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Golden TN, Mani S, Linn RL, Leite R, Trigg NA, Wilson A, Anton L, Mainigi M, Conine CC, Kaufman BA, Strauss JF, Parry S, Simmons RA. Extracellular Vesicles Alter Trophoblast Function in Pregnancies Complicated by COVID-19. J Extracell Vesicles 2025; 14:e70051. [PMID: 40205960 PMCID: PMC11982706 DOI: 10.1002/jev2.70051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 02/05/2025] [Indexed: 04/11/2025] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and resulting coronavirus disease (COVID-19) cause placental dysfunction, which increases the risk of adverse pregnancy outcomes. While abnormal placental pathology resulting from COVID-19 is common, direct infection of the placenta is rare. This suggests that pathophysiology associated with maternal COVID-19, rather than direct placental infection, is responsible for placental dysfunction. We hypothesized that maternal circulating extracellular vesicles (EVs), altered by COVID-19 during pregnancy, contribute to placental dysfunction. To examine this hypothesis, we characterized circulating EVs from pregnancies complicated by COVID-19 and tested their effects on trophoblast cell physiology in vitro. Trophoblast exposure to EVs isolated from patients with an active infection (AI), but not controls, altered key trophoblast functions including hormone production and invasion. Thus, circulating EVs from participants with an AI, both symptomatic and asymptomatic cases, can disrupt vital trophoblast functions. EV cargo differed between participants with COVID-19, depending on the gestational timing of infection, and Controls, which may contribute to the disruption of the placental transcriptome and morphology. Our findings show that COVID-19 can have effects throughout pregnancy on circulating EVs, and circulating EVs are likely to participate in placental dysfunction induced by COVID-19.
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Affiliation(s)
- Thea N. Golden
- Department of Obstetrics and GynecologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Center for Women's Health and Reproductive MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Center for Excellence in Environmental ToxicologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Sneha Mani
- Department of Obstetrics and GynecologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Center for Women's Health and Reproductive MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Rebecca L. Linn
- Department of Pathology and Laboratory MedicineChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
| | - Rita Leite
- Department of Obstetrics and GynecologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Center for Women's Health and Reproductive MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Natalie A. Trigg
- Epigenetics InstitutePerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Annette Wilson
- Department of MedicineUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Lauren Anton
- Department of Obstetrics and GynecologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Center for Women's Health and Reproductive MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Monica Mainigi
- Department of Obstetrics and GynecologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Center for Women's Health and Reproductive MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Colin C. Conine
- Center for Women's Health and Reproductive MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Epigenetics InstitutePerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Institute for Regenerative MedicinePerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of GeneticsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of PediatricsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Division of NeonatologyChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
| | - Brett A. Kaufman
- Department of MedicineUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Jerome F. Strauss
- Department of Obstetrics and GynecologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Center for Women's Health and Reproductive MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Samuel Parry
- Department of Obstetrics and GynecologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Center for Women's Health and Reproductive MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Rebecca A. Simmons
- Center for Women's Health and Reproductive MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Center for Excellence in Environmental ToxicologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of PediatricsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Division of NeonatologyChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
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2
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Yang Y, Deng C, Aldali F, Huang Y, Luo H, Liu Y, Huang D, Cao X, Zhou Q, Xu J, Li Y, Chen H. Therapeutic Approaches and Potential Mechanisms of Small Extracellular Vesicles in Treating Vascular Dementia. Cells 2025; 14:409. [PMID: 40136659 PMCID: PMC11941715 DOI: 10.3390/cells14060409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 02/26/2025] [Accepted: 03/10/2025] [Indexed: 03/27/2025] Open
Abstract
Small extracellular vesicles (sEVs), including exosomes as a subtype, with a diameter typically less than 200 nm and originating from the endosomal system, are capable of transporting a diverse array of bioactive molecules, including proteins, nucleic acids, and lipids, thereby facilitating intercellular communication and modulating cellular functions. Vascular dementia (VaD) represents a form of cognitive impairment attributed to cerebrovascular disease, characterized by a complex and multifaceted pathophysiological mechanism. Currently, the therapeutic approach to VaD predominantly emphasizes symptom management, as no specific pharmacological treatment exists to cure the condition. Recent investigations have illuminated the significant role of sEVs in the pathogenesis of vascular dementia. This review seeks to provide a comprehensive analysis of the characteristics and functions of sEVs, with a particular focus on their involvement in vascular dementia and its underlying mechanisms. The objective is to advance the understanding of the interplays between sEVs and vascular dementia, thereby offering novel insights for future research and therapeutic strategies.
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Affiliation(s)
- Yujie Yang
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.Y.); (C.D.); (F.A.); (Y.H.); (H.L.); (Y.L.); (D.H.); (X.C.); (Q.Z.); (J.X.); (Y.L.)
| | - Chunchu Deng
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.Y.); (C.D.); (F.A.); (Y.H.); (H.L.); (Y.L.); (D.H.); (X.C.); (Q.Z.); (J.X.); (Y.L.)
| | - Fatima Aldali
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.Y.); (C.D.); (F.A.); (Y.H.); (H.L.); (Y.L.); (D.H.); (X.C.); (Q.Z.); (J.X.); (Y.L.)
| | - Yunjie Huang
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.Y.); (C.D.); (F.A.); (Y.H.); (H.L.); (Y.L.); (D.H.); (X.C.); (Q.Z.); (J.X.); (Y.L.)
| | - Hongmei Luo
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.Y.); (C.D.); (F.A.); (Y.H.); (H.L.); (Y.L.); (D.H.); (X.C.); (Q.Z.); (J.X.); (Y.L.)
| | - Yizhou Liu
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.Y.); (C.D.); (F.A.); (Y.H.); (H.L.); (Y.L.); (D.H.); (X.C.); (Q.Z.); (J.X.); (Y.L.)
| | - Danxia Huang
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.Y.); (C.D.); (F.A.); (Y.H.); (H.L.); (Y.L.); (D.H.); (X.C.); (Q.Z.); (J.X.); (Y.L.)
| | - Xiaojian Cao
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.Y.); (C.D.); (F.A.); (Y.H.); (H.L.); (Y.L.); (D.H.); (X.C.); (Q.Z.); (J.X.); (Y.L.)
| | - Qiuzhi Zhou
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.Y.); (C.D.); (F.A.); (Y.H.); (H.L.); (Y.L.); (D.H.); (X.C.); (Q.Z.); (J.X.); (Y.L.)
| | - Jia Xu
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.Y.); (C.D.); (F.A.); (Y.H.); (H.L.); (Y.L.); (D.H.); (X.C.); (Q.Z.); (J.X.); (Y.L.)
- Stem Cell Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yajie Li
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.Y.); (C.D.); (F.A.); (Y.H.); (H.L.); (Y.L.); (D.H.); (X.C.); (Q.Z.); (J.X.); (Y.L.)
| | - Hong Chen
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.Y.); (C.D.); (F.A.); (Y.H.); (H.L.); (Y.L.); (D.H.); (X.C.); (Q.Z.); (J.X.); (Y.L.)
- Stem Cell Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China
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Thetchinamoorthy K, Jarczak J, Kieszek P, Wierzbicka D, Ratajczak J, Kucia M, Ratajczak MZ. Very small embryonic-like stem cells (VSELs) on the way for potential applications in regenerative medicine. Front Bioeng Biotechnol 2025; 13:1564964. [PMID: 40124247 PMCID: PMC11926153 DOI: 10.3389/fbioe.2025.1564964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 02/17/2025] [Indexed: 03/25/2025] Open
Abstract
Evidence has accumulated that adult tissues contain a population of early development stem cells capable of differentiating across germ layers into various types of cells. Our group purified these rare cells, naming them very small embryonic-like stem cells (VSELs). With their broad differentiation potential, VSELs have emerged as a new candidate population for clinical applications. This advancement is now possible due to our recent development of a model for ex vivo expansion of these rare cells. Importantly, no evidence suggests that VSELs, isolated from adult tissues, can form teratomas. In this review paper, we update current research on these cells reported in our laboratory as well as in those of several independent investigators.
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Affiliation(s)
| | - Justyna Jarczak
- Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Patrycja Kieszek
- Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Diana Wierzbicka
- Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Janina Ratajczak
- Stem Cell Institute at Graham Brown Cancer Center, University of Louisville, Louisville, CO, United States
| | - Magdalena Kucia
- Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Mariusz Z. Ratajczak
- Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
- Stem Cell Institute at Graham Brown Cancer Center, University of Louisville, Louisville, CO, United States
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4
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Zhang J, Zheng L. The correlation between the number of endothelial progenitor cells in the peripheral blood and abdominal aortic aneurysm. Medicine (Baltimore) 2024; 103:e40722. [PMID: 39612386 PMCID: PMC11608706 DOI: 10.1097/md.0000000000040722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/08/2024] [Indexed: 12/01/2024] Open
Abstract
This study was to investigate the correlation between the number of endothelial progenitor cells (EPCs) in peripheral blood and abdominal aortic aneurysm (AAA), and provide a potential biomarker for the diagnosis and treatment monitoring of AAA. Patients with AAA evaluated in the First Affiliated Hospital of Soochow University from June 2018 to October 2018 (n = 7) were included in this study. All patients were confirmed as AAA by vascular CTA with an increase of more than 50% of the abdominal aortic diameter. Patients (n = 7) with normal abdominal aorta diameter were included as control group with matching age, sex, blood pressure, and blood sugar concentration between experimental and control groups. Mononuclear cells were collected by density gradient centrifugation, stained by CD34-FITC and CD309-PE antibodies, and analyzed by flow cytometry. The number of EPCs in the peripheral blood of patients with AAA (0.874 ± 0.129‰) was significantly lower than that in the control group (1.420 ± 0.289‰) (P < .01). The number of EPCs may be used as a potential biomarker for the diagnosis and monitoring of AAA following treatment.
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Affiliation(s)
- Jinlong Zhang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lei Zheng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
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Hurwitz SN, Kobulsky DR, Jung SK, Chia JJ, Butler JM, Kurre P. CCR2 cooperativity promotes hematopoietic stem cell homing to the bone marrow. SCIENCE ADVANCES 2024; 10:eadq1476. [PMID: 39292787 PMCID: PMC11409967 DOI: 10.1126/sciadv.adq1476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 08/12/2024] [Indexed: 09/20/2024]
Abstract
Cross-talk between hematopoietic stem and progenitor cells (HSPCs) and bone marrow (BM) cells is critical for homing and sustained engraftment after transplantation. In particular, molecular and physical adaptation of sinusoidal endothelial cells (ECs) promote HSPC BM occupancy; however, signals that govern these events are not well understood. Extracellular vesicles (EVs) are mediators of cell-cell communication crucial in shaping tissue microenvironments. Here, we demonstrate that integrin α4β7 on murine HSPC EVs targets uptake into ECs. In BM ECs, HSPC EVs induce up-regulation of C-C motif chemokine receptor 2 (CCR2) ligands that synergize with CXCL12-CXCR4 signaling to promote BM homing. In nonirradiated murine models, marrow preconditioning with HSPC EVs or recombinant CCR2 ligands improves homing and early graft occupancy after transplantation. These findings identify a role for HSPC EVs in remodeling ECs, newly define CCR2-dependent graft homing, and inform novel translational conditioning strategies to improve HSPC transplantation.
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Affiliation(s)
- Stephanie N. Hurwitz
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Comprehensive Bone Marrow Failure Center, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Danielle R. Kobulsky
- Comprehensive Bone Marrow Failure Center, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Seul K. Jung
- Comprehensive Bone Marrow Failure Center, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Jennifer J. Chia
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, USA
| | - Jason M. Butler
- Division of Hematology/Oncology, University of Florida, Gainesville, FL, USA
| | - Peter Kurre
- Comprehensive Bone Marrow Failure Center, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Golden TN, Mani S, Linn RL, Leite R, Trigg NA, Wilson A, Anton L, Mainigi M, Conine CC, Kaufman BA, Strauss JF, Parry S, Simmons RA. Extracellular vesicles alter trophoblast function in pregnancies complicated by COVID-19. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.17.580824. [PMID: 38464046 PMCID: PMC10925147 DOI: 10.1101/2024.02.17.580824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and resulting coronavirus disease (COVID-19) causes placental dysfunction, which increases the risk of adverse pregnancy outcomes. While abnormal placental pathology resulting from COVID-19 is common, direct infection of the placenta is rare. This suggests that pathophysiology associated with maternal COVID-19, rather than direct placental infection, is responsible for placental dysfunction and alteration of the placental transcriptome. We hypothesized that maternal circulating extracellular vesicles (EVs), altered by COVID-19 during pregnancy, contribute to placental dysfunction. To examine this hypothesis, we characterized maternal circulating EVs from pregnancies complicated by COVID-19 and tested their effects on trophoblast cell physiology in vitro . We found that the gestational timing of COVID-19 is a major determinant of circulating EV function and cargo. In vitro trophoblast exposure to EVs isolated from patients with an active infection at the time of delivery, but not EVs isolated from Controls, altered key trophoblast functions including hormone production and invasion. Thus, circulating EVs from participants with an active infection, both symptomatic and asymptomatic cases, can disrupt vital trophoblast functions. EV cargo differed between participants with COVID-19 and Controls, which may contribute to the disruption of the placental transcriptome and morphology. Our findings show that COVID-19 can have effects throughout pregnancy on circulating EVs and circulating EVs are likely to participate in placental dysfunction induced by COVID-19.
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Pawlicki P, Yurdakok-Dikmen B, Tworzydlo W, Kotula-Balak M. Toward understanding the role of the interstitial tissue architects: Possible functions of telocytes in the male gonad. Theriogenology 2024; 217:25-36. [PMID: 38241912 DOI: 10.1016/j.theriogenology.2024.01.013] [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: 01/27/2023] [Revised: 01/08/2024] [Accepted: 01/11/2024] [Indexed: 01/21/2024]
Abstract
Telocytes represent a relatively recently discovered population of interstitial cells with a unique morphological structure that distinguishes them from other neighboring cells. Through their long protrusions extending from the cell body, telocytes create microenvironments via tissue compartmentalization and create homo- and hetero-cellular junctions. These establish a three-dimensional network enabling the maintenance of interstitial compartment homeostasis through regulation of extracellular matrix organization and activity, structural support, paracrine and juxtracrine communication, immunomodulation, immune surveillance, cell survival, and apoptosis. The presence of telocytes has also been confirmed in testicular interstitial tissue of many species of animals. The objective of this review is to summarize recent findings on telocytes in the male gonad, on which conclusions have been deduced that indicate the involvement of telocytes in maintaining the cytoarchitecture of the testicular interstitial tissue, in the processes of spermatogenesis and steroidogenesis, and photoperiod-mediated changes in the testes in seasonally reproductive animals.
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Affiliation(s)
- Piotr Pawlicki
- Center of Experimental and Innovative Medicine, University of Agriculture in Krakow, Redzina 1c, 30-248, Krakow, Poland.
| | - Begum Yurdakok-Dikmen
- Department of Pharmacology and Toxicology, Ankara University Faculty of Veterinary Medicine, Ankara, 06110, Dışkapı, Turkey.
| | - Waclaw Tworzydlo
- Department of Developmental Biology and Invertebrate Morphology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University in Krakow, Gronostajowa 9, 30-385, Krakow, Poland.
| | - Malgorzata Kotula-Balak
- Department of Animal Anatomy and Preclinical Sciences, University Centre of Veterinary Medicine JU-UA, University of Agriculture in Krakow, Mickiewicza 24/28, 30-059, Krakow, Poland.
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Carbone RG, Negrini S, Murdaca G, Fontana V, Puppo F. Stem cells treatment in chronic ischemic heart disease: a narrative review. AMERICAN JOURNAL OF STEM CELLS 2023; 12:65-72. [PMID: 38021453 PMCID: PMC10658134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 10/12/2023] [Indexed: 12/01/2023]
Abstract
Chronic ischemic heart disease remains a major cause of morbidity and mortality worldwide. Several trials have been performed to evaluate benefit of stem cells transplantation to restore cardiac function in short- and long-term period after myocardial infarction. This narrative review analyzes 24 clinical trials between 2005 and 2023 comprising 1824 patients with chronic heart disease without heart failure. Percent increase in left ventricular ejection fraction (LVEF) and decrease in New York Heart Association (NYHA) class at 6/12 months after stem cells transplantation are reported. Thirteen trials showed a statistically significant percent LVEF increase between 4% to 19% at 6/12 months after stem cells transplantation (p values from 0.05 to 0.0001). No significant differences in LVEF were observed between patients who underwent intracoronary or intramyocardial transplantation. NYHA class decrease from severe to mild/moderate was demonstrated in 10 trials reporting a significant LVEF increase. Patients transplanted with bone marrow and peripheral blood CD133+ stem cells showed a doubling of percentage LVEF increase in comparison to patients transplanted with CD133- cells. This narrative review reports the conflicting results on this topic. Multicenter randomized clinical trials should be performed to define the efficacy of stem cells transplantation in chronic ischemic heart disease.
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Affiliation(s)
| | - Simone Negrini
- Department of Internal Medicine, University of GenoaGenoa, Italy
| | - Giuseppe Murdaca
- Department of Internal Medicine, University of GenoaGenoa, Italy
| | - Vincenzo Fontana
- Clinical Epidemiology Unit, IRCCS San Martino HospitalGenoa, Italy
| | - Francesco Puppo
- Department of Internal Medicine, University of GenoaGenoa, Italy
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Martín-Bórnez M, Falcón D, Morrugares R, Siegfried G, Khatib AM, Rosado JA, Galeano-Otero I, Smani T. New Insights into the Reparative Angiogenesis after Myocardial Infarction. Int J Mol Sci 2023; 24:12298. [PMID: 37569674 PMCID: PMC10418963 DOI: 10.3390/ijms241512298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 07/23/2023] [Accepted: 07/29/2023] [Indexed: 08/13/2023] Open
Abstract
Myocardial infarction (MI) causes massive loss of cardiac myocytes and injury to the coronary microcirculation, overwhelming the limited capacity of cardiac regeneration. Cardiac repair after MI is finely organized by complex series of procedures involving a robust angiogenic response that begins in the peri-infarcted border area of the infarcted heart, concluding with fibroblast proliferation and scar formation. Efficient neovascularization after MI limits hypertrophied myocytes and scar extent by the reduction in collagen deposition and sustains the improvement in cardiac function. Compelling evidence from animal models and classical in vitro angiogenic approaches demonstrate that a plethora of well-orchestrated signaling pathways involving Notch, Wnt, PI3K, and the modulation of intracellular Ca2+ concentration through ion channels, regulate angiogenesis from existing endothelial cells (ECs) and endothelial progenitor cells (EPCs) in the infarcted heart. Moreover, cardiac repair after MI involves cell-to-cell communication by paracrine/autocrine signals, mainly through the delivery of extracellular vesicles hosting pro-angiogenic proteins and non-coding RNAs, as microRNAs (miRNAs). This review highlights some general insights into signaling pathways activated under MI, focusing on the role of Ca2+ influx, Notch activated pathway, and miRNAs in EC activation and angiogenesis after MI.
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Affiliation(s)
- Marta Martín-Bórnez
- Group of Cardiovascular Pathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío/University of Seville/CSIC, Avenida Manuel Siurot s/n, 41013 Seville, Spain; (M.M.-B.); (D.F.); (R.M.)
- Department of Medical Physiology and Biophysics, Faculty of Medicine, University of Seville, 41009 Seville, Spain
| | - Débora Falcón
- Group of Cardiovascular Pathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío/University of Seville/CSIC, Avenida Manuel Siurot s/n, 41013 Seville, Spain; (M.M.-B.); (D.F.); (R.M.)
- Department of Medical Physiology and Biophysics, Faculty of Medicine, University of Seville, 41009 Seville, Spain
| | - Rosario Morrugares
- Group of Cardiovascular Pathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío/University of Seville/CSIC, Avenida Manuel Siurot s/n, 41013 Seville, Spain; (M.M.-B.); (D.F.); (R.M.)
- Department of Medical Physiology and Biophysics, Faculty of Medicine, University of Seville, 41009 Seville, Spain
- Department of Cell Biology, Physiology and Immunology, Universidad de Córdoba, 14071 Córdoba, Spain
| | - Geraldine Siegfried
- RyTME, Bordeaux Institute of Oncology (BRIC)-UMR1312 Inserm, B2 Ouest, Allée Geoffroy St Hilaire CS50023, 33615 Pessac, France (A.-M.K.)
| | - Abdel-Majid Khatib
- RyTME, Bordeaux Institute of Oncology (BRIC)-UMR1312 Inserm, B2 Ouest, Allée Geoffroy St Hilaire CS50023, 33615 Pessac, France (A.-M.K.)
| | - Juan A. Rosado
- Cellular Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers (IMPB), University of Extremadura, 10003 Caceres, Spain;
| | - Isabel Galeano-Otero
- Group of Cardiovascular Pathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío/University of Seville/CSIC, Avenida Manuel Siurot s/n, 41013 Seville, Spain; (M.M.-B.); (D.F.); (R.M.)
- Department of Medical Physiology and Biophysics, Faculty of Medicine, University of Seville, 41009 Seville, Spain
| | - Tarik Smani
- Group of Cardiovascular Pathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío/University of Seville/CSIC, Avenida Manuel Siurot s/n, 41013 Seville, Spain; (M.M.-B.); (D.F.); (R.M.)
- Department of Medical Physiology and Biophysics, Faculty of Medicine, University of Seville, 41009 Seville, Spain
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Yuan F, Peng W, Yang Y, Xu J, Liu Y, Xie Y, Huang T, Shi C, Ding Y, Li C, Qin T, Xie S, Zhu F, Lu H, Huang J, Hu J. Endothelial progenitor cell-derived exosomes promote anti-inflammatory macrophages via SOCS3/JAK2/STAT3 axis and improve the outcome of spinal cord injury. J Neuroinflammation 2023; 20:156. [PMID: 37391774 DOI: 10.1186/s12974-023-02833-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 06/12/2023] [Indexed: 07/02/2023] Open
Abstract
BACKGROUND Macrophage in the spinal cord injury (SCI) area imparts a chronic pro-inflammation effect that challenges the recovery of SCI. Previously, endothelial progenitor cell-produced exosomes (EPC-EXOs) have been noticed to facilitate revascularization and inflammation control after SCI. However, their effects on macrophage polarization remained unclear. This study aimed to investigate the EPC-EXOs' role in macrophage polarization and reveal its underlying mechanism. METHODS We extracted the macrophages and EPC from the bone marrow suspension of C57BL/L mice by centrifugation. After cell identification, the EPC-EXOs were collected by ultra-high-speed centrifugation and exosome extraction kits and identified by transmission electron microscopy and nanoparticle tracking analysis. Then, macrophages were cultured with EPC-EXOs in different concentrations. We labeled the exosome to confirm its internalization by macrophage and detected the macrophage polarization marker level both in vitro and in vivo. We further estimated EPC-EXOs' protective effects on SCI by mice spinal cord tissue H&E staining and motor behavior evaluation. Finally, we performed RT-qPCR to identify the upregulated miRNA in EPC-EXOs and manipulate its expression to estimate its role in macrophage polarization, SOCS3/JAK2/STAT3 pathway activation, and motor behavior improvement. RESULTS We found that EPC-EXOs decreased the macrophages' pro-inflammatory marker expression and increased their anti-inflammatory marker expression on the 7 and 14 days after SCI. The spinal cord H&E staining results showed that EPC-EXOs raised the tissue-sparing area rate significantly after 28 days of SCI and the motor behavior evaluation indicated an increased BMS score and motor-evoked potential by EPC-EXOs treatment after SCI. The RT-qPCR assay identified that miR-222-3P upregulated in EPC-EXOs and its miRNA-mimic also decreased the pro-inflammatory macrophages and increased the anti-inflammatory macrophages. Additionally, miR-222-3P mimic activated the SOCS3/JAK2/STAT3 pathway, and SOCS3/JAK2/STAT3 pathway inhibition blocked miR-2223P's effects on macrophage polarization and mouse motor behavior. CONCLUSION Comprehensively, we discovered that EPC-EXOs-derived miR-222-3p affected macrophage polarization via SOCS3/JAK2/STAT3 pathway and promoted mouse functional repair after SCI, which reveals EPC-EXOs' role in modulation of macrophage phenotype and will provide a novel interventional strategy to induce post-SCI recovery.
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Affiliation(s)
- Feifei Yuan
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wei Peng
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
- Department of Spine Surgery, Wuxi Ninth People's Hospital, Wuxi, Jiangsu, China
| | - Yuying Yang
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jiaqi Xu
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yudong Liu
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yong Xie
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Tingmo Huang
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Chaoran Shi
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yinghe Ding
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Chengjun Li
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Tian Qin
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Shanshan Xie
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Fengzhang Zhu
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Hongbin Lu
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jianjun Huang
- Department of Spine Surgery, Ningde City Hospital, Fujian Medical University, Ningde, China.
| | - Jianzhong Hu
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China.
- Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
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Hassanpour M, Salybekov AA, Kobayashi S, Asahara T. CD34 positive cells as endothelial progenitor cells in biology and medicine. Front Cell Dev Biol 2023; 11:1128134. [PMID: 37138792 PMCID: PMC10150654 DOI: 10.3389/fcell.2023.1128134] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
Abstract
CD34 is a cell surface antigen expressed in numerous stem/progenitor cells including hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs), which are known to be rich sources of EPCs. Therefore, regenerative therapy using CD34+ cells has attracted interest for application in patients with various vascular, ischemic, and inflammatory diseases. CD34+ cells have recently been reported to improve therapeutic angiogenesis in a variety of diseases. Mechanistically, CD34+ cells are involved in both direct incorporation into the expanding vasculature and paracrine activity through angiogenesis, anti-inflammatory, immunomodulatory, and anti-apoptosis/fibrosis roles, which support the developing microvasculature. Preclinical, pilot, and clinical trials have well documented a track record of safety, practicality, and validity of CD34+ cell therapy in various diseases. However, the clinical application of CD34+ cell therapy has triggered scientific debates and controversies in last decade. This review covers all preexisting scientific literature and prepares an overview of the comprehensive biology of CD34+ cells as well as the preclinical/clinical details of CD34+ cell therapy for regenerative medicine.
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Affiliation(s)
- Mehdi Hassanpour
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
- Center for Cell Therapy and Regenerative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Amankeldi A. Salybekov
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
- Center for Cell Therapy and Regenerative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Shuzo Kobayashi
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Takayuki Asahara
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
- Center for Cell Therapy and Regenerative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
- *Correspondence: Takayuki Asahara,
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12
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Wang M, Wu P, Huang J, Liu W, Qian H, Sun Y, Shi H. Skin cell-derived extracellular vesicles: a promising therapeutic strategy for cutaneous injury. BURNS & TRAUMA 2022; 10:tkac037. [PMID: 36267497 PMCID: PMC9580071 DOI: 10.1093/burnst/tkac037] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/12/2022] [Accepted: 07/15/2022] [Indexed: 06/16/2023]
Abstract
Wound healing refers to the healing process that occurs after the skin and other tissues are separated or damaged by internal or external forces. It is a complex combination of tissue regeneration, granulation tissue hyperplasia, and scar formation, and shows the synergistic effects of these processes. After skin damage, the environment around the wound and the cells at site of the damage respond immediately, and a range of cytokines and growth factors are released. In cutaneous injury, extracellular vesicle (EV) signaling plays a vital role in the healing process via paracrine and endocrine mechanisms. EVs are natural intercellular and inter-organ communication tools that carry various bioactive substances for message exchange. Stem cells and stem cell EVs facilitate tissue repair, showing promising potential in regenerative medicine. Nevertheless, EVs derived from specific skin tissue cells, such as epidermal cells, fibroblasts, vascular endothelial cells and inflammatory cells, also play important roles in cutaneous tissue repair. Here, we describe the characteristics of wound healing, concentrating on the production and functions of EVs derived from specific skin cells, and provide new ideas for wound therapy using EVs.
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Affiliation(s)
- Min Wang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang 212000, China
| | - Peipei Wu
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing 214200, China
| | - Jin Huang
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing 214200, China
| | - Wenhui Liu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang 212000, China
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang 212000, China
| | - Yaoxiang Sun
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang 212000, China
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing 214200, China
| | - Hui Shi
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang 212000, China
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Suzhou, Jiangsu 215100, China
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13
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Chen K, Li Y, Xu L, Qian Y, Liu N, Zhou C, Liu J, Zhou L, Xu Z, Jia R, Ge YZ. Comprehensive insight into endothelial progenitor cell-derived extracellular vesicles as a promising candidate for disease treatment. Stem Cell Res Ther 2022; 13:238. [PMID: 35672766 PMCID: PMC9172199 DOI: 10.1186/s13287-022-02921-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 05/29/2022] [Indexed: 12/21/2022] Open
Abstract
Endothelial progenitor cells (EPCs), which are a type of stem cell, have been found to have strong angiogenic and tissue repair capabilities. Extracellular vesicles (EVs) contain many effective components, such as cellular proteins, microRNAs, messenger RNAs, and long noncoding RNAs, and can be secreted by different cell types. The functions of EVs depend mainly on their parent cells. Many researchers have conducted functional studies of EPC-derived EVs (EPC-EVs) and showed that they exhibit therapeutic effects on many diseases, such as cardiovascular disease, acute kidney injury, acute lung injury, and sepsis. In this review article, we comprehensively summarized the biogenesis and functions of EPCs and EVs and the potent role of EPC-EVs in the treatment of various diseases. Furthermore, the current problems and future prospects have been discussed, and further studies are needed to compare the therapeutic effects of EVs derived from various stem cells, which will contribute to the accelerated translation of these applications in a clinical setting.
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Affiliation(s)
- Ke Chen
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Yang Li
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Luwei Xu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Yiguan Qian
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Ning Liu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Changcheng Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Jingyu Liu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Liuhua Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Zheng Xu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Ruipeng Jia
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China.
| | - Yu-Zheng Ge
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China.
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Huang H, Huang W. Regulation of Endothelial Progenitor Cell Functions in Ischemic Heart Disease: New Therapeutic Targets for Cardiac Remodeling and Repair. Front Cardiovasc Med 2022; 9:896782. [PMID: 35677696 PMCID: PMC9167961 DOI: 10.3389/fcvm.2022.896782] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/02/2022] [Indexed: 12/16/2022] Open
Abstract
Ischemic heart disease (IHD) is the leading cause of morbidity and mortality worldwide. Ischemia and hypoxia following myocardial infarction (MI) cause subsequent cardiomyocyte (CM) loss, cardiac remodeling, and heart failure. Endothelial progenitor cells (EPCs) are involved in vasculogenesis, angiogenesis and paracrine effects and thus have important clinical value in alternative processes for repairing damaged hearts. In fact, this study showed that the endogenous repair of EPCs may not be limited to a single cell type. EPC interactions with cardiac cell populations and mesenchymal stem cells (MSCs) in ischemic heart disease can attenuate cardiac inflammation and oxidative stress in a microenvironment, regulate cell survival and apoptosis, nourish CMs, enhance mature neovascularization, alleviate adverse ventricular remodeling after infarction and enhance ventricular function. In this review, we introduce the definition and discuss the origin and biological characteristics of EPCs and summarize the mechanisms of EPC recruitment in ischemic heart disease. We focus on the crosstalk between EPCs and endothelial cells (ECs), smooth muscle cells (SMCs), CMs, cardiac fibroblasts (CFs), cardiac progenitor cells (CPCs), and MSCs during cardiac remodeling and repair. Finally, we discuss the translation of EPC therapy to the clinic and treatment strategies.
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15
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Goutas D, Pergaris A, Goutas N, Theocharis S. Utilizing Exosomal-EPHs/Ephrins as Biomarkers and as a Potential Platform for Targeted Delivery of Therapeutic Exosomes. Int J Mol Sci 2022; 23:ijms23073551. [PMID: 35408909 PMCID: PMC8998366 DOI: 10.3390/ijms23073551] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/18/2022] [Accepted: 03/21/2022] [Indexed: 12/12/2022] Open
Abstract
Exosomes are cell-secreted nanoparticles containing various molecules including small vesicles, microRNAs (miRNAs), messenger RNAs or bioactive proteins which are thought to be of paramount importance for intercellular communication. The unique effects of exosomes in terms of cell penetration capacity, decreased immunogenicity and inherent stability, along with their key role in mediating information exchange among tumor cells and their surrounding tumor microenvironment (TME), render them a promising platform for drug targeted delivery. Compared to synthetic drugs, exosomes boast a plethora of advantages, including higher biocompatibility, lower toxicity and increased ability of tissue infiltration. Nevertheless, the use of artificial exosomes can be limited in practice, partly due to their poor targeting ability and partly due to their limited efficacy. Therefore, efforts have been made to engineer stem cell-derived exosomes in order to increase selectiveness and effectivity, which can then become loaded with various active substances depending on the therapeutic approach followed. Erythropoietin-producing human hepatocellular receptors (EPHs), along with their ligands, the EPH family receptor interacting proteins (ephrins), have been extensively investigated for their key roles in both physiology and cancer pathogenesis. EPHs/ephrins exhibit both tumorigenic and tumor suppressing properties, with their targeting representing a promising, novel therapeutic approach in cancer patients’ management. In our review, the use of ephrin-loaded exosomes as a potential therapeutic targeted delivery system in cancer will be discussed.
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Affiliation(s)
- Dimitrios Goutas
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias Street, Bld 10, Goudi, 11527 Athens, Greece; (A.P.); (S.T.)
- Correspondence:
| | - Alexandros Pergaris
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias Street, Bld 10, Goudi, 11527 Athens, Greece; (A.P.); (S.T.)
| | - Nikolaos Goutas
- Department of Forensic Medicine and Toxicology, Pathology, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias Street, Goudi, 11527 Athens, Greece;
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias Street, Bld 10, Goudi, 11527 Athens, Greece; (A.P.); (S.T.)
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Ekram S, Khalid S, Salim A, Khan I. Regulating the fate of stem cells for regenerating the intervertebral disc degeneration. World J Stem Cells 2021; 13:1881-1904. [PMID: 35069988 PMCID: PMC8727226 DOI: 10.4252/wjsc.v13.i12.1881] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/12/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Lower back pain is a leading cause of disability and is one of the reasons for the substantial socioeconomic burden. The etiology of intervertebral disc (IVD) degeneration is complicated, and its mechanism is still not completely understood. Factors such as aging, systemic inflammation, biochemical mediators, toxic environmental factors, physical injuries, and genetic factors are involved in the progression of its pathophysiology. Currently, no therapy for restoring degenerated IVD is available except pain management, reduced physical activities, and surgical intervention. Therefore, it is imperative to establish regenerative medicine-based approaches to heal and repair the injured disc, repopulate the cell types to retain water content, synthesize extracellular matrix, and strengthen the disc to restore normal spine flexion. Cellular therapy has gained attention for IVD management as an alternative therapeutic option. In this review, we present an overview of the anatomical and molecular structure and the surrounding pathophysiology of the IVD. Modern therapeutic approaches, including proteins and growth factors, cellular and gene therapy, and cell fate regulators are reviewed. Similarly, small molecules that modulate the fate of stem cells for their differentiation into chondrocytes and notochordal cell types are highlighted.
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Affiliation(s)
- Sobia Ekram
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Shumaila Khalid
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Irfan Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan.
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Endothelial Progenitor Cell-Derived Extracellular Vesicles: Potential Therapeutic Application in Tissue Repair and Regeneration. Int J Mol Sci 2021; 22:ijms22126375. [PMID: 34203627 PMCID: PMC8232313 DOI: 10.3390/ijms22126375] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/01/2021] [Accepted: 06/11/2021] [Indexed: 12/19/2022] Open
Abstract
Recently, many studies investigated the role of a specific type of stem cell named the endothelial progenitor cell (EPC) in tissue regeneration and repair. EPCs represent a heterogeneous population of mononuclear cells resident in the adult bone marrow. EPCs can migrate and differentiate in injured sites or act in a paracrine way. Among the EPCs’ secretome, extracellular vesicles (EVs) gained relevance due to their possible use for cell-free biological therapy. They are more biocompatible, less immunogenic, and present a lower oncological risk compared to cell-based options. EVs can efficiently pass the pulmonary filter and deliver to target tissues different molecules, such as micro-RNA, growth factors, cytokines, chemokines, and non-coding RNAs. Their effects are often analogous to their cellular counterparts, and EPC-derived EVs have been tested in vitro and on animal models to treat several medical conditions, including ischemic stroke, myocardial infarction, diabetes, and acute kidney injury. EPC-derived EVs have also been studied for bone, brain, and lung regeneration and as carriers for drug delivery. This review will discuss the pre-clinical evidence regarding EPC-derived EVs in the different disease models and regenerative settings. Moreover, we will discuss the translation of their use into clinical practice and the possible limitations of this process.
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Povsic TJ, Gersh BJ. Stem Cells in Cardiovascular Diseases: 30,000-Foot View. Cells 2021; 10:cells10030600. [PMID: 33803227 PMCID: PMC8001267 DOI: 10.3390/cells10030600] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 12/15/2022] Open
Abstract
Stem cell and regenerative approaches that might rejuvenate the heart have immense intuitive appeal for the public and scientific communities. Hopes were fueled by initial findings from preclinical models that suggested that easily obtained bone marrow cells might have significant reparative capabilities; however, after initial encouraging pre-clinical and early clinical findings, the realities of clinical development have placed a damper on the field. Clinical trials were often designed to detect exceptionally large treatment effects with modest patient numbers with subsequent disappointing results. First generation approaches were likely overly simplistic and relied on a relatively primitive understanding of regenerative mechanisms and capabilities. Nonetheless, the field continues to move forward and novel cell derivatives, platforms, and cell/device combinations, coupled with a better understanding of the mechanisms that lead to regenerative capabilities in more primitive models and modifications in clinical trial design suggest a brighter future.
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Affiliation(s)
- Thomas J. Povsic
- Department of Medicine, and Duke Clinical Research Institute, Duke University, Durham, NC 27705, USA
- Correspondence:
| | - Bernard J. Gersh
- Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA;
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Vincenti M, O'Leary PW, Qureshi MY, Seisler DK, Burkhart HM, Cetta F, Nelson TJ. Clinical Impact of Autologous Cell Therapy on Hypoplastic Left Heart Syndrome After Bidirectional Cavopulmonary Anastomosis. Semin Thorac Cardiovasc Surg 2021; 33:791-801. [DOI: 10.1053/j.semtcvs.2020.11.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 11/05/2020] [Indexed: 01/29/2023]
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Co-Culture of Primary Human Coronary Artery and Internal Thoracic Artery Endothelial Cells Results in Mutually Beneficial Paracrine Interactions. Int J Mol Sci 2020; 21:ijms21218032. [PMID: 33126651 PMCID: PMC7663246 DOI: 10.3390/ijms21218032] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/21/2020] [Accepted: 10/27/2020] [Indexed: 12/12/2022] Open
Abstract
Although saphenous veins (SVs) are commonly used as conduits for coronary artery bypass grafting (CABG), internal thoracic artery (ITA) grafts have significantly higher long-term patency. As SVs and ITA endothelial cells (ECs) have a considerable level of heterogeneity, we suggested that synergistic paracrine interactions between CA and ITA ECs (HCAECs and HITAECs, respectively) may explain the increased resistance of ITA grafts and adjacent CAs to atherosclerosis and restenosis. In this study, we measured the gene and protein expression of the molecules responsible for endothelial homeostasis, pro-inflammatory response, and endothelial-to-mesenchymal transition in HCAECs co-cultured with either HITAECs or SV ECs (HSaVECs) for an ascending duration. Upon the co-culture, HCAECs and HITAECs showed augmented expression of endothelial nitric oxide synthase (eNOS) and reduced expression of endothelial-to-mesenchymal transition transcription factors Snail and Slug when compared to the HCAEC–HSaVEC model. HCAECs co-cultured with HITAECs demonstrated an upregulation of HES1, a master regulator of arterial specification, of which the expression was also exclusively induced in HSaVECs co-cultured with HCAECs, suggestive of their arterialisation. In addition, co-culture of HCAECs and HITAECs promoted the release of pro-angiogenic molecules. To conclude, co-culture of HCAECs and HITAECs results in reciprocal and beneficial paracrine interactions that might contribute to the better performance of ITA grafts upon CABG.
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21
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Hematopoietic stem and progenitor cell signaling in the niche. Leukemia 2020; 34:3136-3148. [PMID: 33077865 DOI: 10.1038/s41375-020-01062-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 09/09/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022]
Abstract
Hematopoietic stem and progenitor cells (HSPCs) are responsible for lifelong maintenance of hematopoiesis through self-renewal and differentiation into mature blood cell lineages. Traditional models hold that HSPCs guard homeostatic function and adapt to regenerative demand by integrating cell-autonomous, intrinsic programs with extrinsic cues from the niche. Despite the biologic significance, little is known about the active roles HSPCs partake in reciprocally shaping the function of their microenvironment. Here, we review evidence of signals emerging from HSPCs through secreted autocrine or paracrine factors, including extracellular vesicles, and via direct contact within the niche. We also discuss the functional impact of direct cellular interactions between hematopoietic elements on niche occupancy in the context of leukemic infiltration. The aggregate data support a model whereby HSPCs are active participants in the dynamic adaptation of the stem cell niche unit during development and homeostasis, and under inflammatory stress, malignancy, or transplantation.
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22
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Wysoczynski M, Pathan A, Moore JB, Farid T, Kim J, Nasr M, Kang Y, Li H, Bolli R. Pro-Angiogenic Actions of CMC-Derived Extracellular Vesicles Rely on Selective Packaging of Angiopoietin 1 and 2, but Not FGF-2 and VEGF. Stem Cell Rev Rep 2020; 15:530-542. [PMID: 31102187 DOI: 10.1007/s12015-019-09891-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
While the fundamental mechanism by which cardiac cell therapy mitigates ventricular dysfunction in the post ischemic heart remains poorly defined, donor cell paracrine signaling is presumed to be a chief contributor to the afforded benefits. Of the many bioactive molecules secreted by transplanted cells, extracellular vesicles (EVs) and their proteinaceous, nucleic acid, and lipid rich contents, comprise a heterogeneous assortment of prospective cardiotrophic factors-whose involvement in the activation of endogenous cardiac repair mechanism(s), including reducing fibrosis and promoting angiogenesis, have yet to be fully explained. In the current study we aimed to interrogate potential mechanisms by which cardiac mesenchymal stromal cell (CMC)-derived EVs contribute to the CMC pro-angiogenic paracrine signaling capacity in vitro. Vesicular transmission and biological activity of human CMC-derived EVs was evaluated in in vitro assays for human umbilical vein endothelial cell (HUVEC) function, including EV uptake, cell survival, migration, tube formation, and intracellular pathway activation. HUVECs incubated with EVs exhibited augmented cell migration, tube formation, and survival under peroxide exposure; findings which paralleled enhanced activation of the archetypal pro-survival/pro-angiogenic pathways, STAT3 and PI3K-AKT. Cytokine array analyses revealed preferential enrichment of a subset of prototypical angiogenic factors, Ang-1 and Ang-2, in CMC EVs. Interestingly, pharmacologic inhibition of Tie2 in HUVECs, the cognate receptors of angiopoietins, efficiently attenuated CMC-EV-induced HUVEC migration. Further, in additional assays a Tie2 kinase inhibitor exhibited specificity to inhibit Ang-1-, but not Ang-2-, induced HUVEC migration. Overall, these findings suggest that the pro-angiogenic activities of CMC EVs are principally mediated by Ang-1-Tie2 signaling.
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Affiliation(s)
- Marcin Wysoczynski
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
- University of Louisville, 580 South Preston St. - Rm 119F, Louisville, KY, 40202, USA.
| | - Asif Pathan
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Joseph B Moore
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Talha Farid
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Jae Kim
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Marjan Nasr
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Yi Kang
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Hong Li
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
- University of Louisville, 550 S Jackson St.- ACB, Third Floor, Louisville, KY, 40292, USA.
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23
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Xing Z, Zhao C, Liu H, Fan Y. Endothelial Progenitor Cell-Derived Extracellular Vesicles: A Novel Candidate for Regenerative Medicine and Disease Treatment. Adv Healthc Mater 2020; 9:e2000255. [PMID: 32378361 DOI: 10.1002/adhm.202000255] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 04/12/2020] [Indexed: 12/15/2022]
Abstract
Extracellular vesicles (EVs) are a heterogeneous group of membranous structures, which can be secreted by most cell types. As a product of paracrine secretion, EVs are considered to be a regulatory mediator for intercellular communication. There are many bioactive cargos in EVs, such as proteins, lipids, and nucleic acids. As the precursor cell of vascular endothelial cells (ECs), endothelial progenitor cells (EPCs) are first discovered in peripheral blood. With the development of studies about the functions of EPCs, an increasing number of researchers focus on EPC-derived EVs (EPC-EVs). EPC-EVs exert key functions for promoting angiogenesis in regenerative medicine and show significant therapeutic effects on a variety of diseases such as circulatory diseases, kidney diseases, diabetes, bone diseases, and tissue/organ damages. This article reviews the current knowledge on the role of EPC-EVs in regenerative medicine and disease treatment, discussing the main challenges and future directions in this field.
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Affiliation(s)
- Zheng Xing
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of EducationSchool of Biological Science and Medical EngineeringBeihang University Beijing 100191 P. R. China
| | - Chen Zhao
- School of Pharmaceutical SciencesTsinghua University Beijing 100084 P. R. China
| | - Haifeng Liu
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of EducationSchool of Biological Science and Medical EngineeringBeihang University Beijing 100191 P. R. China
- Beijing Advanced Innovation Centre for Biomedical EngineeringBeihang University Beijing 100191 P. R. China
| | - Yubo Fan
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of EducationSchool of Biological Science and Medical EngineeringBeihang University Beijing 100191 P. R. China
- Beijing Advanced Innovation Centre for Biomedical EngineeringBeihang University Beijing 100191 P. R. China
- National Research Center for Rehabilitation Technical Aids Beijing 100176 P. R. China
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24
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Santamaria X, Liu JH, Aghajanova L, Isaacson K, Movilla P, Fernandez H, Capmas P, Donnez J, Simón C. Should we consider alternative therapies to operative hysteroscopy for the treatment of Asherman syndrome? Fertil Steril 2020; 113:511-521. [PMID: 32111470 DOI: 10.1016/j.fertnstert.2020.01.022] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 01/20/2020] [Indexed: 12/30/2022]
Affiliation(s)
| | - James H Liu
- Department of Obstetrics and Gynecology, University Hospitals Cleveland, Cleveland, Ohio; Department of Reproductive Biology, Case Western Reserve University, Cleveland, Ohio
| | - Lusine Aghajanova
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Stanford School of Medicine, Stanford, California
| | - Keith Isaacson
- Department of Minimally Invasive Gynecologic Surgery, Newton Wellesley Hospital, Newton, Massachusetts
| | - Peter Movilla
- Department of Minimally Invasive Gynecologic Surgery, Newton Wellesley Hospital, Newton, Massachusetts
| | - Hervé Fernandez
- Department of Gynecology and Obstetrics, AP-HP, GHU-Sud, Hospital Bicêtre, Le Kremlin Bicêtre, France; Faculty of medicine, University Paris-Sud Saclay, Le Kremlin Bicêtre, France; INSERM U1018, Centre of Research in Epidemiology and Population Health (CESP), Le Kremlin Bicêtre, France
| | - Perrine Capmas
- Department of Gynecology and Obstetrics, AP-HP, GHU-Sud, Hospital Bicêtre, Le Kremlin Bicêtre, France; Faculty of medicine, University Paris-Sud Saclay, Le Kremlin Bicêtre, France; INSERM U1018, Centre of Research in Epidemiology and Population Health (CESP), Le Kremlin Bicêtre, France
| | - Jacques Donnez
- Société de Recherche pour l'Infertilité (SRI), Brussels, Belgium
| | - Carlos Simón
- Department of Obstetrics & Gynecology, Valencia University & INCLIVA, Valencia, Spain; Department of Obstetrics & Gynecology, BIDMC Harvard University, Boston, Massachusetts; Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas.
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25
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Stem and Progenitor Cells in the Pathogenesis and Treatment of Digestive Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1201:125-157. [PMID: 31898785 DOI: 10.1007/978-3-030-31206-0_7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The global epidemic of chronic degenerative diseases expands rapidly. The pathogenesis of these noncommunicable disorders revolves around innate immunity, microbiome, and stem cell alterations. Understanding the mechanisms behind stem cell biology and their regulatory pathways is a key to understanding the origin of human disease. Stem cells are involved in tissue and organ damage and regeneration. The evidence is mounting that not only eukaryotic cells but also gut microbiota may release extracellular microvesicles that are absorbed from the gut into the portal and systemic circulation. Linking the fields of stem cells, innate immunity and microbiome research opens up new avenues to develop novel diagnostic (e.g., biomarkers), therapeutic (e.g., microbiome modulation, stem cell-based medicines), and prognostic (personalized diets) tools. In this chapter, we present the short overview of various stem and progenitor cells of adult tissues circulating in peripheral blood and their role in the pathogenesis and treatment of digestive diseases. We also briefly discuss the role of host-stem cell-microbial interactions as a new frontier of research in gastroenterology.
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26
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The Role of Extracellular Vesicles as Paracrine Effectors in Stem Cell-Based Therapies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1201:175-193. [PMID: 31898787 DOI: 10.1007/978-3-030-31206-0_9] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Stem cells act in a paracrine manner through the secretion of biologically active cargo that acts on cells locally and systemically. These active molecules include not only soluble factors but also extracellular vesicles (EVs) that have recently emerged as a mechanism of cell-to-cell communication. EVs act as vehicles that transfer molecules between originator and recipient cells, thereby modifying the phenotype and function of the latter. As EVs released from stem cells may successfully activate regenerative processes in injured cells, their application as a form of therapy can be envisaged. EVs exert these proregenerative effects through the modulation of relevant cellular processes including proliferation, angiogenesis, oxidative stress, inflammation, and immunotolerance, among others. In this chapter, we review the preclinical studies that report the effect of stem cell-derived EVs in various pathological models of human disease.
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27
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Systemic Infusion of Expanded CD133 + Cells and Expanded CD133 + Cell-Derived EVs for the Treatment of Ischemic Cardiomyopathy in a Rat Model of AMI. Stem Cells Int 2019; 2019:4802578. [PMID: 31885610 PMCID: PMC6914904 DOI: 10.1155/2019/4802578] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 10/11/2019] [Indexed: 12/11/2022] Open
Abstract
Myocardial infarction is a leading cause of death among all cardiovascular diseases. Cell therapies using a cell population enriched with endothelial progenitor cells (EPCs), expanded CD133+ cells, have promise as a therapeutic option for the treatment of ischemic areas after infarction. Recently, secreted membrane vesicles, including exosomes and microvesicles, have been recognized as new therapeutic candidates with important roles in intercellular and tissue communication. Expanded CD133+ cells have the ability to produce extracellular vesicles (EVs); however, their effect in the context of the heart is unknown. In the present study, we evaluated the effectiveness of the systemic application of expanded CD133+ cells and expanded CD133+ cell-derived EVs for the treatment of ischemic cardiomyopathy in a rat model of acute myocardial infarction (AMI) and examined the hypothesis that the EVs, because of their critical role in transferring regenerative signals from stem cells to the injured tissues, might elicit an equal or better therapeutic response than the expanded CD133+ cells. We demonstrate that the systemic application of expanded CD133+ cells and EVs has similar effects in infarcted rats. Few animals per group showed improvements in several heart and kidney parameters analyzed, but not significant differences were observed when comparing the groups. The systemic route may not be effective to treat ischemic cardiomyopathy; nonetheless, it may be a beneficial therapy to treat the side effects of AMI such as kidney damage.
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28
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Sheveleva ON, Domaratskaya EI, Payushina OV. Extracellular Vesicles and Prospects of Their Use for Tissue Regeneration. BIOCHEMISTRY MOSCOW SUPPLEMENT SERIES A-MEMBRANE AND CELL BIOLOGY 2019. [DOI: 10.1134/s1990747818040104] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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29
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Santamaria X, Mas A, Cervelló I, Taylor H, Simon C. Uterine stem cells: from basic research to advanced cell therapies. Hum Reprod Update 2019; 24:673-693. [PMID: 30239705 DOI: 10.1093/humupd/dmy028] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 08/04/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Stem cell research in the endometrium and myometrium from animal models and humans has led to the identification of endometrial/myometrial stem cells and their niches. This basic knowledge is beginning to be translated to clinical use for incurable uterine pathologies. Additionally, the implication of bone marrow-derived stem cells (BMDSCs) in uterine physiology has opened the field for the exploration of an exogenous and autologous source of stem cells. OBJECTIVE AND RATIONALE In this review, we outline the progress of endometrial and myometrial stem/progenitor cells in both human and mouse models from their characterization to their clinical application, indicating roles in Asherman syndrome, atrophic endometrium and tissue engineering, among others. SEARCH METHODS A comprehensive search of PubMed and Google Scholar up to December 2017 was conducted to identify peer-reviewed literature related to the contribution of bone marrow, endometrial and myometrial stem cells to potential physiological regeneration as well as their implications in pathologies of the human uterus. OUTCOMES The discovery and main characteristics of stem cells in the murine and human endometrium and myometrium are presented together with the relevance of their niches and cross-regulation. The current state of advanced stem cell therapy using BMDSCs in the treatment of Asherman syndrome and atrophic endometrium is analyzed. In the myometrium, the understanding of genetic and epigenetic defects that result in the development of tumor-initiating cells in the myometrial stem niche and thus contribute to the growth of uterine leiomyoma is also presented. Finally, recent advances in tissue engineering based on the creation of novel three-dimensional scaffolds or decellularisation open up new perspectives for the field of uterine transplantation. WIDER IMPLICATIONS More than a decade after their discovery, the knowledge of uterine stem cells and their niches is crystalising into novel therapeutic approaches aiming to treat with cells those conditions that cannot be cured with drugs, particularly the currently incurable uterine pathologies. Additional work and improvements are needed, but the basis has been formed for this therapeutic application of uterine cells.
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Affiliation(s)
- Xavier Santamaria
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Reproductive Medicine Department, IVI Barcelona, Barcelona, Spain.,Department of Obstetrics and Gynecology, Biomedical Research Group in Gynecology, Vall Hebron Institut de Recerca, Barcelona, Spain
| | - Aymara Mas
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Department of Obstetrics and Gynecology, Reproductive Medicine Research Group, La Fe Health Research Institute, Valencia, Spain
| | - Irene Cervelló
- Department of Obstetrics and Gynecology, Fundación Instituto Valenciano de Infertilidad (FIVI), and Instituto Universitario IVI/INCLIVA, Valencia, Spain
| | - Hugh Taylor
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Carlos Simon
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Department of Pediatrics, Obstetrics, and Gynecology, Valencia University and INCLIVA, Valencia, Spain.,Department of Obstetrics and Gynecology, Stanford University, Stanford, CA, USA
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30
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Bacha NC, Blandinieres A, Rossi E, Gendron N, Nevo N, Lecourt S, Guerin CL, Renard JM, Gaussem P, Angles-Cano E, Boulanger CM, Israel-Biet D, Smadja DM. Endothelial Microparticles are Associated to Pathogenesis of Idiopathic Pulmonary Fibrosis. Stem Cell Rev Rep 2018; 14:223-235. [PMID: 29101610 DOI: 10.1007/s12015-017-9778-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by obliteration of alveolar architecture, resulting in declining lung function and ultimately death. Pathogenic mechanisms remain unclear but involve a concomitant accumulation of scar tissue together with myofibroblasts activation. Microparticles (MPs) have been investigated in several human lung diseases as possible pathogenic elements, prognosis markers and therapeutic targets. We postulated that levels and cellular origins of circulating MPs might serve as biomarkers in IPF patients and/or as active players of fibrogenesis. Flow cytometry analysis showed a higher level of Annexin-V positive endothelial and platelet MPs in 41 IPF patients compared to 22 healthy volunteers. Moreover, in IPF patients with a low diffusing capacity of the lung for carbon monoxide (DLCO<40%), endothelial MPs (EMPs) were found significantly higher compared to those with DLCO>40% (p = 0.02). We then used EMPs isolated from endothelial progenitor cells (ECFCs) extracted from IPF patients or controls to modulate normal human lung fibroblast (NHLF) properties. We showed that EMPs did not modify proliferation, collagen deposition and myofibroblast transdifferentiation. However, EMPs from IPF patients stimulated migration capacity of NHLF. We hypothesized that this effect could result from EMPs fibrinolytic properties and found indeed higher plasminogen activation potential in total circulating MPs and ECFCs derived MPs issued from IPF patients compared to those isolated from healthy controls MPs. Our study showed that IPF is associated with an increased level of EMPs in the most severe patients, highlighting an active process of endothelial activation in the latter. Endothelial microparticles might contribute to the lung fibroblast invasion mediated, at least in part, by a fibrinolytic activity.
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Affiliation(s)
- Nour C Bacha
- Inserm UMR-S1140, Paris, France.,Sorbonne Paris Cite, Université Paris Descartes, Paris, France
| | - Adeline Blandinieres
- Inserm UMR-S1140, Paris, France.,Sorbonne Paris Cite, Université Paris Descartes, Paris, France.,Hematology Department and UMR-S1140, AP-HP, European Hospital Georges Pompidou, 20 rue Leblanc, 75015, Paris, France
| | - Elisa Rossi
- Inserm UMR-S1140, Paris, France.,Sorbonne Paris Cite, Université Paris Descartes, Paris, France
| | - Nicolas Gendron
- Inserm UMR-S1140, Paris, France.,Sorbonne Paris Cite, Université Paris Descartes, Paris, France.,Hematology Department and UMR-S1140, AP-HP, European Hospital Georges Pompidou, 20 rue Leblanc, 75015, Paris, France
| | - Nathalie Nevo
- Inserm UMR-S1140, Paris, France.,Sorbonne Paris Cite, Université Paris Descartes, Paris, France
| | | | - Coralie L Guerin
- National Cytometry Platform, Department of Infection and Immunity, Luxembourg Institute of Health, Luxembourg, France
| | - Jean Marie Renard
- Sorbonne Paris Cite, Université Paris Descartes, Paris, France.,Inserm UMR-S970, PARCC, Paris, France
| | - Pascale Gaussem
- Inserm UMR-S1140, Paris, France.,Sorbonne Paris Cite, Université Paris Descartes, Paris, France.,Hematology Department and UMR-S1140, AP-HP, European Hospital Georges Pompidou, 20 rue Leblanc, 75015, Paris, France
| | - Eduardo Angles-Cano
- Inserm UMR-S1140, Paris, France.,Sorbonne Paris Cite, Université Paris Descartes, Paris, France
| | - Chantal M Boulanger
- Sorbonne Paris Cite, Université Paris Descartes, Paris, France.,Inserm UMR-S970, PARCC, Paris, France
| | - Dominique Israel-Biet
- Inserm UMR-S1140, Paris, France.,Sorbonne Paris Cite, Université Paris Descartes, Paris, France.,Pneumology Department, AP-HP, European Hospital Georges Pompidou, Paris, France
| | - David M Smadja
- Inserm UMR-S1140, Paris, France. .,Sorbonne Paris Cite, Université Paris Descartes, Paris, France. .,Hematology Department and UMR-S1140, AP-HP, European Hospital Georges Pompidou, 20 rue Leblanc, 75015, Paris, France.
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31
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Yuan KM, Zhang PH, Qi SS, Zhu QZ, Li P. Emerging Role for Exosomes in the Progress of Stem Cell Research. Am J Med Sci 2018; 356:481-486. [DOI: 10.1016/j.amjms.2018.07.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 06/27/2018] [Accepted: 07/13/2018] [Indexed: 01/08/2023]
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32
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Bassetti B, Carbucicchio C, Catto V, Gambini E, Rurali E, Bestetti A, Gaipa G, Belotti D, Celeste F, Parma M, Righetti S, Biava L, Arosio M, Bonomi A, Agostoni P, Scacciatella P, Achilli F, Pompilio G. Linking cell function with perfusion: insights from the transcatheter delivery of bone marrow-derived CD133 + cells in ischemic refractory cardiomyopathy trial (RECARDIO). Stem Cell Res Ther 2018; 9:235. [PMID: 30217223 PMCID: PMC6137884 DOI: 10.1186/s13287-018-0969-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 07/30/2018] [Accepted: 08/02/2018] [Indexed: 12/13/2022] Open
Abstract
Background Cell therapy with bone marrow (BM)-derived progenitors has emerged as a promising therapeutic for refractory angina (RA) patients. In the present study, we evaluated the safety and preliminary efficacy of transcatheter delivery of autologous BM-derived advanced therapy medicinal product CD133+ cells (ATMP-CD133) in RA patients, correlating perfusion outcome with cell function. Methods In the phase I “Endocavitary Injection of Bone Marrow Derived CD133+ Cells in Ischemic Refractory Cardiomyopathy” (RECARDIO) trial, a total of 10 patients with left ventricular (LV) dysfunction (ejection fraction ≤ 45%) and evidence of reversible ischemia, as assessed by single-photon emission computed tomography (SPECT), underwent BM aspiration and fluoroscopy-based percutaneous endomyocardial delivery of ATMP-CD133. Patients were evaluated at 6 and 12 months for safety and preliminary efficacy endpoints. ATMP-CD133 samples were used for in vitro correlations. Results Patients were treated safely with a mean number of 6.57 ± 3.45 × 106 ATMP-CD133. At 6-month follow-up, myocardial perfusion at SPECT was significantly ameliorated in terms of changes in summed stress (from 18.2 ± 8.6 to 13.8 ± 7.8, p = 0.05) and difference scores (from 12.0 ± 5.3 to 6.1 ± 4.0, p = 0.02) and number of segments with inducible ischemia (from 7.3 ± 2.2 to 4.0 ± 2.7, p = 0.003). Similarly, Canadian Cardiovascular Society and New York Heart Association classes significantly improved at follow-up vs baseline (p ≤ 0.001 and p = 0.007, respectively). Changes in summed stress score changes positively correlated with ATMP-CD133 release of proangiogenic cytokines HGF and PDGF-bb (r = 0.80, p = 0.009 and r = 0.77, p = 0.01, respectively) and negatively with the proinflammatory cytokines RANTES (r = − 0.79, p = 0.01) and IL-6 (r = − 0.76, p = 0.02). Conclusion Results of the RECARDIO trial suggested safety and efficacy in terms of clinical and perfusion outcomes in patients with RA and LV dysfunction. The observed link between myocardial perfusion improvements and ATMP-CD133 secretome may represent a proof of concept for further mechanistic investigations. Trial registration ClinicalTrials.gov, NCT02059681. Registered 11 February 2014.
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Affiliation(s)
- Beatrice Bassetti
- Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Via Carlo Parea 4, 20138, Milan, Italy
| | - Corrado Carbucicchio
- Heart Rhythm Center, Centro Cardiologico Monzino-IRCCS, Via Carlo Parea 4, 20138, Milan, Italy
| | - Valentina Catto
- Heart Rhythm Center, Centro Cardiologico Monzino-IRCCS, Via Carlo Parea 4, 20138, Milan, Italy
| | - Elisa Gambini
- Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Via Carlo Parea 4, 20138, Milan, Italy
| | - Erica Rurali
- Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Via Carlo Parea 4, 20138, Milan, Italy
| | - Alberto Bestetti
- Service of Nuclear Medicine, IRCCS Multimedica, Via Milanese 300, 20099, Sesto San Giovanni, Milan, Italy
| | - Giuseppe Gaipa
- Laboratory of Cell and Gene Therapy "Stefano Verri", ASST-Monza, San Gerardo Hospital, Via Pergolesi 33, 20900, Monza, Italy.,Tettamanti Research Center, Tettamanti Foundation, Via Pergolesi 33, 20900, Monza, Italy
| | - Daniela Belotti
- Laboratory of Cell and Gene Therapy "Stefano Verri", ASST-Monza, San Gerardo Hospital, Via Pergolesi 33, 20900, Monza, Italy.,University of Milano Bicocca, Via Pergolesi 33, 20900, Monza, Italy
| | - Fabrizio Celeste
- Cardiovascular Imaging Area, Centro Cardiologico Monzino-IRCCS, Via Carlo Parea 4, 20138, Milan, Italy
| | - Matteo Parma
- Haematology Division and BMT Unit, ASST-Monza, San Gerardo Hospital, Via Pergolesi 33, 20900, Monza, Italy
| | - Stefano Righetti
- Department of Cardiology, ASST-Monza, San Gerardo Hospital, Via Pergolesi 33, 20900, Monza, Italy
| | - Lorenza Biava
- Department of Cardiovascular and Thoracic Diseases, Città della Salute e della Scienza Hospital, Corso Bramante 88, 10126, Turin, Italy
| | - Maurizio Arosio
- Nuclear Medicine Unit, ASST-Monza, San Gerardo Hospital and University of Milano Bicocca, Via Pergolesi, 33, 20900, Monza, Italy
| | - Alice Bonomi
- BioStatistical Unit, Centro Cardiologico Monzino-IRCCS, Via Carlo Parea 4, 20138, Milan, Italy
| | - Piergiuseppe Agostoni
- Heart Failure, Clinical Cardiology and Rehabilitation Cardiology Unit, Centro Cardiologico Monzino-IRCCS, Via Carlo Parea 4, 20138, Milan, Italy.,Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Via Festa del Perdono 7, 20122, Milan, Italy
| | - Paolo Scacciatella
- Department of Cardiovascular and Thoracic Diseases, Città della Salute e della Scienza Hospital, Corso Bramante 88, 10126, Turin, Italy
| | - Felice Achilli
- Department of Cardiology, ASST-Monza, San Gerardo Hospital, Via Pergolesi 33, 20900, Monza, Italy
| | - Giulio Pompilio
- Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Via Carlo Parea 4, 20138, Milan, Italy. .,Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Via Festa del Perdono 7, 20122, Milan, Italy.
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33
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Marlicz W, Skonieczna-Żydecka K, Dabos KJ, Łoniewski I, Koulaouzidis A. Emerging concepts in non-invasive monitoring of Crohn's disease. Therap Adv Gastroenterol 2018; 11:1756284818769076. [PMID: 29707039 PMCID: PMC5912292 DOI: 10.1177/1756284818769076] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an umbrella term for Crohn's disease (CD) and ulcerative colitis (UC). In light of evolving epidemiology of CD, its clinical management is still complex and remains a challenge for contemporary physicians. With the advent of new diagnostic and treatment paradigms, there is a growing need for new biomarkers to guide decision-making, differential diagnosis, disease activity monitoring, as well as prognosis. However, both clinical and endoscopic scoring systems, widely utilized for disease monitoring and prognosis, have drawbacks and limitations. In recent years, biochemical peptides have become available for IBD monitoring and more frequently used as surrogate markers of gut inflammation. Emerging concepts that revolve around molecular, stem cell, epigenetic, microbial or metabolomic pathways associated with vascular and epithelial gut barrier could lead to development of new CD biomarkers. Measurement of cell-derived microvesicles (MVs) in the blood of IBD patients is another emerging concept helpful in future disease management. In this review, we discuss novel concepts of non-invasive biomarkers, which may become useful in monitoring of CD activity and prognosis. We discuss metabolomics as a new powerful tool for clinicians to guide differential IBD diagnosis. In the coming years, new developments of prognostic tools are expected, aiming for breakthroughs in the management of patients with CD.
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Affiliation(s)
- Wojciech Marlicz
- Department of Gastroenterology, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland
| | | | | | - Igor Łoniewski
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Szczecin, Poland
- Sanprobi Sp. z o.o. Sp. K., Szczecin, Poland
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Naseri MH, Madani H, Ahmadi Tafti SH, Moshkani Farahani M, Kazemi Saleh D, Hosseinnejad H, Hosseini S, Hekmat S, Hossein Ahmadi Z, Dehghani M, Saadat A, Mardpour S, Hosseini SE, Esmaeilzadeh M, Sadeghian H, Bahoush G, Bassi A, Amin A, Fazeli R, Sharafi Y, Arab L, Movahhed M, Davaran S, Ramezanzadeh N, Kouhkan A, Hezavehei A, Namiri M, Kashfi F, Akhlaghi A, Sotoodehnejadnematalahi F, Vosough Dizaji A, Gourabi H, Syedi N, Shahverdi AH, Baharvand H, Aghdami N. COMPARE CPM-RMI Trial: Intramyocardial Transplantation of Autologous Bone Marrow-Derived CD133+ Cells and MNCs during CABG in Patients with Recent MI: A Phase II/III, Multicenter, Placebo-Controlled, Randomized, Double-Blind Clinical Trial. CELL JOURNAL 2018; 20:267-277. [PMID: 29633605 PMCID: PMC5893299 DOI: 10.22074/cellj.2018.5197] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 07/26/2017] [Indexed: 12/13/2022]
Abstract
Objective: The regenerative potential of bone marrow-derived mononuclear cells (MNCs) and CD133+ stem cells
in the heart varies in terms of their pro-angiogenic effects. This phase II/III, multicenter and double-blind trial is
designed to compare the functional effects of intramyocardial autologous transplantation of both cell types and
placebo in patients with recent myocardial infarction (RMI) post-coronary artery bypass graft. Materials and Methods: This was a phase II/III, randomized, double-blind, placebo-controlled trial COMPARE
CPM-RMI (CD133, Placebo, MNCs - recent myocardial infarction) conducted in accordance with the Declaration
of Helsinki that assessed the safety and efficacy of CD133 and MNCs compared to placebo in patients with
RMI. We randomly assigned 77 eligible RMI patients selected from 5 hospitals to receive CD133+ cells, MNC,
or a placebo. Patients underwent gated single photon emission computed tomography assessments at 6 and 18
months post-intramyocardial transplantation. We tested the normally distributed efficacy outcomes with a mixed
analysis of variance model that used the entire data set of baseline and between-group comparisons as well as
within subject (time) and group×time interaction terms. Results: There were no related serious adverse events reported. The intramyocardial transplantation of both
cell types increased left ventricular ejection fraction by 9% [95% confidence intervals (CI): 2.14% to 15.78%,
P=0.01] and improved decreased systolic wall thickening by -3.7 (95% CI: -7.07 to -0.42, P=0.03). The CD133
group showed significantly decreased non-viable segments by 75% (P=0.001) compared to the placebo and 60%
(P=0.01) compared to the MNC group. We observed this improvement at both the 6- and 18-month time points. Conclusion: Intramyocardial injections of CD133+ cells or MNCs appeared to be safe and efficient with superiority of
CD133+ cells for patients with RMI. Although the sample size precluded a definitive statement about clinical outcomes,
these results have provided the basis for larger studies to confirm definitive evidence about the efficacy of these cell
types (Registration Number: NCT01167751).
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Affiliation(s)
| | - Hoda Madani
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | | | | | | | - Hossein Hosseinnejad
- Department of Cardiac Surgery, Lavasani Hospital, Social Security Organization, Tehran, Iran
| | - Saeid Hosseini
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sepideh Hekmat
- Department of Nuclear Medicine, Hasheminejad Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Zargham Hossein Ahmadi
- Transplantation Research Center, NRITLD, Masih Daneshvari Hospital, Shaheed Beheshti University of Medical Science, Darabad, Niavaran, Tehran, Iran
| | - Majid Dehghani
- Department of Cardiac Surgery, Lavasani Hospital, Social Security Organization, Tehran, Iran
| | - Alireza Saadat
- Department of Internal Medicine, Baqiyatallah Hospital, Tehran, Iran
| | - Soura Mardpour
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Seyedeh Esmat Hosseini
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Student Research Committee, School of Nursing and Midwifery , Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Esmaeilzadeh
- Echocardiography Research Center, Rajaie Cardiovascular Medical and Research Center , Iran University of Medical Sciences, Tehran, Iran
| | - Hakimeh Sadeghian
- Research Department, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Bahoush
- Department of Pediatrics, Ali Asghar Pediatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Bassi
- Department of Hematology and Oncology, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Ahmad Amin
- Department of Heart Failure and Transplantation, Fellowship in Heart Failure and Transplantation, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Roghayeh Fazeli
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Yaser Sharafi
- Department of Internal Medicine, Baqiyatallah Hospital, Tehran, Iran
| | - Leila Arab
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mansour Movahhed
- Department of Nuclear Medicine, Hasheminejad Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeid Davaran
- Research Department, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Narges Ramezanzadeh
- Research Department, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Azam Kouhkan
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Ali Hezavehei
- Department of Internal Medicine, Lavasani Hospital, Social Security Organization, Tehran, Iran
| | - Mehrnaz Namiri
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Fahimeh Kashfi
- Department of Epidemiology and Reproductive Health, Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Ali Akhlaghi
- Department of Epidemiology and Reproductive Health, Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Fattah Sotoodehnejadnematalahi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Ahmad Vosough Dizaji
- Department of Reproductive Imaging, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Hamid Gourabi
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Naeema Syedi
- School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, South Australia, Australia
| | - Abdol Hosein Shahverdi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hossein Baharvand
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Nasser Aghdami
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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35
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Shear stress: An essential driver of endothelial progenitor cells. J Mol Cell Cardiol 2018; 118:46-69. [PMID: 29549046 DOI: 10.1016/j.yjmcc.2018.03.007] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 03/08/2018] [Accepted: 03/09/2018] [Indexed: 02/06/2023]
Abstract
The blood flow through vessels produces a tangential, or shear, stress sensed by their innermost layer (i.e., endothelium) and representing a major hemodynamic force. In humans, endothelial repair and blood vessel formation are mainly performed by circulating endothelial progenitor cells (EPCs) characterized by a considerable expression of vascular endothelial growth factor receptor 2 (VEGFR2), CD34, and CD133, pronounced tube formation activity in vitro, and strong reendothelialization or neovascularization capacity in vivo. EPCs have been proposed as a promising agent to induce reendothelialization of injured arteries, neovascularization of ischemic tissues, and endothelialization or vascularization of bioartificial constructs. A number of preconditioning approaches have been suggested to improve the regenerative potential of EPCs, including the use of biophysical stimuli such as shear stress. However, in spite of well-defined influence of shear stress on mature endothelial cells (ECs), articles summarizing how it affects EPCs are lacking. Here we discuss the impact of shear stress on homing, paracrine effects, and differentiation of EPCs. Unidirectional laminar shear stress significantly promotes homing of circulating EPCs to endothelial injury sites, induces anti-thrombotic and anti-atherosclerotic phenotype of EPCs, increases their capability to form capillary-like tubes in vitro, and enhances differentiation of EPCs into mature ECs in a dose-dependent manner. These effects are mediated by VEGFR2, Tie2, Notch, and β1/3 integrin signaling and can be abrogated by means of complementary siRNA/shRNA or selective pharmacological inhibitors of the respective proteins. Although the testing of sheared EPCs for vascular tissue engineering or regenerative medicine applications is still an unaccomplished task, favorable effects of unidirectional laminar shear stress on EPCs suggest its usefulness for their preconditioning.
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36
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Zhai R, Wang Y, Qi L, Williams GM, Gao B, Song G, Burdick JF, Sun Z. Pharmacological Mobilization of Endogenous Bone Marrow Stem Cells Promotes Liver Regeneration after Extensive Liver Resection in Rats. Sci Rep 2018; 8:3587. [PMID: 29483616 PMCID: PMC5827664 DOI: 10.1038/s41598-018-21961-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 02/14/2018] [Indexed: 02/06/2023] Open
Abstract
Rapid regeneration of the remnant liver is critical for preventing liver failure and promoting recovery after extensive liver resection. Numerous studies have demonstrated the involvement of bone marrow-derived stem cells in liver regeneration and the potential benefits of bone marrow stem cell therapy. To avoid the preparation of stem cells, we proposed in this study to mobilize endogenous bone marrow stem cells pharmacologically with a combination of AMD3100 (A), an antagonist of CXCR4 and low-dose FK506 (F). Here we show that AF combination therapy significantly increased lineage negative (Lin-) CD34+ and Lin-CD133+ stem cells in peripheral blood and enhanced recruitment of CD133+ cells into the remnant liver in a rat model of 85% partial hepatectomy. Recruiting CD133+ stem cells in the remnant liver was associated with increased proliferation of hepatic oval cells and paralleled the increased SDF-1, CXCR4 and HGF expression. Importantly, AF combination therapy increased the number of Ki67 positive hepatocytes and BrdU incorporation in the remnant liver and improved serum levels of albumin. Our results demonstrate that pharmacological mobilization of endogenous bone marrow stem cells with AF combination therapy can enhance endogenous stem cell mobilization to promote liver regeneration and improve liver function after extensive hepatectomy.
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Affiliation(s)
- Rujun Zhai
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute & Hospital and Tianjin Medical University Graduate School, Tianjin, P.R. China.,Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yongchun Wang
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Le Qi
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Bin Gao
- Laboratory of Liver Disease, NIAAA/NIH, Rockville, MD, USA
| | - Guang Song
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - James F Burdick
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Zhaoli Sun
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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37
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Bone marrow-derived cells and their conditioned medium induce microvascular repair in uremic rats by stimulation of endogenous repair mechanisms. Sci Rep 2017; 7:9444. [PMID: 28842629 PMCID: PMC5572734 DOI: 10.1038/s41598-017-09883-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 08/01/2017] [Indexed: 01/11/2023] Open
Abstract
The reduced number of circulating stem/progenitor cells that is found in chronic kidney disease (CKD) patients may contribute to impaired angiogenic repair and decreased capillary density in the heart. Cell therapy with bone marrow-derived cells (BMDCs) has been shown to induce positive effects on the microvasculature and cardiac function, most likely due to secretion of growth factors and cytokines, all of which are present in the conditioned medium (CM); however, this is controversial. Here we showed that treatment with BMDC or CM restored vascular density and decreased the extent of fibrosis in a rat model of CKD, the 5/6 nephrectomy. Engraftment and differentiation of exogenous BMDCs could not be detected. Yet CM led to the mobilization and infiltration of endogenous circulating cells into the heart. Cell recruitment was facilitated by the local expression of pro-inflammatory factors such as the macrophage chemoattractant protein-1, interleukin-6, and endothelial adhesion molecules. Consistently, in vitro assays showed that CM increased endothelial adhesiveness to circulating cells by upregulating the expression of adhesion molecules, and stimulated angiogenesis/endothelial tube formation. Overall, our results suggest that both treatments exert vasculoprotective effects on the heart of uremic rats by stimulating endogenous repair mechanisms.
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38
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Zhou P, Tan YZ, Wang HJ, Wang GD. Hypoxic preconditioning-induced autophagy enhances survival of engrafted endothelial progenitor cells in ischaemic limb. J Cell Mol Med 2017; 21:2452-2464. [PMID: 28374977 PMCID: PMC5618704 DOI: 10.1111/jcmm.13167] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 02/17/2017] [Indexed: 01/08/2023] Open
Abstract
Recent clinical studies have suggested that endothelial progenitor cells (EPCs) transplantation provides a modest benefit for treatment of the ischaemic diseases such as limb ischaemia. However, cell‐based therapies have been limited by poor survival of the engrafted cells. This investigation was designed to establish optimal hypoxia preconditioning and evaluate effects of hypoxic preconditioning‐induced autophagy on survival of the engrafted EPCs. Autophagy of CD34+VEGFR‐2+EPCs isolated from rat bone marrow increased after treatment with 1% O2. The number of the apoptotic cells in the hypoxic cells increased significantly after autophagy was inhibited with 3‐methyladenine. According to balance of autophagy and apoptosis, treatment with 1% O2 for 2 hrs was determined as optimal preconditioning for EPC transplantation. To examine survival of the hypoxic cells, the cells were implanted into the ischaemic pouch of the abdominal wall in rats. The number of the survived cells was greater in the hypoxic group. After the cells loaded with fibrin were transplanted with intramuscular injection, blood perfusion, arteriogenesis and angiogenesis in the ischaemic hindlimb were analysed with laser Doppler‐based perfusion measurement, angiogram and the density of the microvessels in histological sections, respectively. Repair of the ischaemic tissue was improved significantly in the hypoxic preconditioning group. Loading the cells with fibrin has cytoprotective effect on survival of the engrafted cells. These results suggest that activation of autophagy with hypoxic preconditioning is an optimizing strategy for EPC therapy of limb ischaemia.
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Affiliation(s)
- Pei Zhou
- Department of Anatomy, Histology and Embryology, Shanghai Medical School of Fudan University, Shanghai, China
| | - Yu-Zhen Tan
- Department of Anatomy, Histology and Embryology, Shanghai Medical School of Fudan University, Shanghai, China
| | - Hai-Jie Wang
- Department of Anatomy, Histology and Embryology, Shanghai Medical School of Fudan University, Shanghai, China
| | - Guo-Dong Wang
- Department of Anatomy, Histology and Embryology, Shanghai Medical School of Fudan University, Shanghai, China
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39
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Therapeutic Potential of Hematopoietic Stem Cell-Derived Exosomes in Cardiovascular Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 998:221-235. [DOI: 10.1007/978-981-10-4397-0_15] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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40
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Foster BP, Balassa T, Benen TD, Dominovic M, Elmadjian GK, Florova V, Fransolet MD, Kestlerova A, Kmiecik G, Kostadinova IA, Kyvelidou C, Meggyes M, Mincheva MN, Moro L, Pastuschek J, Spoldi V, Wandernoth P, Weber M, Toth B, Markert UR. Extracellular vesicles in blood, milk and body fluids of the female and male urogenital tract and with special regard to reproduction. Crit Rev Clin Lab Sci 2016; 53:379-95. [PMID: 27191915 DOI: 10.1080/10408363.2016.1190682] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Extracellular vesicles (EVs) are released from almost all cells and tissues. They are able to transport substances (e.g. proteins, RNA or DNA) at higher concentrations than in their environment and may adhere in a receptor-controlled manner to specific cells or tissues in order to release their content into the respective target structure. Blood contains high concentrations of EVs mainly derived from platelets, and, at a smaller amount, from erythrocytes. The female and male reproductive tracts produce EVs which may be associated with fertility or infertility and are released into body fluids and mucosas of the urogenital organs. In this review, the currently relevant detection methods are presented and critically compared. During pregnancy, placenta-derived EVs are dynamically detectable in peripheral blood with changing profiles depending upon progress of pregnancy and different pregnancy-associated pathologies, such as preeclampsia. EVs offer novel non-invasive diagnostic tools which may reflect the situation of the placenta and the foetus. EVs in urine have the potential of reflecting urogenital diseases including cancers of the neighbouring organs. Several methods for detection, quantification and phenotyping of EVs have been established, which include electron microscopy, flow cytometry, ELISA-like methods, Western blotting and analyses based on Brownian motion. This review article summarises the current knowledge about EVs in blood and cord blood, in the different compartments of the male and female reproductive tracts, in trophoblast cells from normal and pre-eclamptic pregnancies, in placenta ex vivo perfusate, in the amniotic fluid, and in breast milk, as well as their potential effects on natural killer cells as possible targets.
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Affiliation(s)
- B P Foster
- a Maternal and Fetal Health Research Centre, School of Biomedicine, University of Manchester, and Manchester Academic Health Sciences Centre, University Research , Manchester , UK
| | - T Balassa
- b Department of Medical Microbiology and Immunology , Medical School, University of Pécs , Pécs , Hungary
| | - T D Benen
- c Microtrac GmbH , Krefeld , Germany
| | - M Dominovic
- d Department of Physiology and Immunology , Medical Faculty, University of Rijeka , Rijeka , Croatia
| | - G K Elmadjian
- e Repro Inova Immunology Laboratory , Sofia , Bulgaria
| | - V Florova
- f Department of Obstetrics , Gynecology and Perinatology, First Moscow State Medical University , Moscow , Russia
| | - M D Fransolet
- g Laboratory of Tumor and Development Biology , GIGA-R, University of Liège , Liège , Belgium
| | - A Kestlerova
- h Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine , Charles University Prague , Czech Republic
- i Institute of Biophysics and Informatics, First Faculty of Medicine, Charles University , Prague , Czech Republic
| | - G Kmiecik
- j Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero , Brescia , Italy
| | - I A Kostadinova
- k Department of Immunoneuroendocrinology , Institute of Biology and Immunology of Reproduction , Sofia , Bulgaria
| | - C Kyvelidou
- l Department of Biology , University of Crete , Crete , Greece
| | - M Meggyes
- b Department of Medical Microbiology and Immunology , Medical School, University of Pécs , Pécs , Hungary
| | - M N Mincheva
- m Repro Inova Immunology Laboratory , Sofia , Bulgaria
| | - L Moro
- n ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clínic- Universitat de Barcelona , Barcelona , Spain
- o Department of Obstetrics , Placenta-Lab, University Hospital Jena , Jena , Germany
| | - J Pastuschek
- o Department of Obstetrics , Placenta-Lab, University Hospital Jena , Jena , Germany
| | - V Spoldi
- j Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero , Brescia , Italy
| | - P Wandernoth
- p Institute of Anatomy, University Hospital, University Duisburg-Essen , Essen , Germany
| | - M Weber
- o Department of Obstetrics , Placenta-Lab, University Hospital Jena , Jena , Germany
| | - B Toth
- q Department of Gynecological Endocrinology and Fertility Disorders , Ruprecht-Karls University of Heidelberg , Heidelberg , Germany
| | - U R Markert
- o Department of Obstetrics , Placenta-Lab, University Hospital Jena , Jena , Germany
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Wojakowski W, Jadczyk T, Michalewska-Włudarczyk A, Parma Z, Markiewicz M, Rychlik W, Kostkiewicz M, Gruszczyńska K, Błach A, Dzier Zak-Mietła M, Wańha W, Ciosek J, Ochała B, Rzeszutko Ł, Cybulski W, Partyka Ł, Zasada W, Włudarczyk W, Dworowy S, Kuczmik W, Smolka G, Pawłowski T, Ochała A, Tendera M. Effects of Transendocardial Delivery of Bone Marrow-Derived CD133 + Cells on Left Ventricle Perfusion and Function in Patients With Refractory Angina: Final Results of Randomized, Double-Blinded, Placebo-Controlled REGENT-VSEL Trial. Circ Res 2016; 120:670-680. [PMID: 27903568 DOI: 10.1161/circresaha.116.309009] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 11/20/2016] [Accepted: 11/30/2016] [Indexed: 01/13/2023]
Abstract
RATIONALE New therapies for refractory angina are needed. OBJECTIVE Assessment of transendocardial delivery of bone marrow CD133+ cells in patients with refractory angina. METHODS AND RESULTS Randomized, double-blinded, placebo-controlled trial enrolled 31 patients with recurrent Canadian Cardiovascular Society II-IV angina, despite optimal medical therapy, ≥1 myocardial segment with inducible ischemia in Tc-99m SPECT who underwent bone marrow biopsy and were allocated to cells (n=16) or placebo (n=15). Primary end point was absolute change in myocardial ischemia by SPECT. Secondary end points were left ventricular function and volumes by magnetic resonance imaging and angina severity. After 4 months, there were no significant differences in extent of inducible ischemia between groups (summed difference score mean [±SD]: 2.60 [2.6] versus 3.63 [3.6], P=0.52; total perfusion deficit: 3.60 [3.6] versus 5.01 [4.3], P=0.32; absolute changes of summed difference score: -1.38 [5.2] versus -0.73 [1.9], P=0.65; and total perfusion deficit: -1.33 [3.3] versus -2.19 [6.6], P=0.65). There was a significant reduction of left ventricular volumes (end-systolic volume: -4.3 [11.3] versus 7.4 [11.8], P=0.02; end-diastolic volume: -9.1 [14.9] versus 7.4 [15.8], P=0.02) and no significant change of left ventricular ejection fraction in the cell group. There was no difference in number of patients showing improvement of ≥1 Canadian Cardiovascular Society class after 1 (41.7% versus 58.3%; P=0.68), 4 (50% versus 33.3%; P=0.63), 6 (70% versus 50.0%; P=0.42), and 12 months (55.6% versus 81.8%; P=0.33) and use of nitrates after 12 months. CONCLUSION Transendocardial CD133+ cell therapy was safe. Study was underpowered to conclusively validate the efficacy, but it did not show a significant reduction of myocardial ischemia and angina versus placebo. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01660581.
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Affiliation(s)
- Wojciech Wojakowski
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.).
| | - Tomasz Jadczyk
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Aleksandra Michalewska-Włudarczyk
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Zofia Parma
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Mirosław Markiewicz
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Wojciech Rychlik
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Magdalena Kostkiewicz
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Katarzyna Gruszczyńska
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Anna Błach
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Monika Dzier Zak-Mietła
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Wojciech Wańha
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Joanna Ciosek
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Beata Ochała
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Łukasz Rzeszutko
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Wiesław Cybulski
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Łukasz Partyka
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Wojciech Zasada
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Witold Włudarczyk
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Sebastian Dworowy
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Wacław Kuczmik
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Grzegorz Smolka
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Tomasz Pawłowski
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Andrzej Ochała
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
| | - Michał Tendera
- From the Third Division of Cardiology (W.W., T.J., A.M.-W., Z.P., W.R., A.B., W.W., J.C., B.O., W.C., W.W., S.D., G.S., T.P., A.O., M.T.), Department of Hematology and Bone Marrow Transplantation (M.M., M.D.-M.), and Division of Diagnostic Imaging (K.G.), Medical University of Silesia, Katowice, Poland; Department of Nuclear Medicine Hospital John Paul II, Kraków, Poland (M.K.); 2nd Department of Cardiology and Cardiovascular Interventions (Ł.R., W.Z.) and Department of Angiology (Ł.P.), University Hospital, Krakow, Poland; Krakow Cardiovascular Research Institute, Kraków, Poland (Ł.P., W.Z.); and Department of Vascular Surgery, Medical University of Silesia, Katowice, Poland (W.K.)
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Marlicz W, Sielatycka K, Serwin K, Kubis E, Tkacz M, Głuszko R, Białek A, Starzyńska T, Ratajczak MZ. Effect of colorectal cancer on the number of normal stem cells circulating in peripheral blood. Oncol Rep 2016; 36:3635-3642. [DOI: 10.3892/or.2016.5179] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Accepted: 06/11/2016] [Indexed: 11/05/2022] Open
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Bhatnagar A, Bolli R, Johnstone BH, Traverse JH, Henry TD, Pepine CJ, Willerson JT, Perin EC, Ellis SG, Zhao DXM, Yang PC, Cooke JP, Schutt RC, Trachtenberg BH, Orozco A, Resende M, Ebert RF, Sayre SL, Simari RD, Moyé L, Cogle CR, Taylor DA. Bone marrow cell characteristics associated with patient profile and cardiac performance outcomes in the LateTIME-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Am Heart J 2016; 179:142-50. [PMID: 27595689 PMCID: PMC5014395 DOI: 10.1016/j.ahj.2016.06.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 06/25/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND Although several preclinical studies have shown that bone marrow cell (BMC) transplantation promotes cardiac recovery after myocardial infarction, clinical trials with unfractionated bone marrow have shown variable improvements in cardiac function. METHODS To determine whether in a population of post-myocardial infarction patients, functional recovery after BM transplant is associated with specific BMC subpopulation, we examined the association between BMCs with left ventricular (LV) function in the LateTIME-CCTRN trial. RESULTS In this population, we found that older individuals had higher numbers of BM CD133(+) and CD3(+) cells. Bone marrow from individuals with high body mass index had lower CD45(dim)/CD11b(dim) levels, whereas those with hypertension and higher C-reactive protein levels had higher numbers of CD133(+) cells. Smoking was associated with higher levels of CD133(+)/CD34(+)/VEGFR2(+) cells and lower levels of CD3(+) cells. Adjusted multivariate analysis indicated that CD11b(dim) cells were negatively associated with changes in LV ejection fraction and wall motion in both the infarct and border zones. Change in LV ejection fraction was positively associated with CD133(+), CD34(+), and CD45(+)/CXCR4(dim) cells as well as faster BMC growth rates in endothelial colony forming assays. CONCLUSIONS In the LateTIME population, BM composition varied with patient characteristics and treatment. Irrespective of cell therapy, recovery of LV function was greater in patients with greater BM abundance of CD133(+) and CD34(+) cells and worse in those with higher levels of CD11b(dim) cells. Bone marrow phenotype might predict clinical response before BMC therapy and administration of selected BM constituents could potentially improve outcomes of other future clinical trials.
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Affiliation(s)
| | | | | | - Jay H Traverse
- Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, Minneapolis, MN
| | | | - Carl J Pepine
- University of Florida College of Medicine, Gainesville, FL
| | - James T Willerson
- Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston, TX
| | - Emerson C Perin
- Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston, TX
| | | | | | | | - John P Cooke
- Houston Methodist DeBakey Heart & Vascular Center, Houston, TX
| | - Robert C Schutt
- Houston Methodist DeBakey Heart & Vascular Center, Houston, TX
| | | | - Aaron Orozco
- Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston, TX
| | - Micheline Resende
- Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston, TX
| | - Ray F Ebert
- National Heart, Lung, and Blood Institute, Bethesda, MD
| | - Shelly L Sayre
- University of Texas School of Public Health, Houston, TX
| | | | - Lem Moyé
- University of Texas School of Public Health, Houston, TX.
| | | | - Doris A Taylor
- Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston, TX
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Kidani Y, Miki Y, Nomimura N, Minakawa S, Tanaka N, Miyoshi H, Wakabayashi K, Kudo Y. The therapeutic effect of CD133+ cells derived from human umbilical cord blood on neonatal mouse hypoxic-ischemic encephalopathy model. Life Sci 2016; 157:108-115. [DOI: 10.1016/j.lfs.2016.06.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 05/26/2016] [Accepted: 06/04/2016] [Indexed: 12/22/2022]
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Marycz K, Pazik R, Zawisza K, Wiglusz K, Maredziak M, Sobierajska P, Wiglusz RJ. Multifunctional nanocrystalline calcium phosphates loaded with Tetracycline antibiotic combined with human adipose derived mesenchymal stromal stem cells (hASCs). MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2016; 69:17-26. [PMID: 27612684 DOI: 10.1016/j.msec.2016.06.051] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 05/18/2016] [Accepted: 06/13/2016] [Indexed: 01/02/2023]
Abstract
Osteoconductive drug delivery system composed of nanocrystalline calcium phosphates (Ca10(PO4)6(OH)2/β-Ca3(PO4)2) co-doped with Yb(3+)/Er(3+) ions loaded with Tetracycline antibiotic (TC) was developed. Their effect on human adipose derived mesenchymal stromal stem cells (hASCs) as a potential reconstructive biomaterial for bone tissue regeneration was studied. The XRD and TEM measurements were used in order to determine the crystal structure and morphology of the final products. The characteristics of nanocomposites with the TC and hASCs as potential regenerative materials as well as the antimicrobial activity of the nanoparticles against: Staphylococcus aureus ATCC 25923 as a model of the Gram-positive bacteria, Escherichia coli ATCC 8739 of the Gram-negative bacteria, were shown. These combinations can be a promising material for theranostic due to its regenerative, antimicrobial and fluorescent properties.
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Affiliation(s)
- K Marycz
- Wroclaw University of Environmental and Life Sciences, Faculty of Biology, Kozuchowska 5b, 50-631 Wroclaw, Poland; Wroclaw Research Centre EIT+, Stablowicka 147, 54-066 Wroclaw, Poland
| | - R Pazik
- Institute of Low Temperature and Structure Research, Polish Academy of Sciences, Okolna 2, 50-422 Wroclaw, Poland
| | - K Zawisza
- Institute of Low Temperature and Structure Research, Polish Academy of Sciences, Okolna 2, 50-422 Wroclaw, Poland
| | - K Wiglusz
- Wroclaw Medical University, Faculty of Pharmacy, Borowska 211 A, 50-566 Wroclaw, Poland
| | - M Maredziak
- Wroclaw University of Environmental and Life Sciences, Faculty of Veterinary Medicine, Norwida 31, 50-375 Wroclaw, Poland
| | - P Sobierajska
- Institute of Low Temperature and Structure Research, Polish Academy of Sciences, Okolna 2, 50-422 Wroclaw, Poland
| | - R J Wiglusz
- Institute of Low Temperature and Structure Research, Polish Academy of Sciences, Okolna 2, 50-422 Wroclaw, Poland.
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Ratajczak MZ, Ratajczak J. Horizontal transfer of RNA and proteins between cells by extracellular microvesicles: 14 years later. Clin Transl Med 2016; 5:7. [PMID: 26943717 PMCID: PMC4779088 DOI: 10.1186/s40169-016-0087-4] [Citation(s) in RCA: 109] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 02/19/2016] [Indexed: 02/07/2023] Open
Abstract
Extracellular microvesicles (ExMVs) are part of the cell secretome, and evidence has accumulated for their involvement in several biological processes. Fourteen years ago our team demonstrated for the first time that ExMVs carry functional RNA species and proteins from one cell to another, an observation that opened up the new research field of horizontal transfer of bioactive molecules in cell-to-cell communication. Moreover, the presence of mRNA, noncoding RNA, and miRNA in ExMVs in blood and other biological fluids opened up the possibility of employing ExMVs as new detection markers for pathological processes, and ExMVs became a target for "liquid biopsy" approaches. While ExMV-derived mRNAs may be translated in target cells into appropriate proteins, miRNAs regulate expression of corresponding mRNA species, and both RNA-depended ExMV-mediated mechanisms lead to functional changes in the target cells. Following from this observation, several excellent papers have been published that confirm the existence of the horizontal transfer of RNA. Moreover, in addition to RNA, proteins, bioactive lipids, infectious particles and intact organelles such as mitochondria may follow a similar mechanism. In this review we will summarize the impressive progress in this field-14 years after initial report.
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Affiliation(s)
- Mariusz Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA.
| | - Janina Ratajczak
- Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland.
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Kanayasu-Toyoda T, Tanaka T, Kikuchi Y, Uchida E, Matsuyama A, Yamaguchi T. Cell-Surface MMP-9 Protein Is a Novel Functional Marker to Identify and Separate Proangiogenic Cells from Early Endothelial Progenitor Cells Derived from CD133(+) Cells. Stem Cells 2016; 34:1251-62. [PMID: 26824798 DOI: 10.1002/stem.2300] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 12/15/2015] [Indexed: 01/14/2023]
Abstract
To develop cell therapies for ischemic diseases, endothelial progenitor cells (EPCs) have been expected to play a pivotal role in vascular regeneration. It is desirable to use a molecular marker that is related to the function of the cells. Here, a quantitative polymerase chain reaction array revealed that early EPCs derived from CD133(+) cells exhibited significant expression of MMP-9. Some populations of early EPCs expressed MMP-9 on the cell surface and others did not. We also attempted to separate the proangiogenic fraction from early EPCs derived from CD133(+) cells using a functional cell surface marker, and we then analyzed the MMP-9(+) and MMP-9(-) cell fractions. The MMP-9(+) cells not only revealed higher invasion ability but also produced a high amount of IL-8. Moreover, the stimulative effect of MMP-9(+) cells on angiogenesis in vitro and in vivo was prohibited by anti-IL-8 antibody. These data indicate that MMP-9 is one of the useful cell surface markers for the separation of angiogenic cells. Our treatment of early EPCs with hyaluronidase caused not only a downregulation of cell-surface MMP-9 but also a decrease in invasion ability, indicating that membrane-bound MMP-9, which is one of the useful markers for early EPCs, plays an important role in angiogenesis. Stem Cells 2016;34:1251-1262.
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Affiliation(s)
- Toshie Kanayasu-Toyoda
- Department of Pharmacology, Nihon Pharmaceutical University, Inamachi, Saitama, Japan.,Division of Microbiology, National Institute of Health Sciences, Tokyo, Japan
| | - Takeshi Tanaka
- Department of Pharmacology, Nihon Pharmaceutical University, Inamachi, Saitama, Japan
| | - Yutaka Kikuchi
- Division of Microbiology, National Institute of Health Sciences, Tokyo, Japan
| | - Eriko Uchida
- Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Tokyo, Japan
| | - Akifumi Matsuyama
- National Institute of Biomedical Innovation, Ibaraki-City, Osaka, Japan
| | - Teruhide Yamaguchi
- Department of Pharmacology, Nihon Pharmaceutical University, Inamachi, Saitama, Japan.,Division of Microbiology, National Institute of Health Sciences, Tokyo, Japan
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Marycz K, Krzak J, Marędziak M, Tomaszewski KA, Szczurek A, Moszak K. The influence of metal-based biomaterials functionalized with sphingosine-1-phosphate on the cellular response and osteogenic differentaion potenial of human adipose derived mesenchymal stem cells in vitro. J Biomater Appl 2016; 30:1517-33. [DOI: 10.1177/0885328216628711] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
In this study, stable, homogenous and thin titania dioxide coatings (TiO2) on stainless steel substrate doped with two dosages of bioactive sphingolipids S1P were fabricated using the sol-gel method. S1P belongs to a family of sphingolipids acting as important extracellular signaling molecules and chemoattractants. This study investigated the effect of TiO2, doped with S1P in two different dosages on cellular response as well as osteogenic differentiation potential of human adipose derived multipotent stromal stem cells (hASC). The authors have shown that S1P mediates hASCs morphology, proliferation activity and population doubling time in a dose-dependent manner. They have also demonstrated that functionalization of TiO2 coating with a higher dosage of S1P, i.e. 80 ng/ml [(TiO2/S1P(CII)] activated both S1PR type 1 and type 2 on mRNA level. The results indicated an increase in secretion of BMP-2, Osteopontin and Osteocalcin by osteoblasts progenitor when cultured on [TiO2/S1P(CIIm)]. In addition, the authors observed the highest extracellular matrix mineralization as well as osteonodules formation by the osteoblasts precursors when cultured onto [TiO2/S1P(CIIm)].
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Affiliation(s)
- Krzysztof Marycz
- Department of Biology, University of Environmental and Life Sciences, Wroclaw, Poland
- Wrocławskie Centrum Badan EIT +, Wroclaw, Poland
| | - Justyna Krzak
- Department of Mechanics, Materials Science and Engineering, University of Technology,Wroclaw, Poland
| | - Monika Marędziak
- Faculty of Veterinary Medicine, Department of Animal Physiology and Biostructure University of Environmental and Life Sciences, Wrocław, Poland
| | | | - Anna Szczurek
- Department of Mechanics, Materials Science and Engineering, University of Technology,Wroclaw, Poland
| | - Karolina Moszak
- Faculty of Fundamental Problems of Technology, University of Technology, Wroclaw, Poland
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Ratajczak MZ, Ratajczak D, Pedziwiatr D. Extracellular Microvesicles (ExMVs) in Cell to Cell Communication: A Role of Telocytes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 913:41-49. [PMID: 27796879 DOI: 10.1007/978-981-10-1061-3_3] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
There are several mechanisms by which cells communicate with each other. Evidence accumulates that the evolutionary oldest mechanisms of cell-cell communication involves extracellular microvesicles (ExMVs). Generally, these circular membrane fragments enriched for mRNA, miRNA, proteins, and bioactive lipids are released by exocytosis from endosomal compartment or are directly formed by budding from cell surface membranes. ExMVs from endosomal compartment called exosomes are smaller in size ~100 nM as compared to larger ones released from cell membranes that are in size up to 1 μM. In this chapter we will present an emerging link between ExMVs and recently identified novel cell-cell communication network involving a new type of cell known as telocyte. Mounting evidence accumulates that telocytes mediate several of their biological effects in several organs by releasing ExMVs enriched in mRNA, miRNA, proteins, and several biological mediators to the target cells.
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Affiliation(s)
- Mariusz Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA.
| | - Daniel Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA
| | - Daniel Pedziwiatr
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA
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Mohamadnejad M, Vosough M, Moossavi S, Nikfam S, Mardpour S, Akhlaghpoor S, Ashrafi M, Azimian V, Jarughi N, Hosseini SE, Moeininia F, Bagheri M, Sharafkhah M, Aghdami N, Malekzadeh R, Baharvand H. Intraportal Infusion of Bone Marrow Mononuclear or CD133+ Cells in Patients With Decompensated Cirrhosis: A Double-Blind Randomized Controlled Trial. Stem Cells Transl Med 2016; 5:87-94. [PMID: 26659833 PMCID: PMC4704869 DOI: 10.5966/sctm.2015-0004] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 09/23/2015] [Indexed: 02/07/2023] Open
Abstract
UNLABELLED The present study assessed the effects of intraportal infusions of autologous bone marrow-derived mononuclear cells (MNCs) and/or CD133+ cells on liver function in patients with decompensated cirrhosis. We randomly assigned 27 eligible patients to a placebo, MNCs, and/or CD133+ cells. Cell infusions were performed at baseline and month 3. We considered the absolute changes in the Model for End-Stage Liver Disease (MELD) scores at months 3 and 6 after infusion as the primary outcome. The participants and those who assessed the outcomes were unaware of the treatment intervention assignments. After 6 months, 9 patients were excluded because of liver transplantation (n=3), hepatocellular carcinoma (n=1), loss to follow-up (n=3), and death (n=2). The final analysis included 4 patients from the CD133+ group, 8 from the MNC group, and 6 from the placebo group. No improvement was seen in the MELD score at month 6 using either CD133+ cells or MNC infusions compared with placebo. However, at month 3 after infusion, a trend was seen toward a higher mean absolute change in the MELD score in patients who had received CD133+ cells compared with placebo (-2.00±1.87 vs. -0.13±1.46; p=.08). No significant adverse events occurred in the present study. A transient improvement in the MELD score was observed in subjects treated with CD133+ cells but not in the MNC or placebo group. Although the study was not powered to make definitive conclusions, the data justify further study of CD133+ therapy in cirrhotic patients. SIGNIFICANCE Cell therapy is a new approach in liver disease. Several clinical experiments have been reported on the safety of bone marrow-derived stem cells to treat liver disorders. However, the effectiveness of these approaches in the long-term follow-ups of patients initiated controversial discussions among the scientific community. A double-blind randomized controlled trial was designed to address this concern scientifically. A transient improvement in the patients' signs occurred; however, for a sustainable result, more work is needed. The results of multiple administrations of cells reported in the present study can be compared with the results from other single-injection studies.
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Affiliation(s)
- Mehdi Mohamadnejad
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran Digestive Diseases Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran, Iran
| | - Shirin Moossavi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran Digestive Diseases Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Nikfam
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran Digestive Diseases Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Soura Mardpour
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran, Iran
| | | | - Mandana Ashrafi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran Digestive Diseases Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Vajiheh Azimian
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran, Iran
| | - Neda Jarughi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran, Iran
| | - Seyedeh-Esmat Hosseini
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran, Iran
| | - Fatemeh Moeininia
- Department of Internal Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mohamad Bagheri
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran Digestive Diseases Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Sharafkhah
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran Digestive Diseases Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasser Aghdami
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran, Iran
| | - Reza Malekzadeh
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran Digestive Diseases Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Baharvand
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran, Iran
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