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Su S, Bai J, Wang R, Gao S, Zhou R, Zhou F. A novel strategy for bone defect repair: Stromal cell-derived factor 1α sustained-release acellular fish scale scaffolds combined with injection of bone marrow mesenchymal stem cells promote bone regeneration. Mater Today Bio 2025; 32:101759. [PMID: 40270891 PMCID: PMC12017916 DOI: 10.1016/j.mtbio.2025.101759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/02/2025] [Accepted: 04/09/2025] [Indexed: 04/25/2025] Open
Abstract
Patients with bone defects often have weak cell vitality and differentiation ability of endogenous bone marrow mesenchymal stem cells (BMSCs), which makes bone regeneration face challenges. At present, the bone tissue engineering strategies are mainly to build grafts by loading cells on scaffolds in vitro. These strategies face many difficulties that limit their clinical application. To this end, we developed a new strategy for bone defect repair, namely chemotactic cell-free scaffolds combined with BMSCs injection. We first prepared a polydopamine-functionalized acellular fish scale scaffold that can continuously release stromal cell-derived factor 1α (SDF-1α) (termed as SDF-1α/PAFS) in vivo for at least 10 days. The study results showed that the scaffold not only has excellent mechanical properties and good biocompatibility but also has reactive oxygen scavenging activity, immunomodulation, angiogenesis, and osteogenesis. More importantly, SDF-1α/PAFS can recruit postoperatively injected BMSCs into bone defects for bone repair. We constructed the mouse cranial bone defect model, and in vivo experimental results confirmed that the strategy of combining SDF-1α/PAFS with BMSCs injection can effectively promote bone defect repair. Overall, this study provides a promising strategy for bone defect repair, with better clinical convenience and operability.
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Affiliation(s)
- Shilong Su
- Department of Orthopedics, Peking University Third Hospital, No.49 North Garden Road, Haidian, 100191, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Peking University Third Hospital, No.49 North Garden Road, Haidian, 100191, Beijing, China
| | - Jinwu Bai
- Department of Orthopedics, Peking University Third Hospital, No.49 North Garden Road, Haidian, 100191, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Peking University Third Hospital, No.49 North Garden Road, Haidian, 100191, Beijing, China
| | - Ruideng Wang
- Department of Orthopedics, Peking University Third Hospital, No.49 North Garden Road, Haidian, 100191, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Peking University Third Hospital, No.49 North Garden Road, Haidian, 100191, Beijing, China
| | - Shan Gao
- Department of Orthopedics, Peking University Third Hospital, No.49 North Garden Road, Haidian, 100191, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Peking University Third Hospital, No.49 North Garden Road, Haidian, 100191, Beijing, China
| | - Rubing Zhou
- Department of Orthopedics, Beijing Friendship Hospital, Capital Medical University, No.95 Yong'an Road, Xicheng, 100050, Beijing, China
| | - Fang Zhou
- Department of Orthopedics, Peking University Third Hospital, No.49 North Garden Road, Haidian, 100191, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Peking University Third Hospital, No.49 North Garden Road, Haidian, 100191, Beijing, China
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Guan W, Su X, Ji X, Yuan J, Li Q, Zou Y, Lu Z, Xiao J, Wang M, Guo Z. Comparative analysis of spleen structure, biochemical parameters, and transcriptome of adult and juvenile yellowfin tuna (Thunnus albacares) in the South China Sea. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2025; 54:101445. [PMID: 39970697 DOI: 10.1016/j.cbd.2025.101445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/27/2025] [Accepted: 02/12/2025] [Indexed: 02/21/2025]
Abstract
As one of the top predators in the ocean, yellowfin tuna possesses physiological characteristics that are highly adapted to its high-speed swimming habits, such as high cardiac output and efficient oxygen uptake and transportation systems, which enable it to swim rapidly various diverse layers of the water for feeding activities. These physiological characteristics are intricately associated with the efficient hematopoietic function of its spleen, which plays a crucial role in maintaining its long-distance migration and sustained physical activity in particular. However, there are fewer studies on the developmental biology and function of the spleen in this species. In order to investigate the changes in spleen structure and function during the development of yellowfin tuna, this study compared the histological characteristics, biochemical indexes and transcriptome profiles of the spleen in adult and juvenile yellowfin tuna from the South China Sea. Hematoxylin and eosin (H&E), Masson, and reticular fiber staining revealed that the proportion of white pulp and the mean number of blood sinus in the spleen of adult fish were significantly less than those in juvenile fish (p < 0.05), while the relative area of red pulp displayed no significant difference between the two groups. In addition, the contents of granulocyte-macrophage colony-stimulating factor, erythropoietin, thrombopoietin, and stromal cell-derived factor 1 were significantly lower in the spleen of adult fish than in juvenile fish (p < 0.001), while the contents of bone morphogenetic protein 2 and transforming growth factor β1 were significantly increased in juvenile fish spleens (p < 0.001). Comparative transcriptome analysis revealed that there were 1255 differentially expressed genes (DEGs) between adult and juvenile fish, of which 477 were upregulated and 778 were down-regulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed that these DEGs were mainly related to embryonic hematopoiesis, the development of blood and lymphoid organs, and the HIF-1 signaling pathway. Key DEGs associated with hematopoietic function were further identified, such as pik3r3b, gata1a, klf1, epor, and lmo2. In conclusion, this study offers a comprehensive comparison of spleen histology, cytokine activities related to hematopoiesis and cell development, and transcriptomic differences between adult and juvenile yellowfin tuna. These findings provide valuable insights into the spleen hematopoietic development mechanism of decoding yellowfin tuna and other tuna species.
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Affiliation(s)
- Wanlin Guan
- School of Life and Health Sciences, State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou 570228, China
| | - Xiameng Su
- School of Life and Health Sciences, State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou 570228, China
| | - Xu Ji
- School of Life and Health Sciences, State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou 570228, China
| | - Jigui Yuan
- State Key Laboratory of Mariculture Breeding, College of Ocean and Earth Sciences, Xiamen University, Xiamen 361102, China
| | - Qian Li
- School of Life and Health Sciences, State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou 570228, China
| | - Ying Zou
- School of Life and Health Sciences, State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou 570228, China
| | - Zhiyuan Lu
- College of Marine Science and Engineering, Hainan University, Haikou 570228, China
| | - Juan Xiao
- School of Food Science and Engineering, Hainan University, Haikou 570228, China
| | - Mei Wang
- College of Marine Science and Engineering, Hainan University, Haikou 570228, China.
| | - Zhiqiang Guo
- School of Life and Health Sciences, State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou 570228, China; College of Marine Science and Engineering, Hainan University, Haikou 570228, China; Hainan Technology Innovation Center for Marine Biological Resources Utilization (Preparatory Period), Haikou 570228, China.
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Wang P, Di X, Li F, Rong Z, Lian W, Sun G, Liu C, Ni L. Advancements in Gene-Based Therapeutic Angiogenesis for Chronic Limb-Threatening Ischemia. Hum Gene Ther 2025; 36:787-800. [PMID: 40298175 DOI: 10.1089/hum.2024.245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025] Open
Abstract
The objective of this article is to summarize the research progress and discuss the current difficulties of gene-based therapeutic angiogenesis in lower limb ischemic diseases, so as to provide new research directions for the non-invasive treatment of lower limb ischemia. The basic and clinical trials of gene-based therapeutic angiogenesis in lower limb ischemia in recent years were read and reviewed. Growth factors such as vascular endothelial growth factor, hepatocyte growth factor, and fibroblast growth factor have been extensively studied for their application in lower limb ischemic diseases. However, clinical studies across various phases have shown inconsistent efficacy endpoints. The efficacy of gene therapy remains questionable. Before exploring efficient methods of delivering pro-angiogenic genes to ischemic tissues, clarification is needed regarding whether the goal of gene therapy is to simply promote collateral circulation or create a conducive tissue microenvironment for angiogenesis. In conclusion, pre-clinical and clinical studies have demonstrated the potential of therapeutic angiogenesis, but more systematic and comprehensive research is needed to explore safer, more effective, and cost-effective treatment methods.
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Affiliation(s)
- Peng Wang
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xiao Di
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Fengshi Li
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhihua Rong
- Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Wenzhuo Lian
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Guoqiang Sun
- Department of Information Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - ChangWei Liu
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Leng Ni
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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Khaleel AQ, Altalbawy FMA, Jabir MS, F Hasan T, Jain V, Abbot V, Nakash P, Kumar MR, Mustafa YF, Jawad MA. CXCR4/CXCL12 blockade therapy; a new horizon in TNBC therapy. Med Oncol 2025; 42:161. [PMID: 40216617 DOI: 10.1007/s12032-025-02705-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Accepted: 03/29/2025] [Indexed: 05/03/2025]
Abstract
The only subtype of breast cancer (BC) without specific therapy is triple-negative breast cancer (TNBC), which represents 15-20% of incidence cases of BC. TNBC encompasses transformed and nonmalignant cells, including cancer-associated fibroblasts (CAF), endothelial vasculature, and tumor-infiltrating cells. These nonmalignant cells, soluble factors (e.g., cytokines), and the extracellular matrix (ECM) form the tumor microenvironment (TME). The TME is made up of these nonmalignant cells, ECM, and soluble components, including cytokines. Direct cell-to-cell contact and soluble substances like cytokines (e.g., chemokines) may facilitate interaction between cancer cells and the surrounding TME. Through growth-promoting cytokines, TME not only enables the development of cancer but also confers therapy resistance. New treatment targets will probably be suggested by comprehending the processes behind tumor development and progression as well as the functions of chemokines in TNBC. In this light, several investigations have shown the pivotal function of the C-X-C motif chemokine ligand 12 (CXCL12 or SDF-1) axis and chemokine receptor type 4 (CXCR4) in the pathophysiology of TNBC. This review provides an overview of the CXCR4/CXCL12 axis' function in TNBC development, metastasis, angiogenesis, and treatment resistance. A synopsis of current literature on targeting the CXCR4/CXCL12 axis for treating and managing TNBC has also been provided.
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Affiliation(s)
- Abdulrahman Qais Khaleel
- Department of Medical Instruments Engineering, Al-Maarif University College, Al Anbar, 31001, Iraq.
| | - Farag M A Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | - Majid S Jabir
- Department of Applied Sciences, University of Technology, Baghdad, Iraq
| | - Thikra F Hasan
- College of Health&Medical Technology, Uruk University, Baghdad, Iraq
| | - Vicky Jain
- Department of Chemistry, Marwadi University Research Center, Marwadi University, Rajkot, Gujarat, 360003, India
| | - Vikrant Abbot
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, 140307, India
| | - Prashant Nakash
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | - M Ravi Kumar
- Department of Basic Science & Humanities, Raghu Engineering College, Visakhapatnam, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
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Ballato M, Germanà E, Ricciardi G, Giordano WG, Tralongo P, Buccarelli M, Castellani G, Ricci-Vitiani L, D’Alessandris QG, Giuffrè G, Pizzimenti C, Fiorentino V, Zuccalà V, Ieni A, Caffo M, Fadda G, Martini M. Understanding Neovascularization in Glioblastoma: Insights from the Current Literature. Int J Mol Sci 2025; 26:2763. [PMID: 40141406 PMCID: PMC11943220 DOI: 10.3390/ijms26062763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/15/2025] [Accepted: 03/17/2025] [Indexed: 03/28/2025] Open
Abstract
Glioblastomas (GBMs), among the most aggressive and resilient brain tumors, characteristically exhibit high angiogenic potential, leading to the formation of a dense yet aberrant vasculature, both morphologically and functionally. With these premises, numerous expectations were initially placed on anti-angiogenic therapies, soon dashed by their limited efficacy in concretely improving patient outcomes. Neovascularization in GBM soon emerged as a complex, dynamic, and heterogeneous process, hard to manage with the classical standard of care. Growing evidence has revealed the existence of numerous non-canonical strategies of angiogenesis, variously exploited by GBM to meet its ever-increasing metabolic demand and differently involved in tumor progression, recurrence, and escape from treatments. In this review, we provide an accurate description of each neovascularization mode encountered in GBM tumors to date, highlighting the molecular players and signaling cascades primarily involved. We also detail the key architectural and functional aspects characteristic of the GBM vascular compartment because of an intricate crosstalk between the different angiogenic networks. Additionally, we explore the repertoire of emerging therapies against GBM that are currently under study, concluding with a question: faced with such a challenging scenario, could combined therapies, tailored to the patient's genetic signatures, represent an effective game changer?
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Affiliation(s)
- Mariagiovanna Ballato
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy; (M.B.); (E.G.); (G.R.); (W.G.G.); (P.T.)
| | - Emanuela Germanà
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy; (M.B.); (E.G.); (G.R.); (W.G.G.); (P.T.)
| | - Gabriele Ricciardi
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy; (M.B.); (E.G.); (G.R.); (W.G.G.); (P.T.)
- Istituto Clinico Polispecialistico C.O.T. Cure Ortopediche Traumatologiche s.pa., 98124 Messina, Italy
| | - Walter Giuseppe Giordano
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy; (M.B.); (E.G.); (G.R.); (W.G.G.); (P.T.)
| | - Pietro Tralongo
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy; (M.B.); (E.G.); (G.R.); (W.G.G.); (P.T.)
| | - Mariachiara Buccarelli
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; (M.B.); (G.C.); (L.R.-V.)
| | - Giorgia Castellani
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; (M.B.); (G.C.); (L.R.-V.)
| | - Lucia Ricci-Vitiani
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; (M.B.); (G.C.); (L.R.-V.)
| | | | - Giuseppe Giuffrè
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (G.G.); (V.F.); (V.Z.); (A.I.); (G.F.)
| | | | - Vincenzo Fiorentino
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (G.G.); (V.F.); (V.Z.); (A.I.); (G.F.)
| | - Valeria Zuccalà
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (G.G.); (V.F.); (V.Z.); (A.I.); (G.F.)
| | - Antonio Ieni
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (G.G.); (V.F.); (V.Z.); (A.I.); (G.F.)
| | - Maria Caffo
- Biomedical and Dental Sciences and Morphofunctional Imaging, Unit of Neurosurgery, University of Messina, 98122 Messina, Italy;
| | - Guido Fadda
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (G.G.); (V.F.); (V.Z.); (A.I.); (G.F.)
| | - Maurizio Martini
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (G.G.); (V.F.); (V.Z.); (A.I.); (G.F.)
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Uzun M, Gokcek S, Kaya E, Semiz HS. The prognostic role of systemic immune-inflammation index, SII, in Metastatic Castration-Resistant Prostate Cancer patients. Discov Oncol 2025; 16:317. [PMID: 40085163 PMCID: PMC11908992 DOI: 10.1007/s12672-025-02084-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 03/06/2025] [Indexed: 03/16/2025] Open
Abstract
Our study aimed to examine the predictive relevance of the Systemic Immune-Inflammation Index (SII) in patients with metastatic castration-resistant prostate cancer (mCRPC). A total of 113 mCRPC patients were assessed. In this descriptive study, SII was calculated using the formula (neutrophil count × platelet count)/lymphocyte count. The optimal threshold for SII, determined via the ROC curve, was 700. Patients with SII ≤ 700 were classified as SII-low, while those with SII > 700 were categorized as SII-high. The median overall survival (mOS) was significantly longer in the low SII group compared to the high SII group (*P = 0.015). In multivariate analysis, Gleason score, albumin levels, CHAARTED volume, and SII were identified as significant prognostic factors. Our findings indicate that SII has a strong correlation with survival and can serve as an independent prognostic marker in mCRPC patients.
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Affiliation(s)
- Mehmet Uzun
- Department of Medical Oncology, Necip Fazıl City Hospital, Kahramanmaras, Türkiye.
| | - Savas Gokcek
- Department of Medical Oncology, Necip Fazıl City Hospital, Kahramanmaras, Türkiye
| | - Erhan Kaya
- Department of Public Health, Sütçü Imam University, Kahramanmaraş, Türkiye
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Gomez-Salinero JM, Redmond D, Rafii S. Microenvironmental determinants of endothelial cell heterogeneity. Nat Rev Mol Cell Biol 2025:10.1038/s41580-024-00825-w. [PMID: 39875728 DOI: 10.1038/s41580-024-00825-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2024] [Indexed: 01/30/2025]
Abstract
During development, endothelial cells (ECs) undergo an extraordinary specialization by which generic capillary microcirculatory networks spanning from arteries to veins transform into patterned organotypic zonated blood vessels. These capillary ECs become specialized to support the cellular and metabolic demands of each specific organ, including supplying tissue-specific angiocrine factors that orchestrate organ development, maintenance of organ-specific functions and regeneration of injured adult organs. Here, we illustrate the mechanisms by which microenvironmental signals emanating from non-vascular niche cells induce generic ECs to acquire specific inter-organ and intra-organ functional attributes. We describe how perivascular, parenchymal and immune cells dictate vascular heterogeneity and capillary zonation, and how this system is maintained through tissue-specific signalling activated by vasculogenic and angiogenic factors and deposition of matrix components. We also discuss how perturbation of organotypic vascular niche cues lead to erasure of EC signatures, contributing to the pathogenesis of disease processes. We also describe approaches that use reconstitution of tissue-specific signatures of ECs to promote regeneration of damaged organs.
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Affiliation(s)
- Jesus M Gomez-Salinero
- Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration and Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - David Redmond
- Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration and Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Shahin Rafii
- Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration and Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
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Awad M, Taylor-Diaz E, Tawfik A, Hussein K, Elmansi A, Elashiry M, Elsayed R, Shahoumi L, Borke J, Hill W, Dong F, Elsalanty ME. Zoledronate interrupts pre-osteoclast-induced angiogenesis via SDF-1/CXCR4 pathway. Bone Rep 2024; 23:101812. [PMID: 39583183 PMCID: PMC11585646 DOI: 10.1016/j.bonr.2024.101812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 10/26/2024] [Accepted: 11/03/2024] [Indexed: 11/26/2024] Open
Abstract
Introduction In this study, we tested the hypothesis that pre-osteoclast signaling is key in triggering post-traumatic angiogenesis in alveolar bone via the SDF-1/CXCR4 pathway. Interruption of osteoclast differentiation through zoledronate (Zol) disrupts the crosstalk between pre-osteoclasts and endothelial cells, hindering the initial angiogenic reaction following dental trauma. This disruption could therefore play a role in the pathogenesis of medication-related osteonecrosis of the jaw (MRONJ). Methods The effect of zoledronate on the expression of SDF1 was tested in pre-osteoclasts (POC) in vitro. Then, we tested the effect of pre-osteoclast conditioned medium on HUVEC cell differentiation, migration, tube-formation, and CXCR4 expression and activity in-vitro. Lastly, we quantified the effect of zoledronate treatment on post-traumatic vascular perfusion of alveolar bone, using microCT-angiography and immunohistochemistry. Results SDF-1 mRNA expression decreased in Zol-treated POCs (p = 0.02). Flow-Cytometry analysis showed a decrease in CXCL-12+ (SDF-1α) expressing POCs with Zol treatment (p = 0.0058). On the other hand, CXCR4 mRNA expression was significantly inhibited in Zol-treated HUVECs (p = 0.0063). CXCR4 protein expression and activity showed a corresponding dose-dependent downregulation HUVEC surface treated with conditioned media from POC treated with Zol (p = 0.008 and 0.03, respectively). Similar inhibition was observed of HUVEC migration (p = 0.0012), and tube formation (p < 0.0001), effects that were reversed with SDF-1. Finally, there was a significant reduction of CD31+ HUVECs in Alveolar bone of Zol-treated rats (p = 0.0071), confirmed by significantly lower percentage of blood vessel volume (p = 0.026), and marginally lower vessel number (p = 0.062) in the alveolar bone. Conclusion Pre-osteoclasts play a crucial role in the initial angiogenic response in alveolar bone following dental extraction. Disruption of this process may be a predisposing factor to osteonecrosis.
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Affiliation(s)
- Mohamed Awad
- Dental College of Georgia, Augusta University, Augusta, GA, USA
| | | | - Amany Tawfik
- Oakland University, Eye Research Institute, Rochester, MI, USA
| | - Khaled Hussein
- Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Ahmed Elmansi
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | | | - Ranya Elsayed
- Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Linah Shahoumi
- Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - James Borke
- Western University of Health Sciences, Pomona, CA, USA
| | - William Hill
- Medical University of South Carolina, Charleston, SC, USA
| | - Fanglong Dong
- Western University of Health Sciences, Pomona, CA, USA
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Anastasiadou DP, Couturier N, Goel S, Argyris DG, Vodopyanov S, Rivera-Sanchez L, Gonzalez E, Kreger J, Griffen A, Kazakov A, Burt J, Recoder N, Duran CL, Harney AS, Quesnel A, Filippou PS, Lenis VP, Shukla S, Entenberg D, Zintiridou A, Chen X, Eddy RJ, Oktay MH, Condeelis JS, Karagiannis NS, Briceno A, Guzik H, Alon R, DesMarais V, Ioannou G, Gnjatic S, Raynolds DM, Macedo R, Reshef R, Gil-Henn H, MacLean AL, Torres ER, LaFave LM, Lauvau G, Karagiannis GS. Intratumoral CXCL12 Gradients Contextualize Tumor Cell Invasion, Migration and Immune Suppression in Breast Cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.15.618571. [PMID: 39464015 PMCID: PMC11507869 DOI: 10.1101/2024.10.15.618571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
Although the CXCL12/CXCR4 pathway has been prior investigated for its prometastatic and immuno- suppressive roles in the tumor microenvironment, evidence on the spatiotemporal regulation of these hallmarks has been lacking. Here, we demonstrate that CXCL12 forms a gradient specifically around cancer cell intravasation doorways, also known as Tumor Microenvironment of Metastasis (TMEM) doorways, thus facilitating the chemotactic translocation of prometastatic tumor cells expressing CXCR4 toward the perivascular TMEM doorways for subsequent entry into peripheral circulation. Fur- thermore, we demonstrate that the CXCL12-rich micro-environment around TMEM doorways may cre- ate immunosuppressive niches, whereby CD8 + T cells, despite being attracted to these regions, often exhibit reduced effector functions, limiting their efficacy. While the CXCL12/CXCR4 pathway can mini- mally influence the overall composition of immune cell populations, it biases the distribution of CD8 + T cells away from TMEM doorways, justifying its prior-established role as immunosuppressive factor for CD8 + T cells. Our research suggests that the complex interactions between CXCL12 and the various tumor and immune cell types contributes not only to the completion of the initial steps of the metastatic cascade, but also offers an immunological "sanctuary" to prometastatic tumor cells homed around TMEM doorways. Overall, our study enhances our current understanding on the mechanisms, via which CXCL12 orchestrates tumor cell behavior and immune dynamics, potentially guiding future thera- peutic strategies to combat breast cancer metastasis and improve anti-tumor immunity.
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Xu Z, Geng J, Liu X, Zhao Z, Suo D, Zhang S, Zhong J, Suo G. The extracellular matrix with a continuous gradient of SDF1 αguides the oriented migration of human umbilical cord mesenchymal stem cells. Biomed Mater 2024; 19:065019. [PMID: 39312941 DOI: 10.1088/1748-605x/ad7e91] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 09/23/2024] [Indexed: 09/25/2024]
Abstract
The extracellular matrix (ECM) plays a crucial role in maintaining cell morphology and facilitating intercellular signal transmission within the human body. ECM has been extensively utilized for tissue injury repair. However, the consideration of factor gradients during ECM preparation has been limited. In this study, we developed a novel approach to generate sheet-like ECM with a continuous gradient of stromal cell-derived factor-1 (SDF1α). Briefly, we constructed fibroblasts to overexpress SDF1αfused with the collagen-binding domain (CBD-SDF1α), and cultured these cells on a slanted plate to establish a gradual density cell layer at the bottom surface. Subsequently, excess parental fibroblasts were evenly distributed on the plate laid flat to fill the room between cells. Following two weeks of culture, the monolayer cells were lyophilized to form a uniform ECM sheet possessing a continuous gradient of SDF1α. This engineered ECM material demonstrated its ability to guide oriented migration of human umbilical cord mesenchymal stem cells on the ECM sheet. Our simple yet effective method holds great potential for advancing research in regenerative medicine.
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Affiliation(s)
- Zhongjuan Xu
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, People's Republic of China
- Guangdong Institute of Semiconductor Micro-Nano Manufacturing Technology, Foshan 528000, People's Republic of China
| | - Junsa Geng
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, People's Republic of China
| | - Xingzhi Liu
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, People's Republic of China
| | - Zhe Zhao
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, People's Republic of China
| | - Dylan Suo
- Westlake High School, Austin, TX 78746, United States of America
| | - Sheng Zhang
- Center for Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou 215006, People's Republic of China
| | - Junjie Zhong
- Department of Neurosurgery, National Center for Neurological Disorders, National KeyLaboratory for Medical Neurobiology, Shanghai Key Laboratory of Brain Function and Regeneration, Institutes of Brain Science, MOE Frontiers Center for Brain Science, Fudan University Huashan Hospital, Shanghai Medical College-Fudan University, Shanghai 200040, People's Republic of China
| | - Guangli Suo
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, People's Republic of China
- Division of Nanomaterials, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Nanchang 330200, People's Republic of China
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11
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Raftery RM, Gonzalez Vazquez AG, Walsh DP, Chen G, Laiva AL, Keogh MB, O'Brien FJ. Mobilizing Endogenous Progenitor Cells Using pSDF1α-Activated Scaffolds Accelerates Angiogenesis and Bone Repair in Critical-Sized Bone Defects. Adv Healthc Mater 2024; 13:e2401031. [PMID: 38850118 DOI: 10.1002/adhm.202401031] [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: 03/19/2024] [Revised: 06/05/2024] [Indexed: 06/09/2024]
Abstract
Mobilizing endogenous progenitor cells to repair damaged tissue in situ has the potential to revolutionize the field of regenerative medicine, while the early establishment of a vascular network will ensure survival of newly generated tissue. In this study, a gene-activated scaffold containing a stromal derived factor 1α plasmid (pSDF1α), a pro-angiogenic gene that is also thought to be involved in the recruitment of mesenchymal stromal cells (MSCs) to sites of injury is described. It is shown that over-expression of SDF1α protein enhanced MSC recruitment and induced vessel-like structure formation by endothelial cells in vitro. When implanted subcutaneously, transcriptomic analysis reveals that endogenous MSCs are recruited and significant angiogenesis is stimulated. Just 1-week after implantation into a calvarial critical-sized bone defect, pSDF1α-activated scaffolds are recruited MSCs and rapidly activate angiogenic and osteogenic programs, upregulating Runx2, Dlx5, and Sp7. At the same time-point, pVEGF-activated scaffolds are recruited a variety of cell types, activating endochondral ossification. The early response induced by both scaffolds leads to complete bridging of the critical-sized bone defects within 4-weeks. The versatile cell-free gene-activated scaffold described in this study is capable of harnessing and enhancing the body's own regenerative capacity and has immense potential in a myriad of applications.
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Affiliation(s)
- Rosanne M Raftery
- Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland
- Trinity Centre for Biomedical Engineering (TCBE), Trinity College Dublin, Dublin 2, Dublin, D02 PN40, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), RCSI and TCD, Dublin, D02 YN77, Ireland
- iEd Hub and Department of Anatomy and Neuroscience, College of Medicine and Health, University College Cork, Cork, T12 CY82, Ireland
| | - Arlyng G Gonzalez Vazquez
- Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland
- Trinity Centre for Biomedical Engineering (TCBE), Trinity College Dublin, Dublin 2, Dublin, D02 PN40, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), RCSI and TCD, Dublin, D02 YN77, Ireland
| | - David P Walsh
- Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland
- Trinity Centre for Biomedical Engineering (TCBE), Trinity College Dublin, Dublin 2, Dublin, D02 PN40, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), RCSI and TCD, Dublin, D02 YN77, Ireland
- Translational Research in Nanomedical Devices, School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland
| | - Gang Chen
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Microsurgical Research and Training Facility (MRTF), Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland
| | - Ashang L Laiva
- Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland
- Tisse Engineering Research Group, Royal College of Surgeons in Ireland - Medical University of Bahrain, Adliya, Bahrain
| | - Michael B Keogh
- Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland
- Tisse Engineering Research Group, Royal College of Surgeons in Ireland - Medical University of Bahrain, Adliya, Bahrain
| | - Fergal J O'Brien
- Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland
- Trinity Centre for Biomedical Engineering (TCBE), Trinity College Dublin, Dublin 2, Dublin, D02 PN40, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), RCSI and TCD, Dublin, D02 YN77, Ireland
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12
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Ecsedy M, Kovacs I, Szigeti A, Horvath H, Lenart L, Recsan Z, Medveczki T, Nagy ZZ, Fekete A. Association of SDF-1-3' Gene A Variant with Diabetic Retinopathy in the Hungarian Population. Int J Mol Sci 2024; 25:8036. [PMID: 39125605 PMCID: PMC11311494 DOI: 10.3390/ijms25158036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/08/2024] [Accepted: 07/19/2024] [Indexed: 08/12/2024] Open
Abstract
We investigated the association between the SDF-1-3' (c801G > A) variant and the development of diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR) in a Hungarian cohort. SDF-1-3' (c801G > A) was genotyped in 103 patients with diabetic retinopathy and 31 age- and sex-matched non-diabetic controls. Central retinal and choroidal thickness was measured by swept-source optical coherence tomography. The distribution of heterozygous and homozygous SDF-1-3' (c801G > A) genotypes was similar in diabetic and control subjects. The SDF-3'(c801AA) genotype was associated with DME (n = 94 eyes, allele distribution p = 0.006, genotype distribution p = 0.01 OR: 2.48, 95% CL: 1.21-5.08) in both univariable and multivariable modelling, independent of duration and type of diabetes, HbA1C, hypertension and microalbuminuria (p = 0.03). DME occurred earlier in patients carrying the SDF-1 (c801A) allele (Kaplan-Meier analysis, log-rank test p = 0.02). A marginally significant association was found between the presence of the SDF-1 (c801A) allele and the development of PDR (n = 89 eyes, p = 0.06). The SDF-1-3' (c801A) allele also showed a correlation with central retinal (p = 0.006) and choroidal (p = 0.08) thickness. SDF-1-3' (c801G > A) is involved in the development of macular complications in DM independent of critical clinical factors, suggesting that SDF-1 may be a future therapeutic target for high-risk patients, especially those carrying the SDF-1 (c801A) allele.
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Affiliation(s)
- Monika Ecsedy
- Department of Ophthalmology, Semmelweis University Budapest, 1085 Budapest, Hungary; (I.K.); (A.S.); (H.H.); (Z.R.); (Z.Z.N.)
| | - Illes Kovacs
- Department of Ophthalmology, Semmelweis University Budapest, 1085 Budapest, Hungary; (I.K.); (A.S.); (H.H.); (Z.R.); (Z.Z.N.)
- Department of Clinical Ophthalmology, Faculty of Health Sciences, Semmelweis University Budapest, 1085 Budapest, Hungary
- Department of Ophthalmology, Weill Cornell Medical College, New York, NY 10065, USA
| | - Andrea Szigeti
- Department of Ophthalmology, Semmelweis University Budapest, 1085 Budapest, Hungary; (I.K.); (A.S.); (H.H.); (Z.R.); (Z.Z.N.)
| | - Hajnalka Horvath
- Department of Ophthalmology, Semmelweis University Budapest, 1085 Budapest, Hungary; (I.K.); (A.S.); (H.H.); (Z.R.); (Z.Z.N.)
| | - Lilla Lenart
- MTA-SE Lendület Diabetes Research Group, Hungarian Academy of Sciences and Semmelweis University, 1085 Budapest, Hungary; (L.L.); (T.M.); (A.F.)
| | - Zsuzsanna Recsan
- Department of Ophthalmology, Semmelweis University Budapest, 1085 Budapest, Hungary; (I.K.); (A.S.); (H.H.); (Z.R.); (Z.Z.N.)
| | - Timea Medveczki
- MTA-SE Lendület Diabetes Research Group, Hungarian Academy of Sciences and Semmelweis University, 1085 Budapest, Hungary; (L.L.); (T.M.); (A.F.)
| | - Zoltan Zsolt Nagy
- Department of Ophthalmology, Semmelweis University Budapest, 1085 Budapest, Hungary; (I.K.); (A.S.); (H.H.); (Z.R.); (Z.Z.N.)
- Department of Clinical Ophthalmology, Faculty of Health Sciences, Semmelweis University Budapest, 1085 Budapest, Hungary
| | - Andrea Fekete
- MTA-SE Lendület Diabetes Research Group, Hungarian Academy of Sciences and Semmelweis University, 1085 Budapest, Hungary; (L.L.); (T.M.); (A.F.)
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13
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Tittarelli A, Pereda C, Gleisner MA, López MN, Flores I, Tempio F, Lladser A, Achour A, González FE, Durán-Aniotz C, Miranda JP, Larrondo M, Salazar-Onfray F. Long-Term Survival and Immune Response Dynamics in Melanoma Patients Undergoing TAPCells-Based Vaccination Therapy. Vaccines (Basel) 2024; 12:357. [PMID: 38675738 PMCID: PMC11053591 DOI: 10.3390/vaccines12040357] [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: 12/05/2023] [Revised: 01/05/2024] [Accepted: 01/06/2024] [Indexed: 04/28/2024] Open
Abstract
Cancer vaccines present a promising avenue for treating immune checkpoint blockers (ICBs)-refractory patients, fostering immune responses to modulate the tumor microenvironment. We revisit a phase I/II trial using Tumor Antigen-Presenting Cells (TAPCells) (NCT06152367), an autologous antigen-presenting cell vaccine loaded with heat-shocked allogeneic melanoma cell lysates. Initial findings showcased TAPCells inducing lysate-specific delayed-type hypersensitivity (DTH) reactions, correlating with prolonged survival. Here, we extend our analysis over 15 years, categorizing patients into short-term (<36 months) and long-term (≥36 months) survivors, exploring novel associations between clinical outcomes and demographic, genetic, and immunologic parameters. Notably, DTHpos patients exhibit a 53.1% three-year survival compared to 16.1% in DTHneg patients. Extended remissions are observed in long-term survivors, particularly DTHpos/M1cneg patients. Younger age, stage III disease, and moderate immune events also benefit short-term survivors. Immunomarkers like increased C-type lectin domain family 2 member D on CD4+ T cells and elevated interleukin-17A were detected in long-term survivors. In contrast, toll-like receptor-4 D229G polymorphism and reduced CD32 on B cells are associated with reduced survival. TAPCells achieved stable long remissions in 35.2% of patients, especially M1cneg/DTHpos cases. Conclusions: Our study underscores the potential of vaccine-induced immune responses in melanoma, emphasizing the identification of emerging biological markers and clinical parameters for predicting long-term remission.
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Affiliation(s)
- Andrés Tittarelli
- Programa Institucional de Fomento a la Investigación, Desarrollo e Innovación, Universidad Tecnológica Metropolitana, Santiago 8940577, Chile;
| | - Cristian Pereda
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile; (C.P.); (M.A.G.); (M.N.L.); (I.F.); (F.T.)
| | - María A. Gleisner
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile; (C.P.); (M.A.G.); (M.N.L.); (I.F.); (F.T.)
- Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Mercedes N. López
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile; (C.P.); (M.A.G.); (M.N.L.); (I.F.); (F.T.)
| | - Iván Flores
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile; (C.P.); (M.A.G.); (M.N.L.); (I.F.); (F.T.)
| | - Fabián Tempio
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile; (C.P.); (M.A.G.); (M.N.L.); (I.F.); (F.T.)
| | - Alvaro Lladser
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580702, Chile;
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago 8580702, Chile
| | - Adnane Achour
- Science for Life Laboratory, Department of Medicine Solna, Karolinska Institute, 17176 Stockholm, Sweden;
- Division of Infectious Diseases, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Fermín E. González
- Laboratory of Experimental Immunology & Cancer, Faculty of Dentistry, Universidad de Chile, Santiago 8380000, Chile;
| | - Claudia Durán-Aniotz
- Latin American Brain Health Institute (BrainLat), Center for Social and Cognitive Neuroscience (CSCN), School of Psychology, Universidad Adolfo Ibañez, Santiago 7941169, Chile;
| | | | - Milton Larrondo
- Banco de Sangre, Hospital Clínico de la Universidad de Chile, Santiago 8380453, Chile;
| | - Flavio Salazar-Onfray
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile; (C.P.); (M.A.G.); (M.N.L.); (I.F.); (F.T.)
- Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
- Science for Life Laboratory, Department of Medicine Solna, Karolinska Institute, 17176 Stockholm, Sweden;
- Division of Infectious Diseases, Karolinska University Hospital, 17176 Stockholm, Sweden
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14
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Lee S, Zhan H. Deciphering the differential impact of thrombopoietin/MPL signaling on hematopoietic stem/progenitor cell function in bone marrow and spleen. Stem Cell Reports 2024; 19:211-223. [PMID: 38215758 PMCID: PMC10874852 DOI: 10.1016/j.stemcr.2023.12.004] [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: 04/27/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 01/14/2024] Open
Abstract
Thrombopoietin (TPO) and its receptor MPL play crucial roles in hematopoietic stem cell (HSC) function and platelet production. However, the precise effects of TPO/MPL signaling on HSC regulation in different hematopoietic niches remain unclear. Here, we investigated the effects of TPO/MPL ablation on marrow and splenic hematopoiesis in TPO-/- and MPL-/- mice during aging. Despite severe thrombocytopenia, TPO-/- and MPL-/- mice did not develop marrow failure during a 2-year follow-up. Marrow and splenic HSCs exhibited different responses to TPO/MPL ablation and exogenous TPO treatment. Splenic niche cells compensated for marrow HSC loss in TPO-/- and MPL-/- mice by upregulating CXCL12 levels. These findings provide new insights into the complex regulation of HSCs by TPO/MPL and reveal a previously unknown link between TPO and CXCL12, two key growth factors for HSC maintenance. Understanding the distinct regulatory mechanisms between marrow and spleen hematopoiesis will help to develop novel therapeutic approaches for hematopoietic disorders.
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Affiliation(s)
- Sandy Lee
- Graduate Program in Molecular & Cellular Pharmacology, Stony Brook University, Stony Brook, NY, USA
| | - Huichun Zhan
- Department of Medicine, Stony Brook School of Medicine, Stony Brook, NY, USA; Medical Service, Northport VA Medical Center, Northport, NY, USA.
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15
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Sremac M, Luo H, Deng H, Parr MFE, Hutcheson J, Verde PS, Alagpulinsa DA, Kitzmann JM, Papas KK, Brauns T, Markmann JF, Lei J, Poznansky MC. Short-term function and immune-protection of microencapsulated adult porcine islets with alginate incorporating CXCL12 in healthy and diabetic non-human primates without systemic immune suppression: A pilot study. Xenotransplantation 2023; 30:e12826. [PMID: 37712342 DOI: 10.1111/xen.12826] [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: 04/20/2023] [Revised: 08/10/2023] [Accepted: 08/29/2023] [Indexed: 09/16/2023]
Abstract
Replacement of insulin-producing pancreatic beta-cells by islet transplantation offers a functional cure for type-1 diabetes (T1D). We recently demonstrated that a clinical grade alginate micro-encapsulant incorporating the immune-repellent chemokine and pro-survival factor CXCL12 could protect and sustain the integrity and function of autologous islets in healthy non-human primates (NHPs) without systemic immune suppression. In this pilot study, we examined the impact of the CXCL12 micro encapsulant on the function and inflammatory and immune responses of xenogeneic islets transplanted into the omental tissue bilayer sac (OB; n = 4) and diabetic (n = 1) NHPs. Changes in the expression of cytokines after implantation were limited to 2-6-fold changes in blood, most of which did not persist over the first 4 weeks after implantation. Flow cytometry of PBMCs following transplantation showed minimal changes in IFNγ or TNFα expression on xenoantigen-specific CD4+ or CD8+ T cells compared to unstimulated cells, and these occurred mainly in the first 4 weeks. Microbeads were readily retrievable for assessment at day 90 and day 180 and at retrieval were without microscopic signs of degradation or foreign body responses (FBR). In vitro and immunohistochemistry studies of explanted microbeads indicated the presence of functional xenogeneic islets at day 30 post transplantation in all biopsied NHPs. These results from a small pilot study revealed that CXCL12-microencapsulated xenogeneic islets abrogate inflammatory and adaptive immune responses to the xenograft. This work paves the way toward future larger scale studies of the transplantation of alginate microbeads with CXCL12 and porcine or human stem cell-derived beta cells or allogeneic islets into diabetic NHPs without systemic immunosuppression.
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Affiliation(s)
- Marinko Sremac
- Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Hao Luo
- Division of Transplant Surgery and Center of Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of General Surgery, General Hospital of Western Theater Command, Chengdu, China
| | - Hongping Deng
- Division of Transplant Surgery and Center of Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Madeline F E Parr
- Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | | | - Pushkar S Verde
- Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - David A Alagpulinsa
- Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jenna Miner Kitzmann
- Department of Surgery, Institute for Cellular Transplantation, University of Arizona, Tucson, Arizona, USA
| | - Klearchos K Papas
- Department of Surgery, Institute for Cellular Transplantation, University of Arizona, Tucson, Arizona, USA
| | - Timothy Brauns
- Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - James F Markmann
- Division of Transplant Surgery and Center of Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ji Lei
- Division of Transplant Surgery and Center of Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Mark C Poznansky
- Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
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16
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Wei J, Xia X, Xiao S, Jin S, Zou Q, Zuo Y, Li Y, Li J. Sequential Dual-Biofactor Release from the Scaffold of Mesoporous HA Microspheres and PLGA Matrix for Boosting Endogenous Bone Regeneration. Adv Healthc Mater 2023; 12:e2300624. [PMID: 36938866 DOI: 10.1002/adhm.202300624] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Indexed: 03/21/2023]
Abstract
The combined design of scaffold structure and multi-biological factors is a prominent strategy to promote bone regeneration. Herein, a composite scaffold of mesoporous hydroxyapatite (HA) microspheres loaded with the bone morphogenetic protein-2 (BMP-2) and a poly(DL-lactic-co-glycolic acid) (PLGA) matrix is constructed by 3D printing. Furthermore, the chemokine stromal cell-derived factor-1α (SDF-1α) is adsorbed on a scaffold surface to achieve the sequential release of the dual-biofactors. The results indicate that the rapid release of SDF-1α chemokine on the scaffold surface effectively recruits bone marrow-derived mesenchymal stem cells (BMSCs) to the target defect area, whereas the long-term sustained release of BMP-2 from the HA microspheres in the degradable PLGA matrix successfully triggers the osteogenic differentiation in the recruited BMSCs, significantly promoting bone regeneration and reconstruction. In addition, these structures/biofactors specially combining scaffold exhibit significantly better biological performance than that of other combined scaffolds, including the bare HA/PLGA scaffold, the scaffold loaded with SDF-1α or BMP-2 biofactor alone, and the scaffold with surface SDF-1α and BMP-2 dual-biofactors. The utilization of mesoporous HA, the assembly method, and sequential release of the two biofactors in the 3D printed composite scaffold present a new method for future design of high-performance bone repairing scaffolds.
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Affiliation(s)
- Jiawei Wei
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, P. R. China
| | - Xue Xia
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, P. R. China
| | - Shiqi Xiao
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, P. R. China
| | - Shue Jin
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, P. R. China
| | - Qin Zou
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, P. R. China
| | - Yi Zuo
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, P. R. China
| | - Yubao Li
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, P. R. China
| | - Jidong Li
- Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, 610064, P. R. China
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17
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Amano H, Eshima K, Ito Y, Nakamura M, Kitasato H, Ogawa F, Hosono K, Iwabuchi K, Uematsu S, Akira S, Narumiya S, Majima M. The microsomal prostaglandin E synthase-1/prostaglandin E2 axis induces recovery from ischaemia via recruitment of regulatory T cells. Cardiovasc Res 2023; 119:1218-1233. [PMID: 35986688 PMCID: PMC10411941 DOI: 10.1093/cvr/cvac137] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 07/24/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
AIMS Microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) induces angiogenesis through the prostaglandin E2 receptor (EP1-4). Among immune cells, regulatory T cells (Tregs), which inhibit immune responses, have been implicated in angiogenesis, and PGE2 is known to modulate the function and differentiation of Tregs. We hypothesized that mPGES-1/PGE2-EP signalling could contribute to recovery from ischaemic conditions by promoting the accumulation of Tregs. METHODS AND RESULTS Wild-type (WT), mPGES-1-deficient (mPges-1-/-), and EP4 receptor-deficient (Ep4-/-) male mice, 6-8 weeks old, were used. Hindlimb ischaemia was induced by femoral artery ligation. Recovery from ischaemia was suppressed in mPges-1-/- mice and compared with WT mice. The number of accumulated forkhead box protein P3 (FoxP3)+ cells in ischaemic muscle tissue was decreased in mPges-1-/- mice compared with that in WT mice. Expression levels of transforming growth factor-β (TGF-β) and stromal cell derived factor-1 (SDF-1) in ischaemic tissue were also suppressed in mPges-1-/- mice. The number of accumulated FoxP3+ cells and blood flow recovery were suppressed when Tregs were depleted by injecting antibody against folate receptor 4 in WT mice but not in mPges-1-/- mice. Recovery from ischaemia was significantly suppressed in Ep4-/- mice compared with that in WT mice. Furthermore, mRNA levels of Foxp3 and Tgf-β were suppressed in Ep4-/- mice. Moreover, the number of accumulated FoxP3+ cells in ischaemic tissue was diminished in Ep4-/- mice compared with that in Ep4+/+ mice. CONCLUSION These findings suggested that mPGES-1/PGE2 induced neovascularization from ischaemia via EP4 by promoting the accumulation of Tregs. Highly selective EP4 agonists could be useful for the treatment of peripheral artery disease.
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Affiliation(s)
- Hideki Amano
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Koji Eshima
- Department of Immunology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Yoshiya Ito
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Masaki Nakamura
- Department of Microbiology, Kitasato University School of Allied Health Science, Kanagawa, Japan
| | - Hidero Kitasato
- Department of Microbiology, Kitasato University School of Allied Health Science, Kanagawa, Japan
| | - Fumihiro Ogawa
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Kanako Hosono
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Kazuya Iwabuchi
- Department of Immunology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Satoshi Uematsu
- Department of Immunology and Genomics, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shizuo Akira
- Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
| | - Shuh Narumiya
- Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masataka Majima
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
- Department of Medical Therapeutics, Kanagawa Institute of Technology, Atsugi, Kanagawa, Japan
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18
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Risser GE, Machour M, Hernaez-Estrada B, Li D, Levenberg S, Spiller KL. Effects of Interleukin-4 (IL-4)-releasing microparticles and adoptive transfer of macrophages on immunomodulation and angiogenesis. Biomaterials 2023; 296:122095. [PMID: 36989737 PMCID: PMC10085857 DOI: 10.1016/j.biomaterials.2023.122095] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 02/16/2023] [Accepted: 03/16/2023] [Indexed: 03/29/2023]
Abstract
Macrophages are major regulators of angiogenesis in response to injury, but the mechanisms behind their diverse and phenotypically specific functions are still poorly understood. In particular, the effects of interleukin-4 (IL-4) on macrophage behavior have been well studied in vitro, but it remains unclear whether the release of IL-4 from biomaterials can be used to control macrophage phenotype and subsequent effects on angiogenesis in vivo. We used the murine hindlimb ischemia model to investigate the effects of IL-4-releasing poly(lactic-co-glycolic acid) microparticles co-delivered with IL-4-polarized macrophages on host macrophage phenotype and angiogenesis in vivo. We established a minimum dose of IL-4 required to modulate macrophage phenotype in vivo and evaluated effects on macrophage subpopulation diversity using multidimensional flow cytometry and pseudotime analysis. The delivery of IL-4-releasing microparticles did not affect the density or size of blood vessels as measured by immunohistochemical (IHC) analysis, but it did increase perfused tissue volume as measured by 3D microcomputed tomography (microCT). In contrast, the co-delivery of IL-4-releasing microparticles and exogenously IL-4-polarized macrophages increased the size of blood vessels as measured by IHC, but without effects on perfused tissue volume via microCT. These effects occurred in spite of low recovery of adoptively transferred macrophages at 4 days after administration. Spatial analysis of macrophage-blood vessel interactions via IHC showed that macrophages closely interacted with blood vessels, which was slightly influenced by treatment, and that blood vessel size was positively correlated with number of macrophages in close proximity. Altogether, these findings indicate that delivery of IL-4-releasing microparticles and exogenously IL-4-polarized macrophages can be beneficial for angiogenesis, but further mechanistic investigations are required.
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Affiliation(s)
- Gregory E Risser
- School of Biomedical Engineering, Sciences and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Majd Machour
- Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | - Beatriz Hernaez-Estrada
- School of Biomedical Engineering, Sciences and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Dong Li
- Shanghai Key Tissue Engineering Laboratory, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shulamit Levenberg
- Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | - Kara L Spiller
- School of Biomedical Engineering, Sciences and Health Systems, Drexel University, Philadelphia, PA, USA.
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19
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Lee S, Zhan H. Deciphering the Differential Impact of Thrombopoietin/MPL Signaling on Hematopoietic Stem Cell Function in Bone Marrow and Spleen. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.27.538580. [PMID: 37162918 PMCID: PMC10168386 DOI: 10.1101/2023.04.27.538580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Thrombopoietin (TPO) and its receptor MPL play crucial roles in hematopoietic stem cell (HSC) function and platelet production. However, the precise effects of TPO/MPL signaling on HSC regulation in different hematopoietic niches remain unclear. Here, we investigated the effects of TPO/MPL ablation on marrow and splenic hematopoiesis in TPO-/- and MPL-/- mice during aging. Despite severe thrombocytopenia, TPO-/- and MPL-/- mice did not develop marrow failure during a 2-year follow-up. Marrow and splenic HSCs exhibited different responses to TPO/MPL ablation and exogenous TPO treatment. Splenic niche cells compensated for marrow HSC loss in TPO-/- and MPL-/- mice by upregulating CXCL12 levels. These findings provide new insights into the complex regulation of HSCs by TPO/MPL and reveal a previously unknown link between TPO and CXCL12, two key growth factors for HSC maintenance. Understanding the distinct regulatory mechanisms between marrow and spleen hematopoiesis will help develop novel therapeutic approaches for hematopoietic disorders.
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Affiliation(s)
- Sandy Lee
- Graduate Program in Molecular & Cellular Pharmacology, Stony Brook University, Stony Brook, NY
| | - Huichun Zhan
- Department of Medicine, Stony Brook School of Medicine, Stony Brook, NY
- Medical Service, Northport VA Medical Center, Northport, NY
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20
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Jiang B, Shi A, Xu Y, Zhang Y, Chen Y, Jiang X, Liu H, Zhang L. SDF-1α and CTGF functionalized Gelatin methacryloyl (GelMA) hydrogels enhance fibroblast activation to promote wound healing. MATERIALS TODAY COMMUNICATIONS 2023; 34:105152. [DOI: 10.1016/j.mtcomm.2022.105152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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21
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Hernández-Cano L, Fernández-Infante C, Herranz Ó, Berrocal P, Lozano FS, Sánchez-Martín MA, Porras A, Guerrero C. New functions of C3G in platelet biology: Contribution to ischemia-induced angiogenesis, tumor metastasis and TPO clearance. Front Cell Dev Biol 2022; 10:1026287. [PMID: 36393850 PMCID: PMC9661425 DOI: 10.3389/fcell.2022.1026287] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/06/2022] [Indexed: 07/10/2024] Open
Abstract
C3G is a Rap1 guanine nucleotide exchange factor that controls platelet activation, aggregation, and the release of α-granule content. Transgenic expression of C3G in platelets produces a net proangiogenic secretome through the retention of thrombospondin-1. In a physiological context, C3G also promotes megakaryocyte maturation and proplatelet formation, but without affecting mature platelet production. The aim of this work is to investigate whether C3G is involved in pathological megakaryopoiesis, as well as its specific role in platelet mediated angiogenesis and tumor metastasis. Using megakaryocyte-specific C3G knockout and transgenic mouse models, we found that both C3G overexpression and deletion promoted platelet-mediated angiogenesis, induced by tumor cell implantation or hindlimb ischemia, through differential release of proangiogenic and antiangiogenic factors. However, only C3G deletion resulted in a higher recruitment of hemangiocytes from the bone marrow. In addition, C3G null expression enhanced thrombopoietin (TPO)-induced platelet production, associated with reduced TPO plasma levels. Moreover, after 5-fluorouracil-induced platelet depletion and rebound, C3G knockout mice showed a defective return to homeostatic platelet levels, indicating impaired platelet turnover. Mechanistically, C3G promotes c-Mpl ubiquitination by inducing Src-mediated c-Cbl phosphorylation and participates in c-Mpl degradation via the proteasome and lysosome systems, affecting TPO internalization. We also unveiled a positive role of platelet C3G in tumor cell-induced platelet aggregation, which facilitated metastatic cell homing and adhesion. Overall, these findings revealed that C3G plays a crucial role in platelet-mediated angiogenesis and metastasis, as well as in platelet level modulation in response to pathogenic stimuli.
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Affiliation(s)
- Luis Hernández-Cano
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC), USAL-CSIC, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Cristina Fernández-Infante
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC), USAL-CSIC, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Óscar Herranz
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC), USAL-CSIC, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Pablo Berrocal
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC), USAL-CSIC, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Francisco S. Lozano
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Departamento de Angiología y Cirugía Vascular, Hospital Universitario de Salamanca, Universidad de Salamanca, Salamanca, Spain
| | - Manuel A. Sánchez-Martín
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Servicio de Transgénesis, Nucleus, Universidad of Salamanca, Salamanca, Spain
- Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain
| | - Almudena Porras
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Carmen Guerrero
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC), USAL-CSIC, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain
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22
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Jorge DDMF, Huber SC, Rodrigues BL, Da Fonseca LF, Azzini GOM, Parada CA, Paulus-Romero C, Lana JFSD. The Mechanism of Action between Pulsed Radiofrequency and Orthobiologics: Is There a Synergistic Effect? Int J Mol Sci 2022; 23:ijms231911726. [PMID: 36233026 PMCID: PMC9570243 DOI: 10.3390/ijms231911726] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/07/2022] [Accepted: 09/16/2022] [Indexed: 12/04/2022] Open
Abstract
Radiofrequency energy is a common treatment modality for chronic pain. While there are different forms of radiofrequency-based therapeutics, the common concept is the generation of an electromagnetic field in the applied area, that can result in neuromodulation (pulsed radiofrequency—PRF) or ablation. Our specific focus relates to PRF due to the possibility of modulation that is in accordance with the mechanisms of action of orthobiologics. The proposed mechanism of action of PRF pertaining to pain relief relies on a decrease in pro-inflammatory cytokines, an increase in cytosolic calcium concentration, a general effect on the immune system, and a reduction in the formation of free radical molecules. The primary known properties of orthobiologics constitute the release of growth factors, a stimulus for endogenous repair, analgesia, and improvement of the function of the injured area. In this review, we described the mechanism of action of both treatments and pertinent scientific references to the use of the combination of PRF and orthobiologics. Our hypothesis is a synergic effect with the combination of both techniques which could benefit patients and improve the life quality.
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Affiliation(s)
| | - Stephany Cares Huber
- Orthoregen International Course—Avenida Presidente Kennedy, 1386, Cidade Nova I, Indaiatuba 13334-170, Brazil
| | - Bruno Lima Rodrigues
- Orthoregen International Course—Avenida Presidente Kennedy, 1386, Cidade Nova I, Indaiatuba 13334-170, Brazil
| | - Lucas Furtado Da Fonseca
- Orthopaedic Department, Universidade Federal de São Paulo, 715 Napoleão de Barros St-Vila Clementino, São Paulo 04024-002, Brazil
| | - Gabriel Ohana Marques Azzini
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine, Cidade Nova I, Indaiatuba 13334-170, Brazil
| | - Carlos Amilcar Parada
- Laboratory of Study of Pain, Department of Structural and Functional Biology, University of Campinas, Rua Monteiro Lobato, 255, Campinas 13083-862, Brazil
| | - Christian Paulus-Romero
- American Academy of Regenerative Medicine, 14405 West Colfax Avenue, #291, Lakewood, CO 80401, USA
| | - José Fábio Santos Duarte Lana
- Orthoregen International Course—Avenida Presidente Kennedy, 1386, Cidade Nova I, Indaiatuba 13334-170, Brazil
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine, Cidade Nova I, Indaiatuba 13334-170, Brazil
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23
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Ya G, Ren W, Qin R, He J, Zhao S. Role of myeloid-derived suppressor cells in the formation of pre-metastatic niche. Front Oncol 2022; 12:975261. [PMID: 36237333 PMCID: PMC9552826 DOI: 10.3389/fonc.2022.975261] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 09/12/2022] [Indexed: 11/13/2022] Open
Abstract
Metastasis is a complex process, which depends on the interaction between tumor cells and host organs. Driven by the primary tumor, the host organ will establish an environment suitable for the growth of tumor cells before their arrival, which is called the pre-metastasis niche. The formation of pre-metastasis niche requires the participation of a variety of cells, in which myeloid-derived suppressor cells play a very important role. They reach the host organ before the tumor cells, and promote the establishment of the pre-metastasis niche by influencing immunosuppression, vascular leakage, extracellular matrix remodeling, angiogenesis and so on. In this article, we introduced the formation of the pre-metastasis niche and discussed the important role of myeloid-derived suppressor cells. In addition, this paper also emphasized the targeting of myeloid-derived suppressor cells as a therapeutic strategy to inhibit the formation of pre-metastasis niche, which provided a research idea for curbing tumor metastasis.
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Affiliation(s)
- Guoqi Ya
- The First Clinical Medical Institute, Henan University of Chinese Medicine, Zhengzhou, China
| | - Weihong Ren
- Department of Laboratory Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
- *Correspondence: Weihong Ren,
| | - Rui Qin
- The First Clinical Medical Institute, Henan University of Chinese Medicine, Zhengzhou, China
| | - Jiao He
- The First Clinical Medical Institute, Henan University of Chinese Medicine, Zhengzhou, China
| | - Shuo Zhao
- Department of Laboratory Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
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24
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Chen J, He J, Luo L. Brain vascular damage-induced lymphatic ingrowth is directed by Cxcl12b/Cxcr4a. Development 2022; 149:275687. [PMID: 35694896 DOI: 10.1242/dev.200729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 06/06/2022] [Indexed: 12/15/2022]
Abstract
After ischemic stroke, promotion of vascular regeneration without causing uncontrolled vessel growth appears to be the major challenge for pro-angiogenic therapies. The molecular mechanisms underlying how nascent blood vessels (BVs) are correctly guided into the post-ischemic infarction area remain unknown. Here, using a zebrafish cerebrovascular injury model, we show that chemokine signaling provides crucial guidance cues to determine the growing direction of ingrown lymphatic vessels (iLVs) and, in turn, that of nascent BVs. The chemokine receptor Cxcr4a is transcriptionally activated in the iLVs after injury, whereas its ligand Cxcl12b is expressed in the residual central BVs, the destinations of iLV ingrowth. Mutant and mosaic studies indicate that Cxcl12b/Cxcr4a-mediated chemotaxis is necessary and sufficient to determine the growing direction of iLVs and nascent BVs. This study provides a molecular basis for how the vessel directionality of cerebrovascular regeneration is properly determined, suggesting potential application of Cxcl12b/Cxcr4a in the development of post-ischemic pro-angiogenic therapies.
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Affiliation(s)
- Jingying Chen
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, 400715 Chongqing, China.,University of Chinese Academy of Sciences (Chongqing), Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Beibei, 400714 Chongqing, China
| | - Jianbo He
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, 400715 Chongqing, China
| | - Lingfei Luo
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, 400715 Chongqing, China.,University of Chinese Academy of Sciences (Chongqing), Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Beibei, 400714 Chongqing, China
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25
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Ma Q, Zhang N, You Y, Zhu J, Yu Z, Chen H, Xie X, Yu H. CXCR4 blockade in macrophage promotes angiogenesis in ischemic hindlimb by modulating autophagy. J Mol Cell Cardiol 2022; 169:57-70. [PMID: 35597127 DOI: 10.1016/j.yjmcc.2022.05.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 04/14/2022] [Accepted: 05/07/2022] [Indexed: 11/30/2022]
Abstract
Chemokine receptor CXCR4 plays a crucial role in leukocyte recruitment and inflammation regulation to influence tissue repair in ischemic diseases. Here we assessed the effect of CXCR4 expression in macrophages on angiogenesis in the ischemic hindlimb of a mouse. Inflammatory cells were increased in the ischemic muscles of hindlimb, and CXCR4 was highly expressed in the infiltrated macrophages but not in neutrophils. Myeloid-specific CXCR4 knockout attenuated macrophage infiltration and subsequent reduced inflammatory response in the ischemic hindlimb, accompanied with better blood reperfusion and higher capillary density as compared with that in LysM Cre+/- (Cre) mice. Similar outcomes were also observed in CRE mice whose bone marrow cells were replaced with those from CXCR4-deficient mice. Gene ontology cluster analysis reviewed that Decorin, a negative regulator of angiogenesis, was reduced in CXCR4-deficient macrophages. CXCR4-deficient macrophages were less inducible into M1 phase by lipopolysaccharide and more favorable for M2 polarization under oxygen/glucose deprivation condition. Enhanced autophagy was detected in CXCR4-deficient macrophages, which was associated with less expression of both Decorin and the inflammatory cytokines. In summary, myeloid-specific CXCR4 deficiency reduced monocyte infiltration and the secretion of inflammatory cytokines and Decorin from macrophages, thus blunting inflammation response and promoting angiogenesis in the ischemic hindlimb.
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Affiliation(s)
- Qunchao Ma
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China; Cardiovascular Key Laboratory of Zhejiang Province, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China
| | - Ning Zhang
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China; Cardiovascular Key Laboratory of Zhejiang Province, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China
| | - Yayu You
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China; Cardiovascular Key Laboratory of Zhejiang Province, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China
| | - Jinyun Zhu
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China; Cardiovascular Key Laboratory of Zhejiang Province, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China
| | - Zhaosheng Yu
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Haibo Chen
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China; Cardiovascular Key Laboratory of Zhejiang Province, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China
| | - Xiaojie Xie
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China; Cardiovascular Key Laboratory of Zhejiang Province, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China.
| | - Hong Yu
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China; Cardiovascular Key Laboratory of Zhejiang Province, 88 Jiefang Rd, Hangzhou, Zhejiang Province 310009, PR China.
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26
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Comparative effects of concentrated growth factors on the biological characteristics of periodontal ligament cells and stem cells from apical papilla. J Endod 2022; 48:1029-1037. [DOI: 10.1016/j.joen.2022.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/30/2022] [Accepted: 05/01/2022] [Indexed: 12/14/2022]
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27
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Muire PJ, Thompson MA, Christy RJ, Natesan S. Advances in Immunomodulation and Immune Engineering Approaches to Improve Healing of Extremity Wounds. Int J Mol Sci 2022; 23:4074. [PMID: 35456892 PMCID: PMC9032453 DOI: 10.3390/ijms23084074] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/01/2022] [Accepted: 04/03/2022] [Indexed: 12/04/2022] Open
Abstract
Delayed healing of traumatic wounds often stems from a dysregulated immune response initiated or exacerbated by existing comorbidities, multiple tissue injury or wound contamination. Over decades, approaches towards alleviating wound inflammation have been centered on interventions capable of a collective dampening of various inflammatory factors and/or cells. However, a progressive understanding of immune physiology has rendered deeper knowledge on the dynamic interplay of secreted factors and effector cells following an acute injury. There is a wide body of literature, both in vitro and in vivo, abstracted on the immunomodulatory approaches to control inflammation. Recently, targeted modulation of the immune response via biotechnological approaches and biomaterials has gained attention as a means to restore the pro-healing phenotype and promote tissue regeneration. In order to fully realize the potential of these approaches in traumatic wounds, a critical and nuanced understanding of the relationships between immune dysregulation and healing outcomes is needed. This review provides an insight on paradigm shift towards interventional approaches to control exacerbated immune response following a traumatic injury from an agonistic to a targeted path. We address such a need by (1) providing a targeted discussion of the wound healing processes to assist in the identification of novel therapeutic targets and (2) highlighting emerging technologies and interventions that utilize an immunoengineering-based approach. In addition, we have underscored the importance of immune engineering as an emerging tool to provide precision medicine as an option to modulate acute immune response following a traumatic injury. Finally, an overview is provided on how an intervention can follow through a successful clinical application and regulatory pathway following laboratory and animal model evaluation.
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Affiliation(s)
- Preeti J. Muire
- Combat Wound Care Research Department, US Army Institute of Surgical Research, JBSA Ft Sam Houston, San Antonio, TX 78234, USA; (M.A.T.); (R.J.C.)
| | | | | | - Shanmugasundaram Natesan
- Combat Wound Care Research Department, US Army Institute of Surgical Research, JBSA Ft Sam Houston, San Antonio, TX 78234, USA; (M.A.T.); (R.J.C.)
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28
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Tu S, Wang XY, Zeng LX, Shen ZJ, Zhang ZH. LncRNA TINCR improves cardiac hypertrophy by regulating the miR-211-3p-VEGFB-SDF-1α-CXCR4 pathway. J Transl Med 2022; 102:253-262. [PMID: 34732848 DOI: 10.1038/s41374-021-00678-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 08/12/2021] [Accepted: 09/07/2021] [Indexed: 11/08/2022] Open
Abstract
Cardiac hypertrophy is a common cardiovascular disease that is found worldwide and is characterized by heart enlargement, eventually resulting in heart failure. Exploring the regulatory mechanism of cardiac hypertrophy is beneficial for understanding its pathogenesis and treatment. In our study, we have showed TINCR was downregulated and miR-211-3p was upregulated in TAC- or Ang II-induced models of cardiac hypertrophy. Dual luciferase and RIP assays revealed that TINCR served as a competitive endogenous RNA (ceRNA) for miR-211-3p. Then, we observed that knockdown of miR-211-3p alleviated TAC- or Ang II-induced cardiac hypertrophy both in vivo and in vitro. Mechanistically, we demonstrated that miR-211-3p directly targeted VEGFB and thus regulated the expression of SDF-1α and CXCR4. Rescue assays further confirmed that TINCR suppressed the progression of cardiac hypertrophy by competitively binding to miR-211-3p, thereby enhancing the expression of VEGFB and activating the VEGFB-SDF-1α- CXCR4 signal. Furthermore, overexpression of TINCR suppressed TAC-induced cardiac hypertrophy in vivo by targeting miR-211-3p-VEGFB-SDF-1α- CXCR4 signalling. In conclusion, our research suggests that LncRNA TINCR improves cardiac hypertrophy by targeting miR-211-3p, thus relieving its suppressive effects on the VEGFB-SDF-1α-CXCR4 signalling axis. TINCR and miR-211-3p might act as therapeutic targets for the treatment of cardiac hypertrophy.
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Affiliation(s)
- Shan Tu
- Department of Cardiology, Xiangya Third Hospital, Central South University, Changsha, 410013, Hunan Province, China
| | - Xiao-Yan Wang
- Department of Cardiology, Xiangya Third Hospital, Central South University, Changsha, 410013, Hunan Province, China
| | - Li-Xiong Zeng
- Department of Cardiology, Xiangya Third Hospital, Central South University, Changsha, 410013, Hunan Province, China
| | - Zhi-Jie Shen
- Department of Cardiology, Xiangya Third Hospital, Central South University, Changsha, 410013, Hunan Province, China
| | - Zhi-Hui Zhang
- Department of Cardiology, Xiangya Third Hospital, Central South University, Changsha, 410013, Hunan Province, China.
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29
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Zhao C, Heuslein JL, Zhang Y, Annex BH, Popel AS. Dynamic Multiscale Regulation of Perfusion Recovery in Experimental Peripheral Arterial Disease: A Mechanistic Computational Model. JACC Basic Transl Sci 2022; 7:28-50. [PMID: 35128207 PMCID: PMC8807862 DOI: 10.1016/j.jacbts.2021.10.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 10/13/2021] [Accepted: 10/13/2021] [Indexed: 01/29/2023]
Abstract
In peripheral arterial disease (PAD), the degree of endogenous capacity to modulate revascularization of limb muscle is central to the management of leg ischemia. To characterize the multiscale and multicellular nature of revascularization in PAD, we have developed the first computational systems biology model that mechanistically incorporates intracellular, cellular, and tissue-level features critical for the dynamic reconstitution of perfusion after occlusion-induced ischemia. The computational model was specifically formulated for a preclinical animal model of PAD (mouse hindlimb ischemia [HLI]), and it has gone through multilevel model calibration and validation against a comprehensive set of experimental data so that it accurately captures the complex cellular signaling, cell-cell communication, and function during post-HLI perfusion recovery. As an example, our model simulations generated a highly detailed description of the time-dependent spectrum-like macrophage phenotypes in HLI, and through model sensitivity analysis we identified key cellular processes with potential therapeutic significance in the pathophysiology of PAD. Furthermore, we computationally evaluated the in vivo effects of different targeted interventions on post-HLI tissue perfusion recovery in a model-based, data-driven, virtual mouse population and experimentally confirmed the therapeutic effect of a novel model-predicted intervention in real HLI mice. This novel multiscale model opens up a new avenue to use integrative systems biology modeling to facilitate translational research in PAD.
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Key Words
- ARG1, arginase-1
- EC, endothelial cell
- HLI, hindlimb ischemia
- HMGB1, high-mobility group box 1
- HUVEC, human umbilical vein endothelial call
- IFN, interferon
- IL, interleukin
- MLKL, mixed lineage kinase domain-like protein
- PAD, peripheral arterial disease
- RT-PCR, reverse transcriptase polymerase chain reaction
- TLR4, Toll-like receptor 4
- TNF, tumor necrosis factor
- VEGF, vascular endothelial growth factor
- VMP, virtual mouse population
- hindlimb ischemia
- macrophage polarization
- mathematical modeling
- necrosis/necroptosis
- perfusion recovery
- peripheral arterial disease
- systems biology
- virtual mouse population
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Affiliation(s)
- Chen Zhao
- School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Joshua L. Heuslein
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA
| | - Yu Zhang
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Brian H. Annex
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Aleksander S. Popel
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Oprescu N, Micheu MM, Scafa-Udriste A, Popa-Fotea NM, Dorobantu M. Inflammatory markers in acute myocardial infarction and the correlation with the severity of coronary heart disease. Ann Med 2021; 53:1041-1047. [PMID: 34180324 PMCID: PMC8245096 DOI: 10.1080/07853890.2021.1916070] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 04/03/2021] [Accepted: 04/07/2021] [Indexed: 11/15/2022] Open
Abstract
INTRODUCTION The inflammatory hypothesis of atherosclerosis is appealing in acute coronary syndromes, but the dynamics and precise role are not established. OBJECTIVES The study investigates the levels of C reactive protein (CRP), interleukin 1β (IL-1β) and stromal-derived factor 1α (SDF-1α) at the time of acute myocardial infarction (AMI) and at 1 and 6 months afterwards, compared with a control group. RESULTS In the acute phase of AMI, CRP and SDF-1α were significantly higher, while IL-1β showed lower levels compared with controls. CRP positively correlated with coronary stenosis severity (rho = 0.3, p=.05) and negatively related with left ventricle ejection fraction (LVEF) at 1 month (rho= -0.43, p=.05). IL-1β weakly correlated with the severity of coronary lesions (rho =0.29, p=.02) and strongly with LVEF (rho= -0.8, p=.05). SDF-1α, slightly correlated with LVEF at 1 month (rho = 0.22, p=.01) and with the severity of coronary atherosclerosis (rho= -0.41, p=.003). CONCLUSIONS CRP, IL-1β and SDF-1α have important dynamic in the first 6 months after AMI and CRP and SDF-1α levels correlated with the severity of coronary lesions and LVEF at 1 month after the acute ischaemic event.
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Affiliation(s)
- Nicoleta Oprescu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Romania
| | | | - Alexandru Scafa-Udriste
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Romania
- Cardio-thoracic Department, University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
| | - Nicoleta-Monica Popa-Fotea
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Romania
- Cardio-thoracic Department, University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
| | - Maria Dorobantu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Romania
- Cardio-thoracic Department, University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
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31
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Preferential interaction of platelets with prostate cancer cells with stem cell markers. Thromb Res 2021; 206:42-51. [PMID: 34403851 DOI: 10.1016/j.thromres.2021.08.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 07/29/2021] [Accepted: 08/10/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND Prostate cancer (PCa) may be initiated by CD133+/CD44+ expressing stem cell-like cells (PCSC), which are also thought to drive metastasis. Platelets also contribute to metastasis via tumor cell-induced platelet aggregation (TCIPA), which in part enhances cancer cell invasion. Moreover, activated platelets secrete stromal derived growth factor-1α (SDF-1α) that can mobilize CSCs via the CXCR4 receptor. However, the potential reciprocal interactions between CSCs and platelets have not been investigated. OBJECTIVE To characterize the mechanisms behind PCSC-platelet interaction. METHODS Fluorescence Activated Cell Sorting was utilized to separate DU145 and PC3 PCa cells into CD133+/CD44+, CD133+/CD44-, CD44+/CD133-, and CD133-/CD44- subpopulations and to measure their CXCR4 surface expression. PCa subpopulation TCIPA experiments were performed using aggregometry and immunoblot was used to measure prothrombin. Platelet SDF-1α secretion was measured by ELISA. Modified-Boyden chamber assays were used to assess the role of SDF-1α:CXCR4 pathway in platelet-PCSC interactions. RESULTS DU145 and PC3 expressing both CD133 and CD44 stem cell markers accounted for only small fractions of total cells (DU145: CD133+/CD44+ 3.44 ± 1.45% vs. CD133+/CD44- 1.56 ± 0.45% vs. CD44+/CD133- 68.19 ± 6.25% vs. CD133-/CD44- 20.36 ± 4.51%). However, CD133+ subpopulations induced the greatest amount of aggregation compared to CD44+/CD133- and double-negative DU145, and this aggregation potency of CD133+ PCa cells corresponded with high levels of prothrombin expression. Additionally, CD133+ subpopulations expressed significantly higher level of CXCR4 compared to CD133-/CD44- and CD44+/CD133-. Disruption of SDF-1α:CXCR4 pathway reduced platelet-induced PCSC invasion. CONCLUSIONS CD133+/CD44+ and CD133+/CD44- PCSCs have highest platelet aggregation potency, which could be attributed to their increased prothrombin expression. Reciprocally, platelet-derived SDF-1α stimulates PCSC invasion.
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32
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Li Y, Feng Z, Zhu L, Chen N, Wan Q, Wu J. Deletion of SDF-1 or CXCR4 regulates platelet activation linked to glucose metabolism and mitochondrial respiratory reserve. Platelets 2021; 33:536-542. [PMID: 34346843 DOI: 10.1080/09537104.2021.1961713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Stromal cell-derived factor 1 (SDF-1, also known as CXCL12) and its receptor CXCR4 have shown to play a role in the homing and engraftment of hematopoietic stem and progenitor cells. SDF-1 is highly expressed in platelets and involved in thrombosis formation. However, the exact roles of platelet-derived SDF-1 and CXCR4 in platelet activation and mitochondrial function have not been revealed yet. Deletion of Sdf-1 and Cxcr4 specifically in platelets decreased agonist-induced platelet aggregation and dramatically impaired thrombin-induced glucose uptake. In SDF-1-deficient and CXCR4-deficient platelets, intracellular ATP secretions were reduced when activated by the addition of thrombin. SDF-1 deficiency in platelets can impair the routine respiration during resting state and maximal capacity of the electron transfer system (ETS) during activated state. Mitochondrial respiration measurements in permeabilized platelets indicated an impaired function of the oxidative phosphorylation system in -SDF-1 or CXCR4-deficient platelets. These results suggested a novel role of the SDF-1/CXCR4 axis in modulating platelet energy metabolism and activation by regulating mitochondrial respiration, glucose uptake, and ATP production.
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Affiliation(s)
- Yi Li
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,Department of Endocrinology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ziqian Feng
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Luochen Zhu
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Ni Chen
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Qin Wan
- Department of Endocrinology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jianbo Wu
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
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33
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Schulte JD, Aghi MK, Taylor JW. Anti-angiogenic therapies in the management of glioblastoma. Chin Clin Oncol 2021; 10:37. [PMID: 32389001 PMCID: PMC10631456 DOI: 10.21037/cco.2020.03.06] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/13/2020] [Indexed: 11/06/2022]
Abstract
Angiogenesis is a central feature of glioblastoma (GBM), with contribution from several mechanisms and signaling pathways to produce an irregular, poorly constructed, and poorly connected tumor vasculature. Targeting angiogenesis has been efficacious for disease control in other cancers, and given the (I) highly vascularized environment in GBM and (II) correlation between glioma grade and prognosis, angiogenesis became a prime target of therapy in GBM as well. Here, we discuss the therapies developed to target these pathways including vascular endothelial growth factor (VEGF) signaling, mechanisms of tumor resistance to these drugs in the context of disease progression, and the evolving role of anti-angiogenic therapy in GBM.
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Affiliation(s)
- Jessica D. Schulte
- Department of Neurological Surgery, University of California, San Francisco, CA, USA
| | - Manish K. Aghi
- Department of Neurological Surgery, University of California, San Francisco, CA, USA
| | - Jennie W. Taylor
- Department of Neurological Surgery, University of California, San Francisco, CA, USA
- Department of Neurology, University of California, San Francisco, CA, USA
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34
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Amano H, Matsui Y, Hatanaka K, Hosono K, Ito Y. VEGFR1-tyrosine kinase signaling in pulmonary fibrosis. Inflamm Regen 2021; 41:16. [PMID: 34082837 PMCID: PMC8173728 DOI: 10.1186/s41232-021-00166-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 05/11/2021] [Indexed: 12/11/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) is not only an important factor for angiogenesis but also lung development and homeostasis. VEGF-A binds three tyrosine kinase (TK) receptors VEGFR1–3. Idiopathic pulmonary fibrosis (IPF) is one of the poor prognoses of lung diseases. The relationship of VEGF and IPF remains to be clarified. Treatment with nintedanib used for the treatment of IPF reduced fibroblast proliferation, inhibited TK receptors, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and VEGFR. Because the effect of that treatment is still not satisfactory, the emergence of new therapeutic agents is needed. This review describes the enhancement of pulmonary fibrosis by VEGFR1-TK signal and suggests that the blocking of the VEGFR1-TK signal may be useful for the treatment of pulmonary fibrosis.
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Affiliation(s)
- Hideki Amano
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa, 252-0373, Japan.
| | - Yoshio Matsui
- Department of Thoracic Surgery, Kitasato University School of Medicine, Kanagawa, Japan
| | - Ko Hatanaka
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa, 252-0373, Japan
| | - Kanako Hosono
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa, 252-0373, Japan
| | - Yoshiya Ito
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa, 252-0373, Japan
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35
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Puca AA, Carrizzo A, Spinelli C, Damato A, Ambrosio M, Villa F, Ferrario A, Maciag A, Fornai F, Lenzi P, Valenti V, di Nonno F, Accarino G, Madonna M, Forte M, Calì G, Baragetti A, Norata GD, Catapano AL, Cattaneo M, Izzo R, Trimarco V, Montella F, Versaci F, Auricchio A, Frati G, Sciarretta S, Madeddu P, Ciaglia E, Vecchione C. Single systemic transfer of a human gene associated with exceptional longevity halts the progression of atherosclerosis and inflammation in ApoE knockout mice through a CXCR4-mediated mechanism. Eur Heart J 2021; 41:2487-2497. [PMID: 31289820 PMCID: PMC7340354 DOI: 10.1093/eurheartj/ehz459] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 04/13/2019] [Accepted: 06/22/2019] [Indexed: 12/22/2022] Open
Abstract
Aims Here, we aimed to determine the therapeutic effect of longevity-associated variant (LAV)-BPIFB4 gene therapy on atherosclerosis. Methods and results ApoE knockout mice (ApoE−/−) fed a high-fat diet were randomly allocated to receive LAV-BPIFB4, wild-type (WT)-BPIFB4, or empty vector via adeno-associated viral vector injection. The primary endpoints of the study were to assess (i) vascular reactivity and (ii) atherosclerotic disease severity, by Echo-Doppler imaging, histology and ultrastructural analysis. Moreover, we assessed the capacity of the LAV-BPIFB4 protein to shift monocyte-derived macrophages of atherosclerotic mice and patients towards an anti-inflammatory phenotype. LAV-BPIFB4 gene therapy rescued endothelial function of mesenteric and femoral arteries from ApoE−/− mice; this effect was blunted by AMD3100, a CXC chemokine receptor type 4 (CXCR4) inhibitor. LAV-BPIFB4-treated mice showed a CXCR4-mediated shift in the balance between Ly6Chigh/Ly6Clow monocytes and M2/M1 macrophages, along with decreased T cell proliferation and elevated circulating levels of interleukins IL-23 and IL-27. In vitro conditioning with LAV-BPIFB4 protein of macrophages from atherosclerotic patients resulted in a CXCR4-dependent M2 polarization phenotype. Furthermore, LAV-BPIFB4 treatment of arteries explanted from atherosclerotic patients increased the release of atheroprotective IL-33, while inhibiting the release of pro-inflammatory IL-1β, inducing endothelial nitric oxide synthase phosphorylation and restoring endothelial function. Finally, significantly lower plasma BPIFB4 was detected in patients with pathological carotid stenosis (>25%) and intima media thickness >2 mm. Conclusion Transfer of the LAV of BPIFB4 reduces the atherogenic process and skews macrophages towards an M2-resolving phenotype through modulation of CXCR4, thus opening up novel therapeutic possibilities in cardiovascular disease. ![]()
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Affiliation(s)
- Annibale Alessandro Puca
- Ageing Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138 Milan, Italy.,Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana" University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy
| | | | - Chiara Spinelli
- Ageing Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138 Milan, Italy
| | - Antonio Damato
- IRCCS Neuromed, Loc. Camerelle, 86077 Pozzilli (IS), Italy
| | | | - Francesco Villa
- Ageing Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138 Milan, Italy
| | - Anna Ferrario
- Ageing Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138 Milan, Italy
| | - Anna Maciag
- Ageing Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138 Milan, Italy
| | - Francesco Fornai
- IRCCS Neuromed, Loc. Camerelle, 86077 Pozzilli (IS), Italy.,Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126 Pisa, Italy
| | - Paola Lenzi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126 Pisa, Italy
| | | | | | - Giulio Accarino
- Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana" University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy
| | | | - Maurizio Forte
- IRCCS Neuromed, Loc. Camerelle, 86077 Pozzilli (IS), Italy
| | - Gaetano Calì
- Department of Endocrinology and Experimental Oncology Institute, CNR, Via Sergio Pansini, 80131 Naples, Italy
| | - Andrea Baragetti
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, via Vanvitelli 32, 20129 Milan, Italy
| | - Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, via Vanvitelli 32, 20129 Milan, Italy.,Società Italiana per lo Studio della Arteriosclerosi (SISA) Centro Aterosclerosi, Bassini Hospital, Cinisello Balsamo, 20092 Milan, Italy
| | - Alberico Luigi Catapano
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, via Vanvitelli 32, 20129 Milan, Italy.,IRCCS Multimedica Hospital, 20099 Sesto San Giovanni Milan, Italy
| | - Monica Cattaneo
- Ageing Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138 Milan, Italy
| | - Raffaele Izzo
- Department of Advanced Biomedical Sciences, University Federico II of Naples, 80131 Naples, Italy
| | - Valentina Trimarco
- Department of Advanced Biomedical Sciences, University Federico II of Naples, 80131 Naples, Italy
| | - Francesco Montella
- Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana" University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy
| | - Francesco Versaci
- UOC Cardiologia Ospedale Santa Maria Goretti, 04100 Latina, Italy.,Department of Cardiovascular Disease, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Alberto Auricchio
- Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli (Na), Italy.,Department of Advanced Biomedicine, Federico II University, 80131 Naples, Italy
| | - Giacomo Frati
- IRCCS Neuromed, Loc. Camerelle, 86077 Pozzilli (IS), Italy.,Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, via Faggiana, 40100 Latina, Italy
| | - Sebastiano Sciarretta
- IRCCS Neuromed, Loc. Camerelle, 86077 Pozzilli (IS), Italy.,Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, via Faggiana, 40100 Latina, Italy
| | - Paolo Madeddu
- Bristol Medical School (Translational Health Sciences), Bristol Heart Institute, University of Bristol, Upper Maudlin Street, Bristol BS2 8HW, UK
| | - Elena Ciaglia
- Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana" University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy
| | - Carmine Vecchione
- Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana" University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy.,IRCCS Neuromed, Loc. Camerelle, 86077 Pozzilli (IS), Italy
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Liu D, Ding Q, Dai DF, Padhy B, Nayak MK, Li C, Purvis M, Jin H, Shu C, Chauhan AK, Huang CL, Attanasio M. Loss of diacylglycerol kinase ε causes thrombotic microangiopathy by impairing endothelial VEGFA signaling. JCI Insight 2021; 6:146959. [PMID: 33986189 PMCID: PMC8262293 DOI: 10.1172/jci.insight.146959] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/25/2021] [Indexed: 12/24/2022] Open
Abstract
Loss of function of the lipid kinase diacylglycerol kinase ε (DGKε), encoded by the gene DGKE, causes a form of atypical hemolytic uremic syndrome that is not related to abnormalities of the alternative pathway of the complement, by mechanisms that are not understood. By generating a potentially novel endothelial specific Dgke-knockout mouse, we demonstrate that loss of Dgke in the endothelium results in impaired signaling downstream of VEGFR2 due to cellular shortage of phosphatidylinositol 4,5-biphosphate. Mechanistically, we found that, in the absence of DGKε in the endothelium, Akt fails to be activated upon VEGFR2 stimulation, resulting in defective induction of the enzyme cyclooxygenase 2 and production of prostaglandin E2 (PGE2). Treating the endothelial specific Dgke-knockout mice with a stable PGE2 analog was sufficient to reverse the clinical manifestations of thrombotic microangiopathy and proteinuria, possibly by suppressing the expression of matrix metalloproteinase 2 through PGE2-dependent upregulation of the chemokine receptor CXCR4. Our study reveals a complex array of autocrine signaling events downstream of VEGFR2 that are mediated by PGE2, that control endothelial activation and thrombogenic state, and that result in abnormalities of the glomerular filtration barrier.
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Affiliation(s)
- Dingxiao Liu
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.,Department of Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiong Ding
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Dao-Fu Dai
- Department of Pathology, University of Iowa, Iowa City, Iowa, USA
| | - Biswajit Padhy
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Manasa K Nayak
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Can Li
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Madison Purvis
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Heng Jin
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Chang Shu
- Department of Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Anil K Chauhan
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Chou-Long Huang
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Massimo Attanasio
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
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37
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Otaka F, Ito Y, Nakamoto S, Nishizawa N, Hyodo T, Hosono K, Majima M, Koizumi W, Amano H. Macrophages contribute to liver repair after monocrotaline-induced liver injury via SDF-1/CXCR4. Exp Ther Med 2021; 22:668. [PMID: 33986833 PMCID: PMC8112113 DOI: 10.3892/etm.2021.10100] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 02/18/2021] [Indexed: 12/19/2022] Open
Abstract
Monocrotaline (MCT) administration induces liver injury in rodents that mimics the pathology of human sinusoidal obstruction syndrome. MCT-induced SOS models are used to investigate the mechanism of injury and optimize treatment strategies. However, the processes underlying liver repair are largely unknown. Specifically, the role of macrophages, the key drivers of liver repair, has not been elucidated. The current study aimed to examine the role of macrophages in the repair of MCT-induced liver injury in male C57/BL6 mice. Maximal liver injury occurred at 48 h post-MCT treatment, followed by repair at 120 h post-treatment. Immunofluorescence analysis revealed that CD68+ macrophages were recruited to the injured regions after MCT treatment. This was associated with the decreased expression of genes related to a pro-inflammatory macrophage phenotype and the increased expression of those associated with a reparative macrophage phenotype during the repair phase. The results also revealed that stromal cell-derived factor-1 (SDF-1) and its receptor C-X-C chemokine receptor-4 (CXCR4) were upregulated, and CD68+ macrophages were co-localized with CXCR4 expression. Treatment of mice with AMD3100, a CXCR4 antagonist, delayed liver repair and increased the expression of genes related to a pro-inflammatory macrophage phenotype. In contrast, SDF-1 treatment stimulated liver repair and increased the expression of genes related to a reparative macrophage phenotype. The results suggested that macrophages accumulate in the liver and repair damaged tissue after MCT treatment, and that the SDF-1-CXCR4 axis is involved in this process.
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Affiliation(s)
- Fumisato Otaka
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan.,Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.,Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Yoshiya Ito
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan.,Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Shuji Nakamoto
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan.,Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Nobuyuki Nishizawa
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan.,Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Tetsuya Hyodo
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan.,Department of Plastic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Kanako Hosono
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan.,Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Masataka Majima
- Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.,Department of Medical Therapeutics, Kanagawa Institute of Technology, Atsugi, Kanagawa 243-0292, Japan
| | - Wasaburo Koizumi
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Hideki Amano
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan.,Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
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Barcia Durán JG, Lu T, Houghton S, Geng F, Schreiner R, Xiang J, Rafii S, Redmond D, Lis R. Endothelial Jak3 expression enhances pro-hematopoietic angiocrine function in mice. Commun Biol 2021; 4:406. [PMID: 33767339 PMCID: PMC7994450 DOI: 10.1038/s42003-021-01846-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 02/12/2021] [Indexed: 02/08/2023] Open
Abstract
Jak3 is the only non-promiscuous member of the Jak family of secondary messengers. Studies to date have focused on understanding and targeting the cell-autonomous role of Jak3 in immunity, while functional Jak3 expression outside the hematopoietic system remains largely unreported. We show that Jak3 is expressed in endothelial cells across hematopoietic and non-hematopoietic organs, with heightened expression in the bone marrow. The bone marrow niche is understood as a network of different cell types that regulate hematopoietic function. We show that the Jak3-/- bone marrow niche is deleterious for the maintenance of long-term repopulating hematopoietic stem cells (LT-HSCs) and that JAK3-overexpressing endothelial cells have increased potential to expand LT-HSCs in vitro. This work may serve to identify a novel function for a highly specific tyrosine kinase in the bone marrow vascular niche and to further characterize the LT-HSC function of sinusoidal endothelium.
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Affiliation(s)
- José Gabriel Barcia Durán
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Tyler Lu
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Sean Houghton
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Fuqiang Geng
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Ryan Schreiner
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Department of Ophthalmology, Margaret Dyson Vision Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Jenny Xiang
- Genomics Resources Core Facility, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Shahin Rafii
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY, 10065, USA
| | - David Redmond
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
| | - Raphaël Lis
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY, 10065, USA.
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Kükrek H, Aitzetmüller M, Vodiškar M, Moog P, Machens HG, Duscher D. Erythropoetin can partially restore cigarette smoke induced effects on Adipose derived Stem Cells. Clin Hemorheol Microcirc 2021; 77:27-36. [PMID: 32651309 DOI: 10.3233/ch-200852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Adipose derived Stem Cells (ASCs) have been proven to play a key role in tissue regeneration. However, exposure to large amounts of cigarette smoke can drastically diminish their function. Erythropoetin (EPO), can modulate cellular response to injury. Therefore, we investigated the ability of EPO to restore the regenerative function and differentiation capacity of ASCs. MATERIAL AND METHODS Human ASCs were isolated from abdominoplasty samples using standard isolation procedures. Cell identity was established by means of Fluorescence Activated Cell Scanning. Subsequently, isolated ASCs were cultivated with cigarette smoke extract both with and without EPO. Parameters investigated included cellular metabolic activity, adipogenic and osteogenic differentiation capacity, and in vitro wound closure capacity. For further enhancing wound closure, EPO was combined with Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) or Stromal Derived Factor-1 alpha (SDF-1 a). RESULTS Cigarette smoke reduces adipogenic differentiation, the osteogenic differentiation capacity as well as the in vitro wound healing ability of human derived ASCs. EPO did not change metabolic activity of ASCs significantly. The addition of EPO could partially restore their function. The combination of EPO with GM-CSF or SDF-1 did not result in a synergistic effect regarding wound healing ability. CONCLUSION Exposure to cigarette smoke significantly reduced the regenerative potential of ASCs. Treatment of ASCs exposed to cigarette smoke with EPO has the potential to partially restore their function.
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Affiliation(s)
- Haydar Kükrek
- Department for Plastic and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Matthias Aitzetmüller
- Department for Plastic and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Mateja Vodiškar
- Department for Plastic and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Philipp Moog
- Department for Plastic and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Hans-Günther Machens
- Department for Plastic and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Dominik Duscher
- Department for Plastic and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
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40
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Hardy E, Fernandez-Patron C. Targeting MMP-Regulation of Inflammation to Increase Metabolic Tolerance to COVID-19 Pathologies: A Hypothesis. Biomolecules 2021; 11:biom11030390. [PMID: 33800947 PMCID: PMC7998259 DOI: 10.3390/biom11030390] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 02/28/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
Many individuals infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) develop no or only mild symptoms, but some can go on onto develop a spectrum of pathologies including pneumonia, acute respiratory distress syndrome, respiratory failure, systemic inflammation, and multiorgan failure. Many pathogens, viral and non-viral, can elicit these pathologies, which justifies reconsidering whether the target of therapeutic approaches to fight pathogen infections should be (a) the pathogen itself, (b) the pathologies elicited by the pathogen interaction with the human host, or (c) a combination of both. While little is known about the immunopathology of SARS-CoV-2, it is well-established that the above-mentioned pathologies are associated with hyper-inflammation, tissue damage, and the perturbation of target organ metabolism. Mounting evidence has shown that these processes are regulated by endoproteinases (particularly, matrix metalloproteinases (MMPs)). Here, we review what is known about the roles played by MMPs in the development of COVID-19 and postulate a mechanism by which MMPs could influence energy metabolism in target organs, such as the lung. Finally, we discuss the suitability of MMPs as therapeutic targets to increase the metabolic tolerance of the host to damage inflicted by the pathogen infection, with a focus on SARS-CoV-2.
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Affiliation(s)
- Eugenio Hardy
- Center for Molecular Immunology, 16040 Havana, Cuba
- Correspondence: (E.H.); (C.F.-P.)
| | - Carlos Fernandez-Patron
- Department of Biochemistry, Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
- Correspondence: (E.H.); (C.F.-P.)
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41
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Pecoraro AR, Hosfield BD, Li H, Shelley WC, Markel TA. Angiogenesis: A Cellular Response to Traumatic Injury. Shock 2021; 55:301-310. [PMID: 32826807 DOI: 10.1097/shk.0000000000001643] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
ABSTRACT The development of new vasculature plays a significant role in a number of chronic disease states, including neoplasm growth, peripheral arterial disease, and coronary artery disease, among many others. Traumatic injury and hemorrhage, however, is an immediate, often dramatic pathophysiologic insult that can also necessitate neovascularization to promote healing. Traditional understanding of angiogenesis involved resident endothelial cells branching outward from localized niches in the periphery. Additionally, there are a small number of circulating endothelial progenitor cells that participate directly in the process of neovessel formation. The bone marrow stores a relatively small number of so-called pro-angiogenic hematopoietic progenitor cells-that is, progenitor cells of a hematopoietic potential that differentiate into key structural cells and stimulate or otherwise support local cell growth/differentiation at the site of angiogenesis. Following injury, a number of cytokines and intercellular processes are activated or modulated to promote development of new vasculature. These processes initiate and maintain a robust response to vascular insult, allowing new vessels to canalize and anastomose and provide timely oxygen delivering to healing tissue. Ultimately as we better understand the key players in the process of angiogenesis we can look to develop novel techniques to promote healing following injury.
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Affiliation(s)
- Anthony R Pecoraro
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
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Hu Y, Li X, Zhang Q, Gu Z, Luo Y, Guo J, Wang X, Jing Y, Chen X, Su J. Exosome-guided bone targeted delivery of Antagomir-188 as an anabolic therapy for bone loss. Bioact Mater 2021; 6:2905-2913. [PMID: 33718671 PMCID: PMC7917458 DOI: 10.1016/j.bioactmat.2021.02.014] [Citation(s) in RCA: 123] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/09/2021] [Accepted: 02/13/2021] [Indexed: 12/14/2022] Open
Abstract
The differentiation shift from osteogenesis to adipogenesis of bone marrow mesenchymal stem cells (BMSCs) characterizes many pathological bone loss conditions. Stromal cell-derived factor-1 (SDF1) is highly enriched in the bone marrow for C-X-C motif chemokine receptor 4 (CXCR4)-positive hematopoietic stem cell (HSC) homing and tumor bone metastasis. In this study, we displayed CXCR4 on the surface of exosomes derived from genetically engineered NIH-3T3 cells. CXCR4+ exosomes selectively accumulated in the bone marrow. Then, we fused CXCR4+ exosomes with liposomes carrying antagomir-188 to produce hybrid nanoparticles (NPs). The hybrid NPs specifically gathered in the bone marrow and released antagomir-188, which promoted osteogenesis and inhibited adipogenesis of BMSCs and thereby reversed age-related trabecular bone loss and decreased cortical bone porosity in mice. Taken together, this study presents a novel way to obtain bone-targeted exosomes via surface display of CXCR4 and a promising anabolic therapeutic approach for age-related bone loss.
Surface display of CXCR4 grants exosomes bone targeting properties. Exosome-liposome hybrid nanoparticles carrying nucleic acid target bone. Antagomir-188 loaded hybrid nanoparticles regulate MSC differentiation in aged mice.
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Affiliation(s)
- Yan Hu
- Department of Trauma Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Xiaoqun Li
- Department of Trauma Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Qin Zhang
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
| | - Zhengrong Gu
- Department of Orthopedics, Shanghai Baoshan Luodian Hospital, Shanghai, 201908, China
| | - Ying Luo
- Centre Laboratory, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Jiawei Guo
- Department of Trauma Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Xiuhui Wang
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
| | - Yingying Jing
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
| | - Xiao Chen
- Department of Trauma Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.,Department of Chemistry, Fudan University, Shanghai, 200433, China
| | - Jiacan Su
- Department of Trauma Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
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Chen Y, Pu Q, Ma Y, Zhang H, Ye T, Zhao C, Huang X, Ren Y, Qiao L, Liu HM, Esmon CT, Ding BS, Cao Z. Aging Reprograms the Hematopoietic-Vascular Niche to Impede Regeneration and Promote Fibrosis. Cell Metab 2021; 33:395-410.e4. [PMID: 33357457 DOI: 10.1016/j.cmet.2020.11.019] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 09/23/2020] [Accepted: 11/25/2020] [Indexed: 02/05/2023]
Abstract
Regenerative capacity is frequently impaired in aged organs. Stress to aged organs often causes scar formation (fibrosis) at the expense of regeneration. It remains to be defined how hematopoietic and vascular cells contribute to aging-induced regeneration to fibrotic transition. Here, we find that aging aberrantly reprograms the crosstalk between hematopoietic and vascular cells to impede the regenerative capacity and enhance fibrosis. In aged lung, liver, and kidney, induction of Neuropilin-1/hypoxia-inducible-factor 2α (HIF2α) suppresses anti-thrombotic and anti-inflammatory endothelial protein C receptor (EPCR) pathway, leading to formation of pro-fibrotic platelet-macrophage rosette. Activated platelets via supplying interleukin 1α synergize with endothelial-produced angiocrine chemokine to recruit fibrogenic TIMP1high macrophages. In mouse models, genetic targeting of endothelial Neuropilin-1-HIF2α, platelet interleukin 1α, or macrophage TIMP1 normalized the pro-fibrotic hematopoietic-vascular niche and restored the regenerative capacity of old organs. Targeting of aberrant endothelial node molecules might help propel "regeneration without scarring" in the repair of multiple organs.
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Affiliation(s)
- Yutian Chen
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Qiang Pu
- Department of Thoracic Surgery, National Frontier Center of Disease Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yongyuan Ma
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Hua Zhang
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Tinghong Ye
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Chengjian Zhao
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaojuan Huang
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Yafeng Ren
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Lina Qiao
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Han-Min Liu
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Charles T Esmon
- Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Bi-Sen Ding
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Fibrosis Research Center, Division of Pulmonary and Critical Care Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Regenerative Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Zhongwei Cao
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
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Li C, Kuss M, Kong Y, Nie F, Liu X, Liu B, Dunaevsky A, Fayad P, Duan B, Li X. 3D Printed Hydrogels with Aligned Microchannels to Guide Neural Stem Cell Migration. ACS Biomater Sci Eng 2021; 7:690-700. [PMID: 33507749 DOI: 10.1021/acsbiomaterials.0c01619] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Following traumatic or ischemic brain injury, rapid cell death and extracellular matrix degradation lead to the formation of a cavity at the brain lesion site, which is responsible for prolonged neurological deficits and permanent disability. Transplantation of neural stem/progenitor cells (NSCs) represents a promising strategy for reconstructing the lesion cavity and promoting tissue regeneration. In particular, the promotion of neuronal migration, organization, and integration of transplanted NSCs is critical to the success of stem cell-based therapy. This is particularly important for the cerebral cortex, the most common area involved in brain injuries, because the highly organized structure of the cerebral cortex is essential to its function. Biomaterials-based strategies show some promise for conditioning the lesion site microenvironment to support transplanted stem cells, but the progress in demonstrating organized cell engraftment and integration into the brain is very limited. An effective approach to sufficiently address these challenges has not yet been developed. Here, we have implemented a digital light-processing-based 3D printer and printed hydrogel scaffolds with a designed shape, uniaxially aligned microchannels, and tunable mechanical properties. We demonstrated the capacity to achieve high shape precision to the lesion site with brain tissue-matching mechanical properties. We also established spatial control of bioactive molecule distribution within 3D printed hydrogel scaffolds. These printed hydrogel scaffolds have shown high neuro-compatibility with aligned neuronal outgrowth along with the microchannels. This study will provide a biomaterial-based approach that can serve as a protective and guidance vehicle for transplanted NSC organization and integration for brain tissue regeneration after injuries.
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Affiliation(s)
- Cui Li
- Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.,Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Mitchell Kuss
- Mary & Dick Holland Regenerative Medicine Program, Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Yunfan Kong
- Mary & Dick Holland Regenerative Medicine Program, Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Fujiao Nie
- Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Xiaoyan Liu
- Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Bo Liu
- Mary & Dick Holland Regenerative Medicine Program, Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Anna Dunaevsky
- Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Pierre Fayad
- Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Bin Duan
- Mary & Dick Holland Regenerative Medicine Program, Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Xiaowei Li
- Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
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Jarajapu YPR. Targeting Angiotensin-Converting Enzyme-2/Angiotensin-(1-7)/Mas Receptor Axis in the Vascular Progenitor Cells for Cardiovascular Diseases. Mol Pharmacol 2021; 99:29-38. [PMID: 32321734 PMCID: PMC7725063 DOI: 10.1124/mol.119.117580] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 03/31/2020] [Indexed: 12/20/2022] Open
Abstract
Bone marrow-derived hematopoietic stem/progenitor cells are vasculogenic and play an important role in endothelial health and vascular homeostasis by participating in postnatal vasculogenesis. Progenitor cells are mobilized from bone marrow niches in response to remote ischemic injury and migrate to the areas of damage and stimulate revascularization largely by paracrine activation of angiogenic functions in the peri-ischemic vasculature. This innate vasoprotective mechanism is impaired in certain chronic clinical conditions, which leads to the development of cardiovascular complications. Members of the renin-angiotensin system-angiotensin-converting enzymes (ACEs) ACE and ACE2, angiotensin II (Ang II), Ang-(1-7), and receptors AT1 and Mas-are expressed in vasculogenic progenitor cells derived from humans and rodents. Ang-(1-7), generated by ACE2, is known to produce cardiovascular protective effects by acting on Mas receptor and is considered as a counter-regulatory mechanism to the detrimental effects of Ang II. Evidence has now been accumulating in support of the activation of the ACE2/Ang-(1-7)/Mas receptor pathway by pharmacologic or molecular maneuvers, which stimulates mobilization of progenitor cells from bone marrow, migration to areas of vascular damage, and revascularization of ischemic areas in pathologic conditions. This minireview summarizes recent studies that have enhanced our understanding of the physiology and pharmacology of vasoprotective axis in bone marrow-derived progenitor cells in health and disease. SIGNIFICANCE STATEMENT: Hematopoietic stem progenitor cells (HSPCs) stimulate revascularization of ischemic areas. However, the reparative potential is diminished in certain chronic clinical conditions, leading to the development of cardiovascular diseases. ACE2 and Mas receptor are key members of the alternative axis of the renin-angiotensin system and are expressed in HSPCs. Accumulating evidence points to activation of ACE2 or Mas receptor as a promising approach for restoring the reparative potential, thereby preventing the development of ischemic vascular diseases.
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Affiliation(s)
- Yagna P R Jarajapu
- Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, North Dakota
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Hussain S, Peng B, Cherian M, Song JW, Ahirwar DK, Ganju RK. The Roles of Stroma-Derived Chemokine in Different Stages of Cancer Metastases. Front Immunol 2020; 11:598532. [PMID: 33414786 PMCID: PMC7783453 DOI: 10.3389/fimmu.2020.598532] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 11/17/2020] [Indexed: 12/14/2022] Open
Abstract
The intricate interplay between malignant cells and host cellular and non-cellular components play crucial role in different stages of tumor development, progression, and metastases. Tumor and stromal cells communicate to each other through receptors such as integrins and secretion of signaling molecules like growth factors, cytokines, chemokines and inflammatory mediators. Chemokines mediated signaling pathways have emerged as major mechanisms underlying multifaceted roles played by host cells during tumor progression. In response to tumor stimuli, host cells-derived chemokines further activates signaling cascades that support the ability of tumor cells to invade surrounding basement membrane and extra-cellular matrix. The host-derived chemokines act on endothelial cells to increase their permeability and facilitate tumor cells intravasation and extravasation. The tumor cells-host neutrophils interaction within the vasculature initiates chemokines driven recruitment of inflammatory cells that protects circulatory tumor cells from immune attack. Chemokines secreted by tumor cells and stromal immune and non-immune cells within the tumor microenvironment enter the circulation and are responsible for formation of a "pre-metastatic niche" like a "soil" in distant organs whereby circulating tumor cells "seed' and colonize, leading to formation of metastatic foci. Given the importance of host derived chemokines in cancer progression and metastases several drugs like Mogamulizumab, Plerixafor, Repertaxin among others are part of ongoing clinical trial which target chemokines and their receptors against cancer pathogenesis. In this review, we focus on recent advances in understanding the complexity of chemokines network in tumor microenvironment, with an emphasis on chemokines secreted from host cells. We especially summarize the role of host-derived chemokines in different stages of metastases, including invasion, dissemination, migration into the vasculature, and seeding into the pre-metastatic niche. We finally provide a brief description of prospective drugs that target chemokines in different clinical trials against cancer.
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Affiliation(s)
- Shahid Hussain
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Bo Peng
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Mathew Cherian
- Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, United States.,Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Jonathan W Song
- Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States.,Department of Mechanical and Aerospace Engineering, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Dinesh K Ahirwar
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Ramesh K Ganju
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States.,Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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Zhao Y, Zhang M, Lu GL, Huang BX, Wang DW, Shao Y, Lu MJ. Hypoxic Preconditioning Enhances Cellular Viability and Pro-angiogenic Paracrine Activity: The Roles of VEGF-A and SDF-1a in Rat Adipose Stem Cells. Front Cell Dev Biol 2020; 8:580131. [PMID: 33330455 PMCID: PMC7719676 DOI: 10.3389/fcell.2020.580131] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 11/04/2020] [Indexed: 12/19/2022] Open
Abstract
To achieve the full therapeutic potential of implanted adipose stem cells (ASCs) in vivo, it is crucial to improve the viability and pro-angiogenic properties of the stem cells. Here, we first simulated the conditions of ischemia and hypoxia using the in vitro oxygen-glucose deprivation (OGD) model and confirmed that hypoxic preconditioning of ASCs could provide improved protection against OGD and enhance ASC viability. Second, we assessed the effect of hypoxic preconditioning on pro-angiogenic potential of ASCs, with a particular focus on the role of vascular endothelial growth factor-A (VEGF-A) and stromal derived factor-1a (SDF-1a) paracrine activity in mediating angiogenesis. We found that the conditioned medium of ASCs (ASCCM) with hypoxic preconditioning enhanced angiogenesis by a series of angiogenesis assay models in vivo and in vitro through the upregulation of and a synergistic effect between VEGF-A and SDF-1a. Finally, to investigate the possible downstream mechanisms of VEGF/VEGFR2 and SDF-1a/CXCR4 axes-driven angiogenesis, we evaluated relevant protein kinases involved the signal transduction pathway of angiogenesis and showed that VEGF/VEGFR2 and SDF-1a/CXCR4 axes may synergistically promote angiogenesis by activating Akt. Collectively, our findings demonstrate that hypoxic preconditioning may constitute a promising strategy to enhance cellular viability and angiogenesis of transplanted ASCs, therein improving the success rate of stem cell-based therapies in tissue engineering.
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Affiliation(s)
- Yang Zhao
- Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Department of Urology, Ruijin Hospital North, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ming Zhang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Guo-Liang Lu
- Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Department of Urology, Ruijin Hospital North, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bao-Xing Huang
- Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Department of Urology, Ruijin Hospital North, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Da-Wei Wang
- Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Department of Urology, Ruijin Hospital North, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuan Shao
- Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Department of Urology, Ruijin Hospital North, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Mu-Jun Lu
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Benavente S, Sánchez-García A, Naches S, LLeonart ME, Lorente J. Therapy-Induced Modulation of the Tumor Microenvironment: New Opportunities for Cancer Therapies. Front Oncol 2020; 10:582884. [PMID: 33194719 PMCID: PMC7645077 DOI: 10.3389/fonc.2020.582884] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/16/2020] [Indexed: 12/15/2022] Open
Abstract
Advances in immunotherapy have achieved remarkable clinical outcomes in tumors with low curability, but their effects are limited, and increasing evidence has implicated tumoral and non-tumoral components of the tumor microenvironment as critical mediators of cancer progression. At the same time, the clinical successes achieved with minimally invasive and optically-guided surgery and image-guided and ablative radiation strategies have been successfully implemented in clinical care. More effective, localized and safer treatments have fueled strong research interest in radioimmunotherapy, which has shown the potential immunomodulatory effects of ionizing radiation. However, increasingly more observations suggest that immunosuppressive changes, metabolic remodeling, and angiogenic responses in the local tumor microenvironment play a central role in tumor recurrence. In this review, we address challenges to identify responders vs. non-responders to the immune checkpoint blockade, discuss recent developments in combinations of immunotherapy and radiotherapy for clinical evaluation, and consider the clinical impact of immunosuppressive changes in the tumor microenvironment in the context of surgery and radiation. Since the therapy-induced modulation of the tumor microenvironment presents a multiplicity of forms, we propose that overcoming microenvironment related resistance can become clinically relevant and represents a novel strategy to optimize treatment immunogenicity and improve patient outcome.
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Affiliation(s)
- Sergi Benavente
- Radiation Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Almudena Sánchez-García
- Biomedical Research in Cancer Stem Cells Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Silvia Naches
- Otorhinolaryngology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Matilde Esther LLeonart
- Biomedical Research in Cancer Stem Cells Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.,Spanish Biomedical Research Network Centre in Oncology, CIBERONC, Barcelona, Spain
| | - Juan Lorente
- Otorhinolaryngology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
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Zhang J, Zhang M, Zhao H, Xu X. Identification of proliferative diabetic retinopathy-associated genes on the protein–protein interaction network by using heat diffusion algorithm. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165794. [DOI: 10.1016/j.bbadis.2020.165794] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/25/2020] [Accepted: 04/04/2020] [Indexed: 12/11/2022]
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50
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Sepe P, Martinetti A, Mennitto A, Verzoni E, Claps M, Raimondi A, Sottotetti E, Grassi P, Guadalupi V, Stellato M, Zattarin E, Di Maio M, Procopio G. Prospective Translational Study Investigating Molecular PrEdictors of Resistance to First-Line PazopanIb in Metastatic reNal CEll Carcinoma (PIPELINE Study). Am J Clin Oncol 2020; 43:621-627. [PMID: 32889831 DOI: 10.1097/coc.0000000000000719] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Despite the initial clinical benefit, resistance to antiangiogenic therapies develops through the activation of alternative pathways. We measured plasma levels of circulating angiogenic factors to explore their predictive role in metastatic renal cell carcinoma (mRCC) patients treated with pazopanib. MATERIALS AND METHODS mRCC patients receiving first-line pazopanib were prospectively enrolled. The levels of circulating interleuchine (IL)-6, IL-8, stromal derived factor-1, vascular endothelial growth factor-A, hepatocyte growth factor (HGF), osteopontin, and E-selectin were quantified at baseline and every 4 weeks until disease progression (PD). Patients were dichotomized into "low" and "high" subgroups by a cutoff point defined by the respective median circulating angiogenic factor (CAF) value at baseline. Then, association with the objective response was determined. Changes in CAF levels between baseline and PD were also compared. RESULTS Among 25 patients included in the final data set, 6 patients were still on treatment. As best response, 12 patients presented a partial response (48%), 9 showed stable disease, and 4 showed PD. The median follow-up was 31.9 months. The median progression-free survival was 14.8 months. Low baseline levels of IL-6, IL-8, HGF, and osteopontin were found to be significantly associated with objective response. In addition, patients with low baseline levels of HGF showed longer progression-free survival and overall survival, whereas patients with low baseline levels of IL-8 showed longer overall survival. Among patients experiencing PD, the median plasma levels of stromal derived factor-1 and vascular endothelial growth factor-A were significantly higher compared with the baseline (P=0.01; P=0.011). Conversely, the median levels of E-selectin were significantly lower compared with the baseline (P=0.017). CONCLUSION Changes in levels of selected CAFs were associated with response/resistance to pazopanib in mRCC patients.
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Affiliation(s)
- Pierangela Sepe
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Antonia Martinetti
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Alessia Mennitto
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Elena Verzoni
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Melanie Claps
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Alessandra Raimondi
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Elisa Sottotetti
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Paolo Grassi
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Valentina Guadalupi
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Marco Stellato
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome
| | - Emma Zattarin
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Massimo Di Maio
- Department of Oncology, Ordine Mauriziano Hospital, University of Turin, Turin, Italy
| | - Giuseppe Procopio
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
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