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1
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Durlak W, Thébaud B. The vascular phenotype of BPD: new basic science insights-new precision medicine approaches. Pediatr Res 2024; 96:1162-1171. [PMID: 36550351 DOI: 10.1038/s41390-022-02428-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 10/27/2022] [Accepted: 11/23/2022] [Indexed: 12/24/2022]
Abstract
Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth. Up to 1/3 of children with BPD develop pulmonary hypertension (PH). PH increases mortality, the risk of adverse neurodevelopmental outcome and lacks effective treatment. Current vasodilator therapies address symptoms, but not the underlying arrested vascular development. Recent insights into placental biology and novel technological advances enabling the study of normal and impaired lung development at the single cell level support the concept of a vascular phenotype of BPD. Dysregulation of growth factor pathways results in depletion and dysfunction of putative distal pulmonary endothelial progenitor cells including Cap1, Cap2, and endothelial colony-forming cells (ECFCs), a subset of vascular progenitor cells with self-renewal and de novo angiogenic capacity. Preclinical data demonstrate effectiveness of ECFCs and ECFC-derived particles including extracellular vesicles (EVs) in promoting lung vascular growth and reversing PH, but the mechanism is unknown. The lack of engraftment suggests a paracrine mode of action mediated by EVs that contain miRNA. Aberrant miRNA signaling contributes to arrested pulmonary vascular development, hence using EV- and miRNA-based therapies is a promising strategy to prevent the development of BPD-PH. More needs to be learned about disrupted pathways, timing of intervention, and mode of delivery. IMPACT: Single-cell RNA sequencing studies provide new in-depth view of developmental endothelial depletion underlying BPD-PH. Aberrant miRNA expression is a major cause of arrested pulmonary development. EV- and miRNA-based therapies are very promising therapeutic strategies to improve prognosis in BPD-PH.
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Affiliation(s)
- Wojciech Durlak
- Regenerative Medicine Program, The Ottawa Hospital Research Institute (OHRI), Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Jagiellonian University Medical College, Krakow, Poland
| | - Bernard Thébaud
- Regenerative Medicine Program, The Ottawa Hospital Research Institute (OHRI), Ottawa, ON, Canada.
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
- Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO) and CHEO Research Institute, Ottawa, ON, Canada.
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2
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Zhu D, Barabadi M, McDonald C, Kusuma G, Inocencio IM, Lim R. Implications of maternal-fetal health on perinatal stem cell banking. Gene Ther 2024; 31:65-73. [PMID: 37880336 PMCID: PMC10940157 DOI: 10.1038/s41434-023-00426-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 08/21/2023] [Accepted: 10/09/2023] [Indexed: 10/27/2023]
Abstract
Cell based therapies are being assessed for their therapeutic potential across a variety of diseases. Gestational tissues are attractive sources for cell therapy. The large number of births worldwide ensures sufficient access to gestational tissues, however, limited information has been reported around the impact of birth trends, delivery methods and pregnancy conditions on perinatal stem cell banking. This review describes the current state of banking of gestational tissues and their derived perinatal stem cells, discusses why the changes in birth trends and delivery methods could affect gestational tissue banking practices, and further explores how common pregnancy complications can potentially influence perinatal stem cell banking.
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Affiliation(s)
- Dandan Zhu
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Monash, VIC, Australia
| | - Mehri Barabadi
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.
- Department of Obstetrics and Gynaecology, Monash University, Monash, VIC, Australia.
| | - Courtney McDonald
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Monash, VIC, Australia
| | - Gina Kusuma
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Monash, VIC, Australia
| | - Ishmael Miguel Inocencio
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Monash, VIC, Australia
| | - Rebecca Lim
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Monash, VIC, Australia
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3
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Jing Jia, Ma B, Zhao X. Fetal endothelial colony-forming cells: Possible targets for prevention of the fetal origins of adult diseases. Placenta 2024; 145:80-88. [PMID: 38100962 DOI: 10.1016/j.placenta.2023.12.006] [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: 08/10/2023] [Revised: 11/20/2023] [Accepted: 12/06/2023] [Indexed: 12/17/2023]
Abstract
Endothelial colony-forming cells (ECFCs), a subset of circulating and resident endothelial progenitor cells, are capable of self-renewal and de novo vessel formation, and are known key regulators of vascular integrity and homeostasis. Numerous studies have found that exposure to hostile environment during the fetal development exerts a profound influence on the level and function of ECFCs, which may be the underlying factor linking endothelial dysfunction to cardiovascular disease of the offspring in later life. Herein, we focus on the latest findings regarding the effects of pregnancy-related disorders on the frequency and function of fetal ECFCs. Subsequently, we discuss about placental ECFCs and put forward some details that should be paid attention to in the process of ECFC isolation and culture. Overall, the information presented in this review highlight the potential of ECFCs as a future biomarker or even therapeutic targets for the pregnancy-related adverse maternal and fetal outcomes.
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Affiliation(s)
- Jing Jia
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Baitao Ma
- Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xianlan Zhao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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4
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Chen Y, Wan G, Li Z, Liu X, Zhao Y, Zou L, Liu W. Endothelial progenitor cells in pregnancy-related diseases. Clin Sci (Lond) 2023; 137:1699-1719. [PMID: 37986615 PMCID: PMC10665129 DOI: 10.1042/cs20230853] [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: 08/01/2023] [Revised: 10/09/2023] [Accepted: 10/31/2023] [Indexed: 11/22/2023]
Abstract
Placental neovascularization plays a crucial role in fetomaternal circulation throughout pregnancy and is dysregulated in several pregnancy-related diseases, including preeclampsia, gestational diabetes mellitus, and fetal growth restriction. Endothelial progenitor cells (EPCs) are a heterogeneous population of cells that differentiate into mature endothelial cells, which influence vascular homeostasis, neovascularization, and endothelial repair. Since their discovery in 1997 by Asahara et al., the role of EPCs in vascular biology has garnered a lot of interest. However, although pregnancy-related conditions are associated with changes in the number and function of EPCs, the reported findings are conflicting. This review discusses the discovery, isolation, and classification of EPCs and highlights discrepancies between current studies. Overviews of how various diseases affect the numbers and functions of EPCs, the role of EPCs as biomarkers of pregnancy disorders, and the potential therapeutic applications involving EPCs are also provided.
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Affiliation(s)
- Yangyang Chen
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Gui Wan
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Zeyun Li
- The First Clinical School of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaoxia Liu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yin Zhao
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Li Zou
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Weifang Liu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Singh A, Jaiswar SP, Priyadarshini A, Deo S. Reduced Endothelial Progenitor Cells: A Possible Biomarker for Idiopathic Fetal Growth Restriction in Human Pregnancies. JOURNAL OF MOTHER AND CHILD 2023; 27:182-189. [PMID: 37991978 PMCID: PMC10664836 DOI: 10.34763/jmotherandchild.20232701.d-23-00014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 10/06/2023] [Indexed: 11/24/2023]
Abstract
BACKGROUND Circulating endothelial progenitor cells (EPCs) may be necessary throughout pregnancy by ensuring proper placentation and embryonic growth. The lack of standardized EPC quantification techniques has prevented conclusive proof of an increase in EPC during pregnancy. OBJECTIVES The purpose of this study was to determine whether EPC levels change for healthy and idiopathic fetal growth restriction (FGR) pregnancies. MATERIALS AND METHODS The study population consisted of 48 healthy pregnant females with no previous history of IUGR (10 in the first trimester, 15 in the second, and 23 in the third), 48 women with pregnancy complicated by idiopathic FGR, and 15 non-pregnant women. By using flow cytometry, EPCs in maternal blood were recognized as CD45dim/CD34/KDR cells. ELISA was used to measure plasmatic cytokines. RESULTS We ascertained a progressive rise in EPCs in healthy pregnancies that was apparent in the first but more pronounced in the third trimester. At comparable gestational ages, FGR-complicated pregnancies had impaired EPC growth. Placental growth factor and stromal-derived factor-1 levels in the blood were significantly lower in FGR than in healthy pregnancies, which may have contributed to the degradation of the EPCs. CONCLUSION The count in EPCs might hold considerable promise toward developing a peculiar authentication marker for observing pregnancies, and could be the focus of cutting-edge tactics for the prognosis and treatment of FGR pregnancies.
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Affiliation(s)
- Apurva Singh
- Department of Obstetrics and Gynaecology, King George's Medical University, Lucknow
- Photobiology Division, CSIR-Indian Institute of Toxicology Research, Lucknow
| | - Shyam Pyari Jaiswar
- Department of Obstetrics and Gynaecology, King George's Medical University, Lucknow
| | - Apala Priyadarshini
- Department of Obstetrics and Gynaecology, King George's Medical University, Lucknow
| | - Sujata Deo
- Department of Obstetrics and Gynaecology, King George's Medical University, Lucknow
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Bell A, Watt AP, Dudink I, Pham Y, Sutherland AE, Allison BJ, McDonald CA, Castillo-Melendez M, Jenkin G, Malhotra A, Miller SL, Yawno T. Endothelial colony forming cell administration promotes neurovascular unit development in growth restricted and appropriately grown fetal lambs. Stem Cell Res Ther 2023; 14:29. [PMID: 36788590 PMCID: PMC9930266 DOI: 10.1186/s13287-023-03249-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 02/01/2023] [Indexed: 02/16/2023] Open
Abstract
BACKGROUND Fetal growth restriction (FGR) is associated with deficits in the developing brain, including neurovascular unit (NVU) dysfunction. Endothelial colony forming cells (ECFC) can mediate improved vascular stability, and have demonstrated potential to enhance vascular development and protection. This investigation examined whether ECFCs from human umbilical cord blood (UCB) enhanced NVU development in FGR and appropriate for gestational age (AGA) fetal sheep. METHODS Twin-bearing ewes had surgery performed at 88-90 days' gestation, inducing FGR in one fetus. At 113 days, ECFCs (1 × 107 cells) cultured from human UCB were administered intravenously to fetal sheep in utero. At 127 days, ewes and their fetuses were euthanised, fetal brains collected, and NVU components analysed by immunohistochemistry. RESULTS Twenty-four fetal lambs, arranged in four groups: AGA (n = 7), FGR (n = 5), AGA + ECFC (n = 6), and FGR + ECFC (n = 6), were included in analyses. FGR resulted in lower body weight than AGA (P = 0.002) with higher brain/body weight ratio (P = 0.003). ECFC treatment was associated with increased vascular density throughout the brain in both AGA + ECFC and FGR + ECFC groups, as well as increased vascular-astrocyte coverage and VEGF expression in the cortex (P = 0.003, P = 0.0006, respectively) and in the subcortical white matter (P = 0.01, P = 0.0002, respectively) when compared with the untreated groups. CONCLUSIONS ECFC administration enhanced development of NVU components in both the AGA and FGR fetal brain. Further investigation is required to assess how to optimise the enhanced angiogenic capabilities of ECFCs to provide a therapeutic strategy to protect the developing NVU against vulnerabilities associated with FGR.
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Affiliation(s)
- Alexander Bell
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
| | - Ashalyn P. Watt
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia
| | - Ingrid Dudink
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
| | - Yen Pham
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia
| | - Amy E. Sutherland
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia
| | - Beth J. Allison
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
| | - Courtney A. McDonald
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
| | | | - Graham Jenkin
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
| | - Atul Malhotra
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. .,Department of Paediatrics, Monash University, 246 Clayton Road, Clayton, Melbourne, VIC, 3168, Australia. .,Monash Newborn, Monash Children's Hospital, Melbourne, Australia.
| | - Suzanne L. Miller
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
| | - Tamara Yawno
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Paediatrics, Monash University, 246 Clayton Road, Clayton, Melbourne, VIC 3168 Australia
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7
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Abstract
Endothelial colony-forming cells (ECFCs) are progenitor cells that can give rise to colonies of highly proliferative vascular endothelial cells (ECs) with clonal expansion and in vivo blood vessel-forming potential. More than two decades ago, the identification of ECFCs in human peripheral blood created tremendous opportunities as having a clinically accessible source of autologous ECs could facilitate meaningful therapies with the potential to impact multiple vascular diseases. Nevertheless, until recently, the field of endothelial progenitor cells has been plagued with ambiguities and controversies, and reaching a consensus on the definition of ECFCs has not been straightforward. Moreover, although the basic phenotypical and functional characteristics of cultured ECFCs are now well established, some fundamental questions such as the origin of ECFCs and their physiological roles in health and disease remain incompletely understood. Here, I highlight some critical studies that have shaped our current understanding of ECFCs in humans. Insights into the biological attributes of ECFCs are essential for facilitating the clinical translation of their therapeutic potential.
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Affiliation(s)
- Juan M Melero-Martin
- Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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8
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James JL, Boss AL, Sun C, Allerkamp HH, Clark AR. From stem cells to spiral arteries: A journey through early placental development. Placenta 2021; 125:68-77. [PMID: 34819240 DOI: 10.1016/j.placenta.2021.11.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/11/2021] [Accepted: 11/14/2021] [Indexed: 12/19/2022]
Abstract
Early placental development lays the foundation of a healthy pregnancy, and numerous tightly regulated processes must occur for the placenta to meet the increasing nutrient and oxygen exchange requirements of the growing fetus later in gestation. Inadequacies in early placental development can result in disorders such as fetal growth restriction that do not present clinically until the second half of gestation. Indeed, growth restricted placentae exhibit impaired placental development and function, including reduced overall placental size, decreased branching of villi and the blood vessels within them, altered trophoblast function, and impaired uterine vascular remodelling, which together combine to reduce placental exchange capacity. This review explores the importance of early placental development across multiple anatomical aspects of placentation, from the stem cells and lineage hierarchies from which villous core cells and trophoblasts arise, through extravillous trophoblast invasion and spiral artery remodelling, and finally remodelling of the larger uterine vessels.
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Affiliation(s)
- Joanna L James
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
| | - Anna L Boss
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand
| | - Cherry Sun
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand
| | - Hanna H Allerkamp
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand; Auckland Bioengineering Institute, University of Auckland, New Zealand
| | - Alys R Clark
- Auckland Bioengineering Institute, University of Auckland, New Zealand
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9
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Developmental programming of cardiovascular function: a translational perspective. Clin Sci (Lond) 2021; 134:3023-3046. [PMID: 33231619 DOI: 10.1042/cs20191210] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/07/2020] [Accepted: 11/10/2020] [Indexed: 12/11/2022]
Abstract
The developmental origins of health and disease (DOHaD) is a concept linking pre- and early postnatal exposures to environmental influences with long-term health outcomes and susceptibility to disease. It has provided a new perspective on the etiology and evolution of chronic disease risk, and as such is a classic example of a paradigm shift. What first emerged as the 'fetal origins of disease', the evolution of the DOHaD conceptual framework is a storied one in which preclinical studies played an important role. With its potential clinical applications of DOHaD, there is increasing desire to leverage this growing body of preclinical work to improve health outcomes in populations all over the world. In this review, we provide a perspective on the values and limitations of preclinical research, and the challenges that impede its translation. The review focuses largely on the developmental programming of cardiovascular function and begins with a brief discussion on the emergence of the 'Barker hypothesis', and its subsequent evolution into the more-encompassing DOHaD framework. We then discuss some fundamental pathophysiological processes by which developmental programming may occur, and attempt to define these as 'instigator' and 'effector' mechanisms, according to their role in early adversity. We conclude with a brief discussion of some notable challenges that hinder the translation of this preclinical work.
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10
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Zhang Y, Liu X, Yang L, Zou L. Current Researches, Rationale, Plausibility, and Evidence Gaps on Metformin for the Management of Hypertensive Disorders of Pregnancy. Front Pharmacol 2020; 11:596145. [PMID: 33381040 PMCID: PMC7768035 DOI: 10.3389/fphar.2020.596145] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 10/22/2020] [Indexed: 12/16/2022] Open
Abstract
Hypertensive disorders of pregnancy (HDP) are a group of morbid pregnancy complications, with preeclampsia (PE) being the most common subclassification among them. PE affects 2%–8% of pregnancies globally and threatens maternal and fetal health seriously. However, the only effective treatment of PE to date is the timely termination of pregnancy, albeit with increased perinatal risks. Hence, more emerging therapies for PE management are in urgent need. Originally introduced as the first-line therapy for type 2 diabetes mellitus, metformin (MET) has now been found in clinical trials to significantly reduce the incidence of gestational hypertension and PE in pregnant women with PE-related risks, including but not limited to pregestational diabetes mellitus, gestational diabetes mellitus, polycystic ovary syndrome, or obesity. Additionally, existing clinical data have preliminarily ensured the safety of taking MET during human pregnancies. Relevant lab studies have indicated that the underlying mechanism includes angiogenesis promotion, endothelial protection, anti-inflammatory effects, and particularly protective effects on trophoblast cells against the risk factors, which are beneficial to placental development. Together with its global availability, easy administration, and low cost, MET is expected to be a promising option for the prevention and treatment of PE. Nevertheless, there are still some limitations in current studies, and the design of the relevant research scheme is supposed to be further improved in the future. Herein, we summarize the relevant clinical and experimental researches to discuss the rationale, safety, and feasibility of MET for the management of HDP. At the end of the article, gaps in current researches are proposed. Concretely, experimental MET concentration and PE models should be chosen cautiously. Besides, the clinical trial protocol should be further optimized to evaluate the reduction in the prevalence of PE as a primary endpoint. All of those evidence gaps may be of guiding significance to improve the design of relevant experiments and clinical trials in the future.
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Affiliation(s)
- Yang Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoxia Liu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liu Yang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Zou
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Endothelial Progenitor Cell CD34 + and CD133 + Concentrations and Soluble HLA-G Concentrations During Pregnancy and in Cord Blood in Undifferentiated Connective Tissue Diseases Compared to Controls. Reprod Sci 2020; 28:1382-1389. [PMID: 33237511 DOI: 10.1007/s43032-020-00405-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 11/16/2020] [Indexed: 10/22/2022]
Abstract
The objective of this study is to evaluate endothelial progenitor cells (EPCs) CD34+ CD133- and CD34+ CD133+ and soluble HLA-G (sHLA-G) concentrations among undifferentiated connective tissue disease (UCTD) subjects, compared to controls, during pregnancy and in cord blood. This is a case-control study including 29 controls and 29 UCTDs. CD34+ CD133-, CD34+ CD133+, and sHLA-G concentrations were detected in maternal plasma and in cord blood. This study was approved by the Medical-Ethical Committee of our Institution (Current Research Project N. 901-rcr2017i-23 of IRCCS Foundation Policlinico San Matteo of Pavia). Circulating CD34+ CD133- and CD34+ CD133+ counts and sHLA-G (soluble human leucocyte antigen G) concentrations in maternal peripherical blood were higher in UCTD compared to those in controls in first and third trimester of pregnancy and at delivery (p < 0.001). Maternal CD34+ CD133- and CD34+ CD133+ counts were strongly and significantly correlated in UCTD (Spearman's rho = 0.79, p < 0.0001) but not in controls (Spearman's rho = 0.10, p = 0.35). Cord blood CD34+ CD133- and CD34+ CD133+ median counts and median sHLA-G concentrations were higher among UCTD subjects than in controls (p < 0.001). Cord blood CD34+ and CD133+ counts were inversely and significantly correlated with sHLA-G concentrations among UCTDs, but not in controls. Early UCTD is characterized by increased EPC levels in maternal plasma and in cord blood and higher levels of sHLA-G, compared to controls. Data suggest that fetoplacental unit plays an independent role in the EPC response to a systemic autoimmune disease.
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12
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Lyons CJ, O’Brien T. The Functionality of Endothelial-Colony-Forming Cells from Patients with Diabetes Mellitus. Cells 2020; 9:cells9071731. [PMID: 32698397 PMCID: PMC7408543 DOI: 10.3390/cells9071731] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 07/15/2020] [Accepted: 07/18/2020] [Indexed: 12/18/2022] Open
Abstract
Endothelial-colony-forming cells (ECFCs) are a population of progenitor cells which have demonstrated promising angiogenic potential both in vitro and in vivo. However, ECFCs from diabetic patients have been shown to be dysfunctional compared to ECFCs from healthy donors. Diabetes mellitus itself presents with many vascular co-morbidities and it has been hypothesized that ECFCs may be a potential cell therapy option to promote revascularisation in these disorders. While an allogeneic cell therapy approach would offer the potential of an ‘off the shelf’ therapeutic product, to date little research has been carried out on umbilical cord-ECFCs in diabetic models. Alternatively, autologous cell therapy using peripheral blood-ECFCs allows the development of a personalised therapeutic approach to medicine; however, autologous diabetic ECFCs are dysfunctional and need to be repaired so they can effectively treat diabetic co-morbidities. Many different groups have modified autologous diabetic ECFCs to improve their function using a variety of methods including pre-treatment with different factors or with genetic modification. While the in vitro and in vivo data from the literature is promising, no ECFC therapy has proceeded to clinical trials to date, indicating that more research is needed for a potential ECFC therapy in the future to treat diabetic complications.
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13
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Díaz del Moral S, Barrena S, Muñoz-Chápuli R, Carmona R. Embryonic circulating endothelial progenitor cells. Angiogenesis 2020; 23:531-541. [DOI: 10.1007/s10456-020-09732-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 06/22/2020] [Indexed: 12/26/2022]
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14
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Eggenberger S, Boucard C, Schoeberlein A, Guzman R, Limacher A, Surbek D, Mueller M. Stem cell treatment and cerebral palsy: Systemic review and meta-analysis. World J Stem Cells 2019; 11:891-903. [PMID: 31692977 PMCID: PMC6828595 DOI: 10.4252/wjsc.v11.i10.891] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 07/31/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Perinatal complications may result in life-long morbidities, among which cerebral palsy (CP) is the most severe motor disability. Once developed, CP is a non-progressive disease with a prevalence of 1-2 per 1000 live births in developed countries. It demands an extensive and multidisciplinary care. Therefore, it is a challenge for our health system and a burden for patients and their families. Recently, stem cell therapy emerged as a promising treatment option and raised hope in patients and their families.
AIM The aim is to evaluate the efficacy and safety of stem cell treatment in children with CP using a systematic review and meta-analysis
METHODS We performed a systematic literature search on PubMed and EMBASE to find randomized controlled clinical trials (RCT) investigating the effect of stem cell transplantation in children with CP. After the review, we performed a random-effects meta-analysis focusing on the change in gross motor function, which was quantified using the gross motor function measure. We calculated the pooled standardized mean differences of the 6- and/or 12-mo-outcome by the method of Cohen. We quantified the heterogeneity using the I-squared measure.
RESULTS We identified a total of 8 RCT for a qualitative review. From the initially selected trials, 5 met the criteria and were included in the meta-analysis. Patients’ population ranged from 0.5 up to 35 years (n = 282). We detected a significant improvement in the gross motor function with a pooled standard mean difference of 0.95 (95% confidence interval: 0.13-1.76) favoring the stem cell group and a high heterogeneity (I2 = 90.1%). Serious adverse events were rare and equally distributed among both intervention and control groups.
CONCLUSION Stem cell therapy for CP compared with symptomatic standard care only, shows a significant positive effect on the gross motor function, although the magnitude of the improvement is limited. Short-term safety is present and further high-quality RCTs are needed.
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Affiliation(s)
- Simone Eggenberger
- Department of Obstetrics and Gynaecology, Inselspital, University Hospital Bern, Bern 3010, Switzerland
| | - Céline Boucard
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
| | | | - Raphael Guzman
- Department of Neurosurgery, University Hospital of Basel, Basel 4056, Switzerland
| | | | - Daniel Surbek
- Department of Obstetrics and Gynaecology, Inselspital, University Hospital Bern, Bern 3010, Switzerland
| | - Martin Mueller
- Department of Obstetrics and Gynaecology, Inselspital, University Hospital Bern, Bern 3010, Switzerland
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15
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Il'yasova D, Kinev A, Grégoire R, Beeson CC. A Cell-Based Approach to Study the Associations Between Mitochondrial Health, Early Life Exposures, and Consequent Health Outcomes. Front Public Health 2019; 7:36. [PMID: 30918888 PMCID: PMC6424859 DOI: 10.3389/fpubh.2019.00036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 02/12/2019] [Indexed: 11/13/2022] Open
Affiliation(s)
- Dora Il'yasova
- Department of Population Health Science, School of Public Health, Georgia State University, Atlanta, GA, United States
| | | | - Rose Grégoire
- Department of Population Health Science, School of Public Health, Georgia State University, Atlanta, GA, United States
| | - Craig C Beeson
- Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States
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16
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Umbilical cord blood cells for treatment of cerebral palsy; timing and treatment options. Pediatr Res 2018; 83:333-344. [PMID: 28937975 DOI: 10.1038/pr.2017.236] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 09/19/2017] [Indexed: 12/23/2022]
Abstract
Cerebral palsy is the most common cause of physical disability in children, and there is no cure. Umbilical cord blood (UCB) cell therapy for the treatment of children with cerebral palsy is currently being assessed in clinical trials. Although there is much interest in the use of UCB stem cells for neuroprotection and neuroregeneration, the mechanisms of action are not fully understood. Further, UCB contains many stem and progenitor cells of interest, and we will point out that individual cell types within UCB may elicit specific effects. UCB is a clinically proven source of hemotopoietic stem cells (HSCs). It also contains mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs), and immunosupressive cells such as regulatory T cells (Tregs) and monocyte-derived supressor cells. Each of these cell types may be individual candidates for the prevention of brain injury following hypoxic and inflammatory events in the perinatal period. We will discuss specific properties of cell types in UCB, with respect to their therapeutic potential and the importance of optimal timing of administration. We propose that tailored cell therapy and targeted timing of administration will optimize the results for future clinical trials in the neuroprotective treatment of perinatal brain injury.
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17
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Hernandez-Lopez R, Chavez-Gonzalez A, Torres-Barrera P, Moreno-Lorenzana D, Lopez-DiazGuerrero N, Santiago-German D, Isordia-Salas I, Smadja D, C. Yoder M, Majluf-Cruz A, Alvarado-Moreno JA. Reduced proliferation of endothelial colony-forming cells in unprovoked venous thromboembolic disease as a consequence of endothelial dysfunction. PLoS One 2017; 12:e0183827. [PMID: 28910333 PMCID: PMC5598948 DOI: 10.1371/journal.pone.0183827] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 08/11/2017] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Venous thromboembolic disease (VTD) is a public health problem. We recently reported that endothelial colony-forming cells (ECFCs) derived from endothelial cells (EC) (ECFC-ECs) from patients with VTD have a dysfunctional state. For this study, we proposed that a dysfunctional status of these cells generates a reduction of its proliferative ability, which is also associated with senescence and reactive oxygen species (ROS). METHODS AND RESULTS Human mononuclear cells (MNCs) were obtained from peripheral blood from 40 healthy human volunteers (controls) and 50 patients with VTD matched by age (20-50 years) and sex to obtain ECFCs. We assayed their proliferative ability with plasma of patients and controls and supernatants of cultures from ECFC-ECs, senescence-associated β-galactosidase (SA-β-gal), ROS, and expression of ephrin-B2/Eph-B4 receptor. Compared with cells from controls, cells from VTD patients showed an 8-fold increase of ECFCs that emerged 1 week earlier, reduced proliferation at long term (39%) and, in passages 4 and 10, a highly senescent rate (30±1.05% vs. 91.3±15.07%, respectively) with an increase of ROS and impaired expression of ephrin-B2/Eph-4 genes. Proliferation potential of cells from VTD patients was reduced in endothelial medium [1.4±0.22 doubling population (DP)], control plasma (1.18±0.31 DP), or plasma from VTD patients (1.65±0.27 DP). CONCLUSIONS As compared with controls, ECFC-ECs from individuals with VTD have higher oxidative stress, proliferation stress, cellular senescence, and low proliferative potential. These findings suggest that patients with a history of VTD are ECFC-ECs dysfunctional that could be associated to permanent risk for new thrombotic events.
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Affiliation(s)
- Rubicel Hernandez-Lopez
- Unidad de Investigacion Medica en Trombosis, Hemostasia y Aterogenesis, Instituto Mexicano del Seguro Social, Mexico City, Mexico
- Posgrado en Biologia Experimental, Universidad Autonoma Metropolitana, Iztapalapa. Mexico City, Mexico
| | - Antonieta Chavez-Gonzalez
- Unidad de Investigacion Medica en Enfermedades Oncologicas, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Patricia Torres-Barrera
- Unidad de Investigacion Medica en Enfermedades Oncologicas, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Dafne Moreno-Lorenzana
- Unidad de Investigacion Medica en Enfermedades Oncologicas, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Norma Lopez-DiazGuerrero
- Posgrado en Biologia Experimental, Universidad Autonoma Metropolitana, Iztapalapa. Mexico City, Mexico
| | | | - Irma Isordia-Salas
- Unidad de Investigacion Medica en Trombosis, Hemostasia y Aterogenesis, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - David Smadja
- Paris Descartes University, INSERM UMR-S 1140, Faculté de Pharmacie de Paris, Paris, France
- AP-HP, Hôpital Européen Georges Pompidou, Hematology department, Paris, France
| | - Mervin C. Yoder
- Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Abraham Majluf-Cruz
- Unidad de Investigacion Medica en Trombosis, Hemostasia y Aterogenesis, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - J. Antonio Alvarado-Moreno
- Unidad de Investigacion Medica en Trombosis, Hemostasia y Aterogenesis, Instituto Mexicano del Seguro Social, Mexico City, Mexico
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18
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Gumina DL, Su EJ. Endothelial Progenitor Cells of the Human Placenta and Fetoplacental Circulation: A Potential Link to Fetal, Neonatal, and Long-term Health. Front Pediatr 2017; 5:41. [PMID: 28361046 PMCID: PMC5350128 DOI: 10.3389/fped.2017.00041] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 02/15/2017] [Indexed: 12/16/2022] Open
Abstract
The fetoplacental circulation plays a key role in both short- and long-term outcomes, and aberrant flow indices as manifested by abnormal fetal Doppler velocimetry within this compartment have been associated with significant adverse consequences. These include fetal growth restriction, which often coexists with preeclampsia, and long-lasting medical issues as a result of both the underlying pathology and prematurity such as bronchopulmonary dysplasia, chronic lung disease, and neurodevelopmental delay. Furthermore, it is also clear that exposure to an abnormal in utero environment increases risk for long-term, adulthood issues such as cardiovascular disease. Endothelial progenitor cells (EPCs) have been implicated in vasculogenesis and angiogenesis, and they have been isolated from both human placenta and umbilical cord blood. This review outlines the extensive nomenclature of EPCs, summarizes existing literature surrounding human placental and umbilical cord blood EPCs, explores their potential role in pregnancy complications and adverse perinatal outcome, and highlights key areas where future investigations are needed.
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Affiliation(s)
- Diane L Gumina
- Obstetrics and Gynecology, University of Colorado School of Medicine , Aurora, CO , USA
| | - Emily J Su
- Obstetrics and Gynecology, University of Colorado School of Medicine , Aurora, CO , USA
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19
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Gumina DL, Black CP, Balasubramaniam V, Winn VD, Baker CD. Umbilical Cord Blood Circulating Progenitor Cells and Endothelial Colony-Forming Cells Are Decreased in Preeclampsia. Reprod Sci 2016; 24:1088-1096. [PMID: 27879452 DOI: 10.1177/1933719116678692] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Preeclampsia (PE) is a pregnancy-specific disease characterized by the new onset of hypertension and proteinuria. Mothers with PE are known to develop endothelial dysfunction, but its effect on infants has been understudied, as newborns are often asymptomatic. Recent studies indicate that infants born from preeclamptic pregnancies develop endothelial dysfunction including higher blood pressure during childhood and an increased risk of stroke later in life. We hypothesize that PE reduces the number and function of fetal angiogenic progenitor cells and may contribute to this increased risk. We quantified 2 distinct types of angiogenic progenitors, pro-angiogenic circulating progenitor cells (CPCs) and endothelial colony-forming cells (ECFCs), from the umbilical cord blood of preeclamptic pregnancies and normotensive controls. Pro-angiogenic and nonangiogenic CPCs were enumerated via flow cytometry and ECFCs by cell culture. Additionally, we studied the growth, migration, and tube formation of ECFCs from PE and gestational age-matched normotensive control pregnancies. We found that PE resulted in decreased cord blood pro-angiogenic CPCs and ECFCs. Nonangiogenic CPCs were also decreased. Preeclamptic ECFCs demonstrated decreased growth and migration but formed tube-like structures in vitro similar to controls. Our results suggest that the preeclamptic environment alters the number and function of angiogenic progenitor cells and may increase the risk of later vascular disease.
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Affiliation(s)
- Diane L Gumina
- 1 Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Claudine P Black
- 2 Department of Pediatrics, Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO, USA
| | - Vivek Balasubramaniam
- 3 Pediatric Pulmonology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Virginia D Winn
- 1 Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO, USA
- 4 Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA
- Authors contributed equally to the article
| | - Christopher D Baker
- 2 Department of Pediatrics, Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO, USA
- Authors contributed equally to the article
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20
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Morton JS, Cooke CL, Davidge ST. In Utero Origins of Hypertension: Mechanisms and Targets for Therapy. Physiol Rev 2016; 96:549-603. [DOI: 10.1152/physrev.00015.2015] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The developmental origins of health and disease theory is based on evidence that a suboptimal environment during fetal and neonatal development can significantly impact the evolution of adult-onset disease. Abundant evidence exists that a compromised prenatal (and early postnatal) environment leads to an increased risk of hypertension later in life. Hypertension is a silent, chronic, and progressive disease defined by elevated blood pressure (>140/90 mmHg) and is strongly correlated with cardiovascular morbidity/mortality. The pathophysiological mechanisms, however, are complex and poorly understood, and hypertension continues to be one of the most resilient health problems in modern society. Research into the programming of hypertension has proposed pharmacological treatment strategies to reverse and/or prevent disease. In addition, modifications to the lifestyle of pregnant women might impart far-reaching benefits to the health of their children. As more information is discovered, more successful management of hypertension can be expected to follow; however, while pregnancy complications such as fetal growth restriction, preeclampsia, preterm birth, etc., continue to occur, their offspring will be at increased risk for hypertension. This article reviews the current knowledge surrounding the developmental origins of hypertension, with a focus on mechanistic pathways and targets for therapeutic and pharmacologic interventions.
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Affiliation(s)
- Jude S. Morton
- Departments of Obstetrics and Gynaecology and of Physiology, University of Alberta, Edmonton, Canada; Women and Children's Health Research Institute, Edmonton, Canada; and Cardiovascular Research Centre, Edmonton, Canada
| | - Christy-Lynn Cooke
- Departments of Obstetrics and Gynaecology and of Physiology, University of Alberta, Edmonton, Canada; Women and Children's Health Research Institute, Edmonton, Canada; and Cardiovascular Research Centre, Edmonton, Canada
| | - Sandra T. Davidge
- Departments of Obstetrics and Gynaecology and of Physiology, University of Alberta, Edmonton, Canada; Women and Children's Health Research Institute, Edmonton, Canada; and Cardiovascular Research Centre, Edmonton, Canada
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21
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Mandò C, Razini P, Novielli C, Anelli GM, Belicchi M, Erratico S, Banfi S, Meregalli M, Tavelli A, Baccarin M, Rolfo A, Motta S, Torrente Y, Cetin I. Impaired Angiogenic Potential of Human Placental Mesenchymal Stromal Cells in Intrauterine Growth Restriction. Stem Cells Transl Med 2016; 5:451-63. [PMID: 26956210 DOI: 10.5966/sctm.2015-0155] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 12/21/2015] [Indexed: 01/12/2023] Open
Abstract
UNLABELLED Human placental mesenchymal stromal cells (pMSCs) have never been investigated in intrauterine growth restriction (IUGR). We characterized cells isolated from placental membranes and the basal disc of six IUGR and five physiological placentas. Cell viability and proliferation were assessed every 7 days during a 6-week culture. Expression of hematopoietic, stem, endothelial, and mesenchymal markers was evaluated by flow cytometry. We characterized the multipotency of pMSCs and the expression of genes involved in mitochondrial content and function. Cell viability was high in all samples, and proliferation rate was lower in IUGR compared with control cells. All samples presented a starting heterogeneous population, shifting during culture toward homogeneity for mesenchymal markers and occurring earlier in IUGR than in controls. In vitro multipotency of IUGR-derived pMSCs was restricted because their capacity for adipocyte differentiation was increased, whereas their ability to differentiate toward endothelial cell lineage was decreased. Mitochondrial content and function were higher in IUGR pMSCs than controls, possibly indicating a shift from anaerobic to aerobic metabolism, with the loss of the metabolic characteristics that are typical of undifferentiated multipotent cells. SIGNIFICANCE This study demonstrates that the loss of endothelial differentiation potential and the increase of adipogenic ability are likely to play a significant role in the vicious cycle of abnormal placental development in intrauterine growth restriction (IUGR). This is the first observation of a potential role for placental mesenchymal stromal cells in intrauterine growth restriction, thus leading to new perspectives for the treatment of IUGR.
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Affiliation(s)
- Chiara Mandò
- "L. Sacco" Department of Biomedical and Clinical Sciences, Center for Fetal Research Giorgio Pardi, Universitá degli Studi di Milano, Milan, Italy
| | - Paola Razini
- Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Universitá degli Studi di Milano, Milan, Italy
| | - Chiara Novielli
- "L. Sacco" Department of Biomedical and Clinical Sciences, Center for Fetal Research Giorgio Pardi, Universitá degli Studi di Milano, Milan, Italy
| | - Gaia Maria Anelli
- "L. Sacco" Department of Biomedical and Clinical Sciences, Center for Fetal Research Giorgio Pardi, Universitá degli Studi di Milano, Milan, Italy
| | - Marzia Belicchi
- Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Universitá degli Studi di Milano, Milan, Italy Ystem S.R.L., Milan, Italy
| | | | - Stefania Banfi
- Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Universitá degli Studi di Milano, Milan, Italy
| | - Mirella Meregalli
- Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Universitá degli Studi di Milano, Milan, Italy Ystem S.R.L., Milan, Italy
| | - Alessandro Tavelli
- Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Universitá degli Studi di Milano, Milan, Italy
| | - Marco Baccarin
- Laboratory of Medical Genetics, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Alessandro Rolfo
- Department of Surgical Science, University of Turin, Turin, Italy
| | - Silvia Motta
- Laboratory of Medical Genetics, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Yvan Torrente
- Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Universitá degli Studi di Milano, Milan, Italy Ystem S.R.L., Milan, Italy UNISTEM Interdepartmental Centre for Stem Cell Research, Milan, Italy
| | - Irene Cetin
- "L. Sacco" Department of Biomedical and Clinical Sciences, Center for Fetal Research Giorgio Pardi, Universitá degli Studi di Milano, Milan, Italy Department of Mother and Child, Luigi Sacco Hospital, Milan, Italy
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22
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Gu W, Sun W, Guo C, Yan Y, Liu M, Yao X, Yang B, Zheng J. Culture and Characterization of Circulating Endothelial Progenitor Cells in Patients with Renal Cell Carcinoma. J Urol 2015; 194:214-22. [PMID: 25659661 DOI: 10.1016/j.juro.2015.01.100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2015] [Indexed: 12/20/2022]
Affiliation(s)
- Wenyu Gu
- Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Wei Sun
- Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Changcheng Guo
- Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Yang Yan
- Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Min Liu
- Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Xudong Yao
- Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Bin Yang
- Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Junhua Zheng
- Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
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23
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Blue EK, Sheehan BM, Nuss ZV, Boyle FA, Hocutt CM, Gohn CR, Varberg KM, McClintick JN, Haneline LS. Epigenetic Regulation of Placenta-Specific 8 Contributes to Altered Function of Endothelial Colony-Forming Cells Exposed to Intrauterine Gestational Diabetes Mellitus. Diabetes 2015; 64:2664-75. [PMID: 25720387 PMCID: PMC4477353 DOI: 10.2337/db14-1709] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 02/15/2015] [Indexed: 12/19/2022]
Abstract
Intrauterine exposure to gestational diabetes mellitus (GDM) is linked to development of hypertension, obesity, and type 2 diabetes in children. Our previous studies determined that endothelial colony-forming cells (ECFCs) from neonates exposed to GDM exhibit impaired function. The current goals were to identify aberrantly expressed genes that contribute to impaired function of GDM-exposed ECFCs and to evaluate for evidence of altered epigenetic regulation of gene expression. Genome-wide mRNA expression analysis was conducted on ECFCs from control and GDM pregnancies. Candidate genes were validated by quantitative RT-PCR and Western blotting. Bisulfite sequencing evaluated DNA methylation of placenta-specific 8 (PLAC8). Proliferation and senescence assays of ECFCs transfected with siRNA to knockdown PLAC8 were performed to determine functional impact. Thirty-eight genes were differentially expressed between control and GDM-exposed ECFCs. PLAC8 was highly expressed in GDM-exposed ECFCs, and PLAC8 expression correlated with maternal hyperglycemia. Methylation status of 17 CpG sites in PLAC8 negatively correlated with mRNA expression. Knockdown of PLAC8 in GDM-exposed ECFCs improved proliferation and senescence defects. This study provides strong evidence in neonatal endothelial progenitor cells that GDM exposure in utero leads to altered gene expression and DNA methylation, suggesting the possibility of altered epigenetic regulation.
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Affiliation(s)
- Emily K Blue
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - BreAnn M Sheehan
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - Zia V Nuss
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - Frances A Boyle
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - Caleb M Hocutt
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - Cassandra R Gohn
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN
| | - Kaela M Varberg
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN
| | - Jeanette N McClintick
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
| | - Laura S Haneline
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN
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Lin RZ, Hatch A, Antontsev VG, Murthy SK, Melero-Martin JM. Microfluidic capture of endothelial colony-forming cells from human adult peripheral blood: phenotypic and functional validation in vivo. Tissue Eng Part C Methods 2014; 21:274-83. [PMID: 25091645 DOI: 10.1089/ten.tec.2014.0323] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
INTRODUCTION Endothelial colony-forming cells (ECFCs) are endothelial progenitors that circulate in peripheral blood and are currently the subject of intensive investigation due to their therapeutic potential. However, in adults, ECFCs comprise a very small subset among circulating cells, which makes their isolation a challenge. MATERIALS AND METHODS Currently, the standard method for ECFC isolation relies on the separation of mononuclear cells and erythrocyte lysis, steps that are time consuming and known to increase cell loss. Alternatively, we previously developed a novel disposable microfluidic platform containing antibody-functionalized degradable hydrogel coatings that is ideally suited for capturing low-abundance circulating cells from unprocessed blood. In this study, we reasoned that this microfluidic approach could effectively isolate rare ECFCs by virtue of their CD34 expression. RESULTS We conducted preclinical experiments with peripheral blood from four adult volunteers and demonstrated that the actual microfluidic capture of circulating CD34(+) cells from unprocessed blood was compatible with the subsequent differentiation of these cells into ECFCs. Moreover, the ECFC yield obtained with the microfluidic system was comparable to that of the standard method. Importantly, we unequivocally validated the phenotypical and functional properties of the captured ECFCs, including the ability to form microvascular networks following transplantation into immunodeficient mice. DISCUSSION We showed that the simplicity and versatility of our microfluidic system could be very instrumental for ECFC isolation while preserving their therapeutic potential. We anticipate our results will facilitate additional development of clinically suitable microfluidic devices by the vascular therapeutic and diagnostic industry.
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Affiliation(s)
- Ruei-Zeng Lin
- 1 Department of Cardiac Surgery, Boston Children's Hospital , Boston, Massachusetts
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25
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von Versen-Höynck F, Brodowski L, Dechend R, Myerski AC, Hubel CA. Vitamin D antagonizes negative effects of preeclampsia on fetal endothelial colony forming cell number and function. PLoS One 2014; 9:e98990. [PMID: 24892558 PMCID: PMC4044051 DOI: 10.1371/journal.pone.0098990] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 05/08/2014] [Indexed: 12/22/2022] Open
Abstract
CONTEXT Endothelial dysfunction is a primary feature of preeclampsia, a pregnancy complication associated with an increased future cardiovascular risk for mother and offspring. Endothelial colony forming cells (ECFC) are endothelial progenitor cells that participate in vasculogenesis and endothelial repair. OBJECTIVE We hypothesized that the number and functional properties of fetal cord blood-derived ECFCs are reduced in preeclampsia compared to uncomplicated pregnancy (controls), and asked if adverse effects of preeclampsia on ECFC function are reversed by 1,25 (OH)2 vitamin D3. DESIGN, SETTING, PATIENTS This was a nested, case-control study. Forty women with uncomplicated pregnancy and 33 women with PE were recruited at Magee-Womens Hospital (USA) or at Hannover Medical School (Germany). MAIN OUTCOME MEASURES Time to ECFC colony appearance in culture, and number of colonies formed, were determined. Functional abilities of ECFCs were assessed in vitro by tubule formation in Matrigel assay, migration, and proliferation. ECFC function was tested in the presence or absence of 1,25 (OH)2 vitamin D3, and after vitamin D receptor (VDR) or VEGF signaling blockade. RESULTS The number of cord ECFC colonies was lower (P = 0.04) in preeclampsia compared to controls. ECFCs from preeclampsia showed reduced proliferation (P<0.0001), formed fewer tubules (P = 0.02), and migrated less (P = 0.049) than control. Vitamin D3 significantly improved preeclampsia ECFC functional properties. VDR- or VEGF blockade reduced tubule formation, partially restorable by vitamin D3. CONCLUSION Fetal ECFCs from preeclamptic pregnancies are reduced in number and dysfunctional. Vitamin D3 had rescuing effects. This may have implications for the increased cardiovascular risk associated with preeclampsia.
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Affiliation(s)
- Frauke von Versen-Höynck
- Department of Obstetrics and Gynecology, Gynecology Research Unit, Hannover Medical School, Hannover, Germany
| | - Lars Brodowski
- Department of Obstetrics and Gynecology, Gynecology Research Unit, Hannover Medical School, Hannover, Germany
| | - Ralf Dechend
- Experimental and Clinical Research Center (Max-Delbrück Center for Molecular Medicine and Medical Faculty of the Charité and Franz-Volhard Clinic), Helios Klinikum Berlin-Buch, Berlin, Germany
| | - Ashley C. Myerski
- Magee-Womens Research Institute and Department of Obstetrics, Gynecology & Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Carl A. Hubel
- Magee-Womens Research Institute and Department of Obstetrics, Gynecology & Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
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Brodowski L, Burlakov J, Myerski AC, von Kaisenberg CS, Grundmann M, Hubel CA, von Versen-Höynck F. Vitamin D prevents endothelial progenitor cell dysfunction induced by sera from women with preeclampsia or conditioned media from hypoxic placenta. PLoS One 2014; 9:e98527. [PMID: 24887145 PMCID: PMC4041729 DOI: 10.1371/journal.pone.0098527] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 05/01/2014] [Indexed: 01/17/2023] Open
Abstract
CONTEXT Placenta-derived circulating factors contribute to the maternal endothelial dysfunction underlying preeclampsia. Endothelial colony forming cells (ECFC), a sub-population of endothelial progenitor cells (EPCs), are thought to be involved in vasculogenesis and endothelial repair. Low vitamin D concentrations are associated with an increased risk for preeclampsia. OBJECTIVE We hypothesized that the function of human fetal ECFCs in culture would be suppressed by exposure to preeclampsia-related factors--preeclampsia serum or hypoxic placental conditioned medium--in a fashion reversed by vitamin D. DESIGN, SETTING, PATIENTS ECFCs were isolated from cord blood of uncomplicated pregnancies and expanded in culture. Uncomplicated pregnancy villous placenta in explant culture were exposed to either 2% (hypoxic), 8% (normoxic) or 21% (hyperoxic) O2 for 48 h, after which the conditioned media (CM) was collected. OUTCOME MEASURES ECFC tubule formation (Matrigel assay) and migration were examined in the presence of either maternal serum from preeclampsia cases or uncomplicated pregnancy controls, or pooled CM, in the presence or absence of 1,25(OH)2 vitamin D3. RESULTS 1,25(OH)2 vitamin D3 reversed the adverse effects of preeclampsia serum or CM from hypoxic placenta on ECFCs capillary-tube formation and migration. Silencing of VDR expression by VDR siRNA, VDR blockade, or VEGF pathway blockade reduced ECFC functional abilities. Effects of VDR or VEGF blockade were partially prevented by vitamin D. CONCLUSION Vitamin D promotes the capillary-like tubule formation and migration of ECFCs in culture, minimizing the negative effects of exposure to preeclampsia-related factors. Further evaluation of the role of vitamin D in ECFC regulation and preeclampsia is warranted.
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Affiliation(s)
- Lars Brodowski
- Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany
| | - Jennifer Burlakov
- Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany
| | - Ashley C. Myerski
- Magee- Womens Research Institute and Foundation, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | | | - Magdalena Grundmann
- Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany
| | - Carl A. Hubel
- Magee- Womens Research Institute and Foundation, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
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Reduction of maternal circulating endothelial progenitor cells in human pregnancies with intrauterine growth restriction. Placenta 2014; 35:431-6. [PMID: 24819155 DOI: 10.1016/j.placenta.2014.04.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 04/10/2014] [Accepted: 04/15/2014] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Circulating endothelial progenitor cells (EPCs) may play a crucial role during pregnancy by sustaining adequate placentation and fetal growth. Unambiguous demonstration of EPC increase during pregnancy has been hampered so far by lack of standardized methods for EPC quantification. In this study we used the currently most accepted phenotype for EPC detection for investigating whether maternal circulating EPCs might increase during normal pregnancy and whether they may fail to increase in pregnancy complicated by idiopathic intrauterine growth restriction (IUGR), a leading cause of perinatal mortality and morbidity characterized by insufficient placental perfusion. METHODS Twenty-one non-pregnant women, 44 women during healthy pregnancy progression (9, 13 and 22 women in the first, second and third trimester, respectively) and 11 with pregnancy complicated by idiopathic IUGR were recruited in a cross-sectional study. EPCs in maternal blood were identified as CD45(dim)/CD34+ / KDR+ cells by flow cytometry. Plasmatic cytokines were measured by ELISA. RESULTS We observed a significant and progressive increase of EPCs in normal pregnancy, yet detectable in early pregnancy but even more pronounced in the third trimester. The increase of EPCs was impaired in IUGR-complicated pregnancies at comparable gestational age. The circulating levels of placental growth-factor and stromal-derived-factor-1 were significantly lower in IUGR than normal pregnancies, possibly contributing to EPC impairment. CONCLUSIONS EPC count in maternal circulation may have a great potential as a novel biomarker for pregnancy monitoring and may represent the target of novel therapeutic strategies designed to prevent adverse pregnancy outcomes often occurring in IUGR.
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Muñoz-Hernandez R, Miranda ML, Stiefel P, Lin RZ, Praena-Fernández JM, Dominguez-Simeon MJ, Villar J, Moreno-Luna R, Melero-Martin JM. Decreased level of cord blood circulating endothelial colony-forming cells in preeclampsia. Hypertension 2014; 64:165-71. [PMID: 24752434 DOI: 10.1161/hypertensionaha.113.03058] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Preeclampsia is a pregnancy-related disorder associated with increased cardiovascular risk for the offspring. Endothelial colony-forming cells (ECFCs) are a subset of circulating endothelial progenitor cells that participate in the formation of vasculature during development. However, the effect of preeclampsia on fetal levels of ECFCs is largely unknown. In this study, we sought to determine whether cord blood ECFC abundance and function are altered in preeclampsia. We conducted a prospective cohort study that included women with normal (n=35) and preeclamptic (n=15) pregnancies. We measured ECFC levels in the umbilical cord blood of neonates and characterized ECFC phenotype, cloning-forming ability, proliferation, and migration toward vascular endothelial growth factor-A and fibroblast growth factor-2, in vitro formation of capillary-like structures, and in vivo vasculogenic ability in immunodeficient mice. We found that the level of cord blood ECFCs was statistically lower in preeclampsia than in control pregnancies (P=0.04), a reduction that was independent of other obstetric factors. In addition, cord blood ECFCs from preeclamptic pregnancies required more time to emerge in culture than control ECFCs. However, once derived in culture, ECFC function was deemed normal and highly similar between preeclampsia and control, including the ability to form vascular networks in vivo. This study demonstrates that preeclampsia affects ECFC abundance in neonates. A reduced level of ECFCs during preeclamptic pregnancies may contribute to an increased risk of developing future cardiovascular events.
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Affiliation(s)
- Rocio Muñoz-Hernandez
- From the CSIC/Universidad de Sevilla, Unidad Clínico-Experimental de Riesgo Vascular (UCAMI-UCERV) (R.M.-H., M.L.M., P.S., M.J.D.-S., J.V., R.M.-L.) and Unidad de Asesoría Estadística, Metodología y Evaluación de Investigación, Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI) (J.M.P.-F.), Instituto de Biomedicina de Sevilla (IBiS) and Hospital Universitario Virgen del Rocío, Seville, Spain; Department of Cardiac Surgery, Boston Children's Hospital, MA (R.M.-H., R.-Z.L., R.M.-L., J.M.M.-M.); Department of Surgery, Harvard Medical School, Boston, MA (R.-Z.L., R.M.-L., J.M.M.-M.); and Harvard Stem Cell Institute, Cambridge, MA (J.M.M.-M.)
| | - Maria L Miranda
- From the CSIC/Universidad de Sevilla, Unidad Clínico-Experimental de Riesgo Vascular (UCAMI-UCERV) (R.M.-H., M.L.M., P.S., M.J.D.-S., J.V., R.M.-L.) and Unidad de Asesoría Estadística, Metodología y Evaluación de Investigación, Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI) (J.M.P.-F.), Instituto de Biomedicina de Sevilla (IBiS) and Hospital Universitario Virgen del Rocío, Seville, Spain; Department of Cardiac Surgery, Boston Children's Hospital, MA (R.M.-H., R.-Z.L., R.M.-L., J.M.M.-M.); Department of Surgery, Harvard Medical School, Boston, MA (R.-Z.L., R.M.-L., J.M.M.-M.); and Harvard Stem Cell Institute, Cambridge, MA (J.M.M.-M.)
| | - Pablo Stiefel
- From the CSIC/Universidad de Sevilla, Unidad Clínico-Experimental de Riesgo Vascular (UCAMI-UCERV) (R.M.-H., M.L.M., P.S., M.J.D.-S., J.V., R.M.-L.) and Unidad de Asesoría Estadística, Metodología y Evaluación de Investigación, Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI) (J.M.P.-F.), Instituto de Biomedicina de Sevilla (IBiS) and Hospital Universitario Virgen del Rocío, Seville, Spain; Department of Cardiac Surgery, Boston Children's Hospital, MA (R.M.-H., R.-Z.L., R.M.-L., J.M.M.-M.); Department of Surgery, Harvard Medical School, Boston, MA (R.-Z.L., R.M.-L., J.M.M.-M.); and Harvard Stem Cell Institute, Cambridge, MA (J.M.M.-M.)
| | - Ruei-Zeng Lin
- From the CSIC/Universidad de Sevilla, Unidad Clínico-Experimental de Riesgo Vascular (UCAMI-UCERV) (R.M.-H., M.L.M., P.S., M.J.D.-S., J.V., R.M.-L.) and Unidad de Asesoría Estadística, Metodología y Evaluación de Investigación, Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI) (J.M.P.-F.), Instituto de Biomedicina de Sevilla (IBiS) and Hospital Universitario Virgen del Rocío, Seville, Spain; Department of Cardiac Surgery, Boston Children's Hospital, MA (R.M.-H., R.-Z.L., R.M.-L., J.M.M.-M.); Department of Surgery, Harvard Medical School, Boston, MA (R.-Z.L., R.M.-L., J.M.M.-M.); and Harvard Stem Cell Institute, Cambridge, MA (J.M.M.-M.)
| | - Juan M Praena-Fernández
- From the CSIC/Universidad de Sevilla, Unidad Clínico-Experimental de Riesgo Vascular (UCAMI-UCERV) (R.M.-H., M.L.M., P.S., M.J.D.-S., J.V., R.M.-L.) and Unidad de Asesoría Estadística, Metodología y Evaluación de Investigación, Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI) (J.M.P.-F.), Instituto de Biomedicina de Sevilla (IBiS) and Hospital Universitario Virgen del Rocío, Seville, Spain; Department of Cardiac Surgery, Boston Children's Hospital, MA (R.M.-H., R.-Z.L., R.M.-L., J.M.M.-M.); Department of Surgery, Harvard Medical School, Boston, MA (R.-Z.L., R.M.-L., J.M.M.-M.); and Harvard Stem Cell Institute, Cambridge, MA (J.M.M.-M.)
| | - Maria J Dominguez-Simeon
- From the CSIC/Universidad de Sevilla, Unidad Clínico-Experimental de Riesgo Vascular (UCAMI-UCERV) (R.M.-H., M.L.M., P.S., M.J.D.-S., J.V., R.M.-L.) and Unidad de Asesoría Estadística, Metodología y Evaluación de Investigación, Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI) (J.M.P.-F.), Instituto de Biomedicina de Sevilla (IBiS) and Hospital Universitario Virgen del Rocío, Seville, Spain; Department of Cardiac Surgery, Boston Children's Hospital, MA (R.M.-H., R.-Z.L., R.M.-L., J.M.M.-M.); Department of Surgery, Harvard Medical School, Boston, MA (R.-Z.L., R.M.-L., J.M.M.-M.); and Harvard Stem Cell Institute, Cambridge, MA (J.M.M.-M.)
| | - Jose Villar
- From the CSIC/Universidad de Sevilla, Unidad Clínico-Experimental de Riesgo Vascular (UCAMI-UCERV) (R.M.-H., M.L.M., P.S., M.J.D.-S., J.V., R.M.-L.) and Unidad de Asesoría Estadística, Metodología y Evaluación de Investigación, Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI) (J.M.P.-F.), Instituto de Biomedicina de Sevilla (IBiS) and Hospital Universitario Virgen del Rocío, Seville, Spain; Department of Cardiac Surgery, Boston Children's Hospital, MA (R.M.-H., R.-Z.L., R.M.-L., J.M.M.-M.); Department of Surgery, Harvard Medical School, Boston, MA (R.-Z.L., R.M.-L., J.M.M.-M.); and Harvard Stem Cell Institute, Cambridge, MA (J.M.M.-M.)
| | - Rafael Moreno-Luna
- From the CSIC/Universidad de Sevilla, Unidad Clínico-Experimental de Riesgo Vascular (UCAMI-UCERV) (R.M.-H., M.L.M., P.S., M.J.D.-S., J.V., R.M.-L.) and Unidad de Asesoría Estadística, Metodología y Evaluación de Investigación, Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI) (J.M.P.-F.), Instituto de Biomedicina de Sevilla (IBiS) and Hospital Universitario Virgen del Rocío, Seville, Spain; Department of Cardiac Surgery, Boston Children's Hospital, MA (R.M.-H., R.-Z.L., R.M.-L., J.M.M.-M.); Department of Surgery, Harvard Medical School, Boston, MA (R.-Z.L., R.M.-L., J.M.M.-M.); and Harvard Stem Cell Institute, Cambridge, MA (J.M.M.-M.)
| | - Juan M Melero-Martin
- From the CSIC/Universidad de Sevilla, Unidad Clínico-Experimental de Riesgo Vascular (UCAMI-UCERV) (R.M.-H., M.L.M., P.S., M.J.D.-S., J.V., R.M.-L.) and Unidad de Asesoría Estadística, Metodología y Evaluación de Investigación, Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI) (J.M.P.-F.), Instituto de Biomedicina de Sevilla (IBiS) and Hospital Universitario Virgen del Rocío, Seville, Spain; Department of Cardiac Surgery, Boston Children's Hospital, MA (R.M.-H., R.-Z.L., R.M.-L., J.M.M.-M.); Department of Surgery, Harvard Medical School, Boston, MA (R.-Z.L., R.M.-L., J.M.M.-M.); and Harvard Stem Cell Institute, Cambridge, MA (J.M.M.-M.).
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Can we fix it? Evaluating the potential of placental stem cells for the treatment of pregnancy disorders. Placenta 2014; 35:77-84. [DOI: 10.1016/j.placenta.2013.12.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 12/18/2013] [Accepted: 12/22/2013] [Indexed: 12/14/2022]
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