obstetrics and Gynecology, Fundación Instituto Valenciano de Infertilidad (FIVI), and Instituto Universitario IVI/INCLIVA, Valencia, Spain
| | - Hugh Taylor
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Carlos Simon
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Department of Pediatrics, Obstetrics, and Gynecology, Valencia University and INCLIVA, Valencia, Spain.,Department of Obstetrics and Gynecology, Stanford University, Stanford, CA, USA
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Imai T, Tanaka H, Hamazaki Y, Minato N. Rap1 signal modulators control the maintenance of hematopoietic progenitors in bone marrow and adult long-term hematopoiesis. Cancer Sci 2019; 110:1317-1330. [PMID: 30767320 PMCID: PMC6447830 DOI: 10.1111/cas.13974] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 02/07/2019] [Accepted: 02/12/2019] [Indexed: 01/22/2023] Open
Abstract
Adult long‐term hematopoiesis depends on sustaining hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM) niches, where their balance of quiescence, self‐renewal, and hematopoietic differentiation is tightly regulated. Although various BM stroma cells that produce niche factors have been identified, regulation of the intrinsic responsiveness of HSPC to the niche factors remains elusive. We previously reported that mice deficient for Sipa1, a Rap1 GTPase‐activating protein, develop diverse hematopoietic disorders of late onset. Here we showed that transplantation of BM cells expressing membrane‐targeted C3G (C3G‐F), a Rap1 GTP/GDP exchanger, resulted in the progressive decline of the numbers of HSPC repopulated in BM with time and impaired long‐term hematopoiesis of all cell lineages. C3G‐F/HSPC were sustained for months in spleen retaining hematopoietic potential, but these cells inefficiently contributed to overall hematopoietic reconstitution. C3G‐F/HSPC showed enhanced proliferation and differentiation with accelerated progenitor cell exhaustion in response to stem cell factor (SCF). Using a Ba/F3 cell line, we confirmed that the increased basal Rap1GTP levels with C3G‐F expression caused a markedly prolonged activation of c‐Kit receptor and downstream signaling through SCF ligation. A minor population of C3G‐F/HSPC also showed enhanced proliferation in the presence of thrombopoietin (TPO) compared to Vect/HSPC. Current results suggest an important role of basal Rap1 activation status of HSPC in their maintenance in BM for sustaining long‐term adult hematopoiesis.
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Affiliation(s)
- Takahiko Imai
- Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroki Tanaka
- Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoko Hamazaki
- Center for iPS Research and Application, Kyoto University, Kyoto, Japan
| | - Nagahiro Minato
- Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Torabi T, Abroun S. Amniotic fluid, an effective factor for umbilical cord blood hematopoietic stem cells in cell culture: An approach for bone marrow transplantation. Transfus Apher Sci 2019; 58:169-173. [PMID: 30890311 DOI: 10.1016/j.transci.2019.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 01/14/2019] [Indexed: 11/29/2022]
Abstract
Bone marrow transplantation is a treatment used for hematologic and non-hematologic disorders. A theory suggests that proliferation of cells in non-body condition helps to increase the efficiency of bone marrow transplant. There are different ways for proliferation of stem cells, in which, most studies have focused on stem cell culture in body-like conditions. The use of amniotic fluid as a rich resource of growth factors is developing in repair of tissues cornea. With regards to this condition, we discuss about the influence of amniotic fluid in proliferation and implantation of blood stem cells. The aim of this study was investigation of human amnion fluid (HAF) in support of growth and proliferation of umbilical cord in order to transplant and long period erythropoiesis. First, separating of CD-34+ stem cells by MACS was performed and check in 5% and 8% concentration of amniotic fluid (AF) in comprise with FBS10% in culture environment. After 7, 14 days cell count, and checking gene expression level of cyclinD1, BCL2, CXCR4, SDF1 by real-time PCR. The result show that BCL2, CXCR4 and cyclinD1 gene expression level were increased in cells that are growth in 5% AF with 5% FBS than other groups. After statistical analysis, proliferation of umbilical cord blood stem cells in 5% AF with 5% FBS was more than 8% AF with 2% FBS and 10% FBS. Therefore, HAF can play an effective role in increasing hematopoietic stem cells in cell culture before bone marrow transplant.
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Affiliation(s)
- Tayebe Torabi
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Saeid Abroun
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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Zhang H, Xiao B, Jiang L, Yao W, Shen H, Xiang X. Inhibition of mesenchymal stromal cells' chemotactic effect to ameliorate paraquat-induced pulmonary fibrosis. Toxicol Lett 2019; 307:1-10. [PMID: 30658152 DOI: 10.1016/j.toxlet.2019.01.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/12/2018] [Accepted: 01/13/2019] [Indexed: 01/09/2023]
Abstract
BACKGROUND Paraquat (PQ) poisoning is one of the leading causes of suicide attempts in China signature by acute onset of respiratory distress with massive matrix production resulting in progressive pulmonary fibrosis. There is no specific antidote and mortality remains high without effective treatment available. The cellular mechanisms underlying PQ-induced pulmonary fibrosis remain largely unknown. OBJECTIVES To determine the origin of mesenchymal stem cells (MSCs) migrated to the lung after PQ exposure and their roles in PQ-induced pulmonary fibrosis, to further explore the possible mechanisms involved in these processes, and to help finding novel therapies. METHODS We used a combination of lineage tracking techniques to investigate the contributions of several cells of MSCs, marked by Nestin or CXCL12, and traced their co-expression of α-smooth muscle actin (α-SMA), a marker for fibrosis, or their co-location with matrix production, marked by collagen-1 production (Col1-GFP) following PQ exposure. Then, we used a CXCL12flox/flox; Prx1-Cre mice and a pharmacologic agent AMD3100 to selectively deplete chemotactic mechanism of the MSCs, and tested pro-fibrotic pathways, fibrotic processes and survival of mice after PQ exposure. RESULTS Our results showed that after paraquat exposure, the residential Nestin + MSCs were quickly expanded and contributed to extracellular matrix production. Moreover, when we used a CXCL12flox/flox; Prx1-Cre mice to selectively deplete chemotactic mechanism of the MSC, we found that PQ exposure in these mice failed to activate pro-fibrotic pathways including TGF-β, Wnt and EGFR signaling. Furthermore, when the chemotactic effect of MSCs via CXCL12 was blocked by a pharmacologic agent, AMD3100, it alleviated the development of the fibrotic process and improved survival rate in mice exposed to PQ. CONCLUSION Collectively, our data suggest paraquat intoxication rapidly activated Nestin + MSCs and that blocking chemotactic effects of MSCs by perivascular CXCL12 inhibition may effectively protect pulmonary injury following paraquat exposure. Our results revealed a novel mechanism for post-PQ lung injury and indicated a novel therapeutic option to attenuate fibrosis induced by paraquat.
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Affiliation(s)
- Hongliang Zhang
- Department of Emergency Medicine, The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University, Changsha, Hunan, PR China; Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, 95817, USA
| | - Bing Xiao
- Department of Emergency Medicine, The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University, Changsha, Hunan, PR China
| | - Li Jiang
- Department of Emergency Medicine, Dalian Medical University, Dalian, Liaoning, PR China
| | - Wei Yao
- Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, 95817, USA
| | - Huahao Shen
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Institute of Respiratory Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
| | - Xudong Xiang
- Department of Emergency Medicine, The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University, Changsha, Hunan, PR China.
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Ha TW, Kang HS, Kim TH, Kwon JH, Kim HK, Ryu A, Jeon H, Han J, Broxmeyer HE, Hwang Y, Lee YK, Lee MR. MiR-9 Controls Chemotactic Activity of Cord Blood CD34⁺ Cells by Repressing CXCR4 Expression. Int J Stem Cells 2018; 11:187-195. [PMID: 30343551 PMCID: PMC6285292 DOI: 10.15283/ijsc18057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 08/30/2018] [Accepted: 09/07/2018] [Indexed: 11/09/2022] Open
Abstract
Improved approaches for promoting umbilical cord blood (CB) hematopoietic stem cell (HSC) homing are clinically important to enhance engraftment of CB-HSCs. Clinical transplantation of CB-HSCs is used to treat a wide range of disorders. However, an improved understanding of HSC chemotaxis is needed for facilitation of the engraftment process. We found that ectopic overexpression of miR-9 and antisense-miR-9 respectively down- and up-regulated C-X-C chemokine receptor type 4 (CXCR4) expression in CB-CD34+ cells as well as in 293T and TF-1 cell lines. Since CXCR4 is a specific receptor for the stromal cell derived factor-1 (SDF-1) chemotactic factor, we investigated whether sense miR-9 and antisense miR-9 influenced CXCR4-mediated chemotactic mobility of primary CB CD34+ cells and TF-1 cells. Ectopic overexpression of sense miR-9 and antisense miR-9 respectively down- and up-regulated SDF-1-mediated chemotactic cell mobility. To our knowledge, this study is the first to report that miR-9 may play a role in regulating CXCR4 expression and SDF-1-mediated chemotactic activity of CB CD34+ cells.
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Affiliation(s)
- Tae Won Ha
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soon Chun Hyang University, Cheonan, Korea
| | - Hyun Soo Kang
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soon Chun Hyang University, Cheonan, Korea
| | - Tae-Hee Kim
- Department of Obstetrics and Gynecology, Soon Chun Hyang University College of Medicine, Bucheon, Korea
| | - Ji Hyun Kwon
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soon Chun Hyang University, Cheonan, Korea
| | - Hyun Kyu Kim
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soon Chun Hyang University, Cheonan, Korea
| | - Aeli Ryu
- Department of Obstetrics and Gynecology, Soon Chun Hyang University Cheonan Hospital, Cheonan, Korea
| | - Hyeji Jeon
- Department of Obstetrics and Gynecology, Soon Chun Hyang University Cheonan Hospital, Cheonan, Korea
| | - Jaeseok Han
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soon Chun Hyang University, Cheonan, Korea
| | - Hal E Broxmeyer
- Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, USA
| | - Yongsung Hwang
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soon Chun Hyang University, Cheonan, Korea
| | - Yun Kyung Lee
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soon Chun Hyang University, Cheonan, Korea
| | - Man Ryul Lee
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soon Chun Hyang University, Cheonan, Korea
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Quantitative Analysis of Red Bone Marrow Microenvironment Cells in Patients with Chronic Myeloid Leukemia, Multiple Myeloma, and Chronic Lymphocytic Leukemia in the Dynamics of Chemotherapy. Bull Exp Biol Med 2018; 165:786-789. [PMID: 30353331 DOI: 10.1007/s10517-018-4265-9] [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: 03/15/2018] [Indexed: 10/28/2022]
Abstract
We performed comparative analysis of quantitative changes in the populations of bone marrow microenvironment cells in patients with chronic myeloid leukemia, multiple myeloma, and chronic lymphocytic leukemia in the debut, during response to chemotherapy, and during relapse/progression/loss of response. It was shown that in the active phase of hemoblastoses, the number of reticular cells and fibroblasts in trephine biopsy specimens was higher than in the phase of response to chemotherapy and than in the control group. In patients with relapse of multiple myeloma and loss of response in chronic myeloid leukemia, the percentage ratio of adipocytes in the bone marrow significantly (by 9-13-fold) increased. In addition, endotheliocytes appear in the active phase of all hemoblastoses in trephine biopsy specimens, while in the phase of response to chemotherapy and in the control group, these cells were absent. The revealed quantitative changes in bone marrow stromal cells can be taken into account during assessing the phase of hemoblastosis and effectiveness of chemotherapy.
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Hitchinson B, Eby JM, Gao X, Guite-Vinet F, Ziarek JJ, Abdelkarim H, Lee Y, Okamoto Y, Shikano S, Majetschak M, Heveker N, Volkman BF, Tarasova NI, Gaponenko V. Biased antagonism of CXCR4 avoids antagonist tolerance. Sci Signal 2018; 11:11/552/eaat2214. [PMID: 30327409 DOI: 10.1126/scisignal.aat2214] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Repeated dosing of drugs targeting G protein-coupled receptors can stimulate antagonist tolerance, which reduces their efficacy; thus, strategies to avoid tolerance are needed. The efficacy of AMD3100, a competitive antagonist of the chemokine receptor CXCR4 that mobilizes leukemic blasts from the bone marrow into the blood to sensitize them to chemotherapy, is reduced after prolonged treatment. Tolerance to AMD3100 increases the abundance of CXCR4 on the surface of leukemic blasts, which promotes their rehoming to the bone marrow. AMD3100 inhibits both G protein signaling by CXCR4 and β-arrestin1/2-dependent receptor endocytosis. We demonstrated that biased antagonists of G protein-dependent chemotaxis but not β-arrestin1/2 recruitment and subsequent receptor endocytosis avoided tolerance. The peptide antagonist X4-2-6, which is derived from transmembrane helix 2 and extracellular loop 1 of CXCR4, limited chemotaxis and signaling but did not promote CXCR4 accumulation on the cell surface or cause tolerance. The activity of X4-2-6 was due to its distinct mechanism of inhibition of CXCR4. The peptide formed a ternary complex with the receptor and its ligand, the chemokine CXCL12. Within this complex, X4-2-6 released the portion of CXCL12 critical for receptor-mediated activation of G proteins but enabled the rest of the chemokine to recruit β-arrestins to the receptor. In contrast, AMD3100 displaced all components of the chemokine responsible for CXCR4 activation. We further identified a small molecule with similar biased antagonist properties to those of X4-2-6, which may provide a viable alternative to patients when antagonist tolerance prevents drugs from reaching efficacy.
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Affiliation(s)
- Ben Hitchinson
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA
| | - Jonathan M Eby
- Department of Surgery, Burn and Shock Trauma Research Institute, Loyola University Chicago, Chicago, IL, USA
| | - Xianlong Gao
- Department of Surgery, Burn and Shock Trauma Research Institute, Loyola University Chicago, Chicago, IL, USA.,Department of Surgery, Morsani College of Medicine, University of South Florida, College of Medicine, Tampa, FL, USA
| | - Francois Guite-Vinet
- Department of Biochemistry, Research Centre, Sainte-Justine Hospital, Montréal, Quebec, Canada
| | - Joshua J Ziarek
- Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, USA.,Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Hazem Abdelkarim
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA
| | - Youngshim Lee
- Division of Bioscience and Biotechnology, Biomolecular Informatics Center, Konkuk University, Seoul 05029, Republic of Korea
| | - Yukari Okamoto
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA
| | - Sojin Shikano
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA
| | - Matthias Majetschak
- Department of Surgery, Burn and Shock Trauma Research Institute, Loyola University Chicago, Chicago, IL, USA.,Department of Surgery, Morsani College of Medicine, University of South Florida, College of Medicine, Tampa, FL, USA
| | - Nikolaus Heveker
- Department of Biochemistry, Research Centre, Sainte-Justine Hospital, Montréal, Quebec, Canada
| | - Brian F Volkman
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Nadya I Tarasova
- Cancer and Inflammation Program, National Cancer Institute, P.O. Box B, Frederick, MD, USA
| | - Vadim Gaponenko
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA.
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47
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Galán-Díez M, Cuesta-Domínguez Á, Kousteni S. The Bone Marrow Microenvironment in Health and Myeloid Malignancy. Cold Spring Harb Perspect Med 2018; 8:a031328. [PMID: 28963115 PMCID: PMC6027930 DOI: 10.1101/cshperspect.a031328] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Hematopoietic stem cells (HSCs) interact dynamically with an intricate network of cells in the bone marrow (BM) microenvironment or niche. These interactions provide instructive cues that influence the production and lineage determination of different types of blood cells and maintenance of HSC quiescence. They also contribute to hematopoietic deregulation and hematological myeloid malignancies. Alterations in the BM niche are commonly observed in myeloid malignancies and contribute to the aberrant function of myelodysplastic and leukemia-initiating stem cells. In this work, we review how different components of the BM niche affect normal hematopoiesis, the molecular signals that govern this interaction, and how genetic changes in stromal cells or alterations in remodeled malignant BM niches contribute to myeloid malignancies. Understanding the intricacies between normal and malignant niches and their modulation may provide insights into developing novel therapeutics for blood disorders.
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Affiliation(s)
- Marta Galán-Díez
- Department of Physiology & Cellular Biophysics, College of Physicians & Surgeons, Columbia University, New York, New York 10032
| | - Álvaro Cuesta-Domínguez
- Department of Physiology & Cellular Biophysics, College of Physicians & Surgeons, Columbia University, New York, New York 10032
| | - Stavroula Kousteni
- Department of Physiology & Cellular Biophysics, College of Physicians & Surgeons, Columbia University, New York, New York 10032
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48
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Signorelli F, Sela S, Gesualdo L, Chevrel S, Tollet F, Pailler-Mattei C, Tacconi L, Turjman F, Vacca A, Schul DB. Hemodynamic Stress, Inflammation, and Intracranial Aneurysm Development and Rupture: A Systematic Review. World Neurosurg 2018; 115:234-244. [DOI: 10.1016/j.wneu.2018.04.143] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Revised: 04/18/2018] [Accepted: 04/19/2018] [Indexed: 10/17/2022]
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49
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Kalimuthu S, Zhu L, Oh JM, Gangadaran P, Lee HW, Baek SH, Rajendran RL, Gopal A, Jeong SY, Lee SW, Lee J, Ahn BC. Migration of mesenchymal stem cells to tumor xenograft models and in vitro drug delivery by doxorubicin. Int J Med Sci 2018; 15:1051-1061. [PMID: 30013447 PMCID: PMC6036160 DOI: 10.7150/ijms.25760] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 06/01/2018] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) show therapeutic effects in various types of diseases. MSCs have been shown to migrate towards inflamed or cancerous tissues, and visualized after sacrificing the animal. MSCs are able to deliver drugs to target cells, and are an ideal candidate for cancer therapy. The purpose of this study was to track the migration of MSCs in tumor-bearing mice; MSCs were also used as drug delivery vehicles. Human breast cancer cells (MDA-MB-231) and anaplastic thyroid cancer cells (CAL62) were transduced with lentiviral particles, to express the Renilla luciferase and mCherry (mCherry-Rluc) reporter genes. Human bone marrow-derived MSCs were transduced with lentiviral particles, to express the firefly luciferase and enhanced green fluorescence protein (Fluc2-eGFP) reporter genes (MSC/Fluc). Luciferase activity of the transduced cells was measured by bioluminescence imaging (BLI). Further in vitro migration assays were performed to confirm cancer cells conditioned medium dependent MSC and doxorubicin (DOX) treated MSC migration. MSCs were loaded with DOX, and their therapeutic effects against the cancer cells were studied in vitro. In vivo MSC/Fluc migration in mice having thyroid or breast cancer xenografts was evaluated after systemic injection. Rluc activity of CAL62/Rluc (R2=0.911), MDA-MB-231/Rluc (R2=0.934) cells and Fluc activity of MSC/Fluc (R2=0.91) cells increased with increasing cell numbers, as seen by BLI. eGFP expression of MSC/Fluc was confirmed by confocal microscopy. Similar migration potential was observed between MSC/Fluc and naïve MSCs in migration assay. DOX treated MSCs migration was not decreased compared than MSCs. Migration of the systemically injected MSC/Fluc cells into tumor xenografts (thyroid and breast cancer) was visualized in animal models (p<0.05) and confirmed by ex vivo (p<0.05) BLI. Additionally, MSCs delivered DOX to CAL62/Rluc and MDA-MB-231/Rluc cells, thereby decreasing their Rluc activities. In this study, we confirmed the migration of MSCs to tumor sites in cancer xenograft models using both in vivo and ex vivo BLI imaging. DOX-pretreated MSCs showed enhanced cytotoxic effects. Therefore, this noninvasive reporter gene (Fluc2)-based BLI may be useful for visualizing in vivo tracking of MSCs, which can be used as a drug delivery vehicle for cancer therapy.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
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50
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Wang A, Zhong H. Roles of the bone marrow niche in hematopoiesis, leukemogenesis, and chemotherapy resistance in acute myeloid leukemia. ACTA ACUST UNITED AC 2018; 23:729-739. [PMID: 29902132 DOI: 10.1080/10245332.2018.1486064] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVES To summarize the effects of the bone marrow niche on hematopoiesis and leukemogenesis and discuss the chemotherapy resistance that can arise from interactions between the niche and leukemia stem cells. METHODS We review the major roles of the bone marrow niche in cell proliferation, adhesion and drug resistance. The signaling pathways and major molecular participants in the niche are discussed. We also address potential niche-targeting strategies for the treatment of acute myeloid leukemia (AML). RESULTS The bone marrow niche supports normal hematopoiesis and affects acute myeloid leukemia (AML) initiation, progression and chemotherapy resistance. DISCUSSION AML is a group of heterogeneous malignant diseases characterized by the excessive proliferation of hematopoietic stem and/or progenitor cells. Even with intensive chemotherapy regimens and stem cell transplantation, the overall survival rate for AML is poor. The bone marrow niches of malignant cells are remodeled into a leukemia-permissive environment, and these reformed niches protect AML cells from chemotherapy-induced cell death. Inhibiting the cellular and molecular interactions between the niche and leukemia cells is a promising direction for targeted therapies for AML treatment. CONCLUSIONS Interactions between leukemia cells and the bone marrow niche influence hematopoiesis, leukemogenesis, and chemotherapy resistance in AML and require ongoing study. Understanding the mechanisms that underlie these interactions will help identify rational niche-targeting therapies to improve treatment outcomes in AML patients.
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Affiliation(s)
- Andi Wang
- a Department of Hematology , South Campus Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , People's Republic of China
| | - Hua Zhong
- a Department of Hematology , South Campus Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , People's Republic of China
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