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Liu N, Bowen CM, Shoja MM, Castro de Pereira KL, Dongur LP, Saad A, Russell WK, Broderick TC, Fair JH, Fagg WS. Comparative Analysis of Co-Cultured Amniotic Cell-Conditioned Media with Cell-Free Amniotic Fluid Reveals Differential Effects on Epithelial–Mesenchymal Transition and Myofibroblast Activation. Biomedicines 2022; 10:biomedicines10092189. [PMID: 36140291 PMCID: PMC9495976 DOI: 10.3390/biomedicines10092189] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
Myofibroblast activation is a cellular response elicited by a variety of physiological or pathological insults whereby cells initiate a coordinated response intended to eradicate the insult and then revert back to a basal state. However, an underlying theme in various disease states is persistent myofibroblast activation that fails to resolve. Based on multiple observations, we hypothesized that the secreted factors harvested from co-culturing amniotic stem cells might mimic the anti-inflammatory state that cell-free amniotic fluid (AF) elicits. We optimized an amnion epithelial and amniotic fluid cell co-culture system, and tested this hypothesis in the context of myofibroblast activation. However, we discovered that co-cultured amniotic cell conditioned media (coACCM) and AF have opposing effects on myofibroblast activation: coACCM activates the epithelial–mesenchymal transition (EMT) and stimulates gene expression patterns associated with myofibroblast activation, while AF does the opposite. Intriguingly, extracellular vesicles (EVs) purified from AF are necessary and sufficient to activate EMT and inflammatory gene expression patterns, while the EV-depleted AF potently represses these responses. In summary, these data indicate that coACCM stimulates myofibroblast activation, while AF represses it. We interpret these findings to suggest that coACCM, AF, and fractionated AF represent unique biologics that elicit different cellular responses that are correlated with a wide variety of pathological states, and therefore could have broad utility in the clinic and the lab.
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Affiliation(s)
- Naiyou Liu
- Division of Transplant, Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Charles M. Bowen
- Division of Transplant, Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
- John Sealy School of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Mohammadali M. Shoja
- Division of Transplant, Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
| | | | - Laxmi Priya Dongur
- Division of Transplant, Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
- John Sealy School of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Antonio Saad
- Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - William K. Russell
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Thomas Christopher Broderick
- Merakris Therapeutics, RTP Frontier, Research Triangle Park, NC 27709, USA
- Golden LEAF Biomanufacturing Training and Education Center, North Carolina State University, Raleigh, NC 27606, USA
| | - Jeffrey H. Fair
- Division of Transplant, Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - William Samuel Fagg
- Division of Transplant, Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
- Merakris Therapeutics, RTP Frontier, Research Triangle Park, NC 27709, USA
- Correspondence: ; Tel.: +1-(409)-772-2412; Fax: +1-(409)-747-7364
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Placental Tissues as Biomaterials in Regenerative Medicine. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6751456. [PMID: 35496035 PMCID: PMC9050314 DOI: 10.1155/2022/6751456] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 03/19/2022] [Indexed: 12/02/2022]
Abstract
Placental tissues encompass all the tissues which support fetal development, including the placenta, placental membrane, umbilical cord, and amniotic fluid. Since the 1990s there has been renewed interest in the use of these tissues as a raw material for regenerative medicine applications. Placental tissues have been extensively studied for their potential contribution to tissue repair applications. Studies have attributed their efficacy in augmenting the healing process to the extracellular matrix scaffolds rich in collagens, glycosaminoglycans, and proteoglycans, as well as the presence of cytokines within the tissues that have been shown to stimulate re-epithelialization, promote angiogenesis, and aid in the reduction of inflammation and scarring. The compositions and properties of all birth tissues give them the potential to be valuable biomaterials for the development of new regenerative therapies. Herein, the development and compositions of each of these tissues are reviewed, with focus on the structural and signaling components that are relevant to medical applications. This review also explores current configurations and recent innovations in the use of placental tissues as biomaterials in regenerative medicine.
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Lamadé EK, Hendlmeier F, Wudy SA, Blum WF, Witt SH, Rietschel M, Coenen M, Gilles M, Deuschle M. Childhood trauma and insulin-like growth factors in amniotic fluid: An exploratory analysis of 79 women. Psychoneuroendocrinology 2021; 127:105180. [PMID: 33690109 DOI: 10.1016/j.psyneuen.2021.105180] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 02/26/2021] [Accepted: 02/26/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Perinatal stress has adverse effects on fetal outcome, yet the effect of early maternal trauma on fetal outcome has scarcely been studied. We investigated effects of maternal childhood trauma and current environment on important regulators of prenatal growth, fetal insulin-like growth factor (IGF)-1 and IGF-2 in amniotic fluid and assessed the impact of IGFs on newborn anthropometrics. METHODS 79 pregnant women in their second trimester who underwent amniocentesis (15.9 ± 0.9 weeks of gestational age) and their newborns at birth were analyzed. Maternal childhood trauma was assessed using the childhood trauma questionnaire (CTQ) and current environment was operationalized by assessing maternal psychosocial, physical health and endocrine measurements in amniotic fluid. RESULTS In this exploratory analysis of 79 pregnant women, maternal childhood trauma, defined as reporting at least low scores on any of the CTQ subscales, negatively correlated with fetal IGF-1 (Mln = 3.48 vs. 2.98; p = 0.012) and IGF-2 (Mdnln = 4.99 vs. 4.70; p = 0.002). Trauma severity, defined as the overall trauma score, negatively correlated with fetal IGF-2 (r = -0.24; p = 0.037). From trauma subscales, maternal sexual abuse correlated with fetal IGF-1 (r = -0.32; p = 0.006) and IGF-2 (r = -0.39; p = 0.001). Maternal BMI negatively correlated with fetal IGF-1 (r = -0.26; p = 0.023) and IGF-2 (r = -0.29; p = 0.011). Newborn anthropometrics were operationalized by length, weight, sex, gestational age, length/gestational age and weight/gestational age at birth. Fetal weight at birth associated with a trend with fetal IGF-1 when controlling for BMI. Maternal hypothalamus-pituitary-adrenal axis activity and maternal exercise did not contribute significantly to predicting fetal IGFs. Maternal childhood trauma (β = -0.27; p = 0.011) and BMI (β = -0.24; p = 0.026) remained significantly associated with fetal IGF-1. Maternal childhood trauma (β = -0.32; p = 0.003), maternal BMI (β = -0.30; p = 0.005) and maternal sexual abuse (β = -0.22; p = 0.049) remained significantly associated with fetal IGF-2 and with a trend with fetal IGF-1 (β = -0.21; p = 0.076) when excluding women with gestational diabetes. CONCLUSION Maternal childhood trauma and BMI associate negatively with fetal IGF-1 and IGF-2 in amniotic fluid. Controlling for maternal BMI, fetal weight at birth remains associated with a trend with fetal IGF-1. The presented data suggests that childhood trauma can affect endocrine measurements of the developing next generation, providing a mechanism by which adverse maternal life events are transmitted to the next generation.
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Affiliation(s)
- Eva Kathrin Lamadé
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
| | - Ferdinand Hendlmeier
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Stefan A Wudy
- Laboratory for Translational Hormone Analytics, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany
| | - Werner F Blum
- Laboratory for Translational Hormone Analytics, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany
| | - Stephanie H Witt
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Marcella Rietschel
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Michaela Coenen
- Institute for Medical Information Processing, Biometry and Epidemiology, Chair of Public Health and Health Services Research, LMU Munich, Munich, Germany; Pettenkofer School of Public Health, Munich, Germany
| | - Maria Gilles
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Michael Deuschle
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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Liao J, Zeng TB, Pierce N, Tran DA, Singh P, Mann JR, Szabó PE. Prenatal correction of IGF2 to rescue the growth phenotypes in mouse models of Beckwith-Wiedemann and Silver-Russell syndromes. Cell Rep 2021; 34:108729. [PMID: 33567274 PMCID: PMC7968144 DOI: 10.1016/j.celrep.2021.108729] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 12/02/2020] [Accepted: 01/15/2021] [Indexed: 12/19/2022] Open
Abstract
Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are imprinting disorders manifesting as aberrant fetal growth and severe postnatal-growth-related complications. Based on the insulator model, one-third of BWS cases and two-thirds of SRS cases are consistent with misexpression of insulin-like growth factor 2 (IGF2), an important facilitator of fetal growth. We propose that the IGF2-dependent BWS and SRS cases can be identified by prenatal diagnosis and can be prevented by prenatal intervention targeting IGF2. We test this hypothesis using our mouse models of IGF2-dependent BWS and SRS. We find that genetically normalizing IGF2 levels in a double rescue experiment corrects the fetal overgrowth phenotype in the BWS model and the growth retardation in the SRS model. In addition, we pharmacologically rescue the BWS growth phenotype by reducing IGF2 signaling during late gestation. This animal study encourages clinical investigations to target IGF2 for prenatal diagnosis and prenatal prevention in human BWS and SRS. Liao et al. use mouse models to test a prenatal approach for correcting growth anomalies in two imprinting diseases, BWS and SRS. They find that cases where the fetal growth factor IGF2 is misregulated can be diagnosed, and growth can be corrected by prenatally adjusting IGF2 or its signaling output.
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Affiliation(s)
- Ji Liao
- Center for Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Tie-Bo Zeng
- Center for Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Nicholas Pierce
- Center for Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Diana A Tran
- Division of Molecular and Cellular Biology, City of Hope Cancer Center, Duarte, CA 91010, USA; Irell and Manella Graduate School, City of Hope, Duarte, CA 91010, USA
| | - Purnima Singh
- Division of Molecular and Cellular Biology, City of Hope Cancer Center, Duarte, CA 91010, USA
| | - Jeffrey R Mann
- Division of Molecular and Cellular Biology, City of Hope Cancer Center, Duarte, CA 91010, USA
| | - Piroska E Szabó
- Center for Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.
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Usuda H, Watanabe S, Saito M, Ikeda H, Koshinami S, Sato S, Musk GC, Fee E, Carter S, Kumagai Y, Takahashi T, Takahashi Y, Kawamura S, Hanita T, Kure S, Yaegashi N, Newnham JP, Kemp MW. Successful use of an artificial placenta-based life support system to treat extremely preterm ovine fetuses compromised by intrauterine inflammation. Am J Obstet Gynecol 2020; 223:755.e1-755.e20. [PMID: 32380175 DOI: 10.1016/j.ajog.2020.04.036] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 04/23/2020] [Accepted: 04/28/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND Ex vivo uterine environment therapy is an experimental intensive care strategy for extremely preterm infants born between 21 and 24 weeks of gestation. Gas exchange is performed by membranous oxygenators connected by catheters to the umbilical vessels. The fetus is submerged in a bath of synthetic amniotic fluid. The lungs remain fluid filled, and pulmonary respiration does not occur. Intrauterine inflammation is strongly associated with extremely preterm birth and fetal injury. At present, there are no data that we are aware of to show that artificial placenta-based systems can be used to support extremely preterm fetuses compromised by exposure to intrauterine inflammation. OBJECTIVE To evaluate the ability of our ex vivo uterine environment therapy platform to support extremely preterm ovine fetuses (95-day gestational age; approximately equivalent to 24 weeks of human gestation) exposed to intrauterine inflammation for a period of 120 hours, the following primary endpoints were chosen: (1) maintenance of key physiological variables within normal ranges, (2) absence of infection and inflammation, (3) absence of brain injury, and (4) gross fetal growth and cardiovascular function matching that of age-matched in utero controls. STUDY DESIGN Ten ewes with singleton pregnancies were each given a single intraamniotic injection of 10-mg Escherichia coli lipopolysaccharides under ultrasound guidance 48 hours before undergoing surgical delivery for adaptation to ex vivo uterine environment therapy at 95-day gestation (term=150 days). Fetuses were adapted to ex vivo uterine environment therapy and maintained for 120 hours with constant monitoring of key vital parameters (ex vivo uterine environment group) before being killed at 100-day equivalent gestational age. Umbilical artery blood samples were regularly collected to assess blood gas data, differential counts, biochemical parameters, inflammatory markers, and microbial load to exclude infection. Ultrasound was conducted at 48 hours after intraamniotic lipopolysaccharides (before surgery) to confirm fetal viability and at the conclusion of the experiments (before euthanasia) to evaluate cardiac function. Brain injury was evaluated by gross anatomic and histopathologic investigations. Eight singleton pregnant control animals were similarly exposed to intraamniotic lipopolysaccharides at 93-day gestation and were killed at 100-day gestation to allow comparative postmortem analyses (control group). Biobanked samples from age-matched saline-treated animals served as an additional comparison group. Successful instillation of lipopolysaccharides into the amniotic fluid exposure was confirmed by amniotic fluid analysis at the time of administration and by analyzing cytokine levels in fetal plasma and amniotic fluid. Data were tested for mean differences using analysis of variance. RESULTS Six of 8 lipopolysaccharide control group (75%) and 8 of 10 ex vivo uterine environment group fetuses (80%) successfully completed their protocols. Six of 8 ex vivo uterine environment group fetuses required dexamethasone phosphate treatment to manage profound refractory hypotension. Weight and crown-rump length were reduced in ex vivo uterine environment group fetuses at euthanasia than those in lipopolysaccharide control group fetuses (P<.05). There were no biologically significant differences in cardiac ultrasound measurement, differential leukocyte counts (P>.05), plasma tumor necrosis factor α, monocyte chemoattractant protein-1 concentrations (P>.05), or liver function tests between groups. Daily blood cultures were negative for aerobic and anaerobic growth in all ex vivo uterine environment group animals. No cases of intraventricular hemorrhage were observed. White matter injury was identified in 3 of 6 lipopolysaccharide control group fetuses and 3 of 8 vivo uterine environment group fetuses. CONCLUSION We report the use of an artificial placenta-based system to support extremely preterm lambs compromised by exposure to intrauterine inflammation. Our data highlight key challenges (refractory hypotension, growth restriction, and white matter injury) to be overcome in the development and use of artificial placenta technology for extremely preterm infants. As such challenges seem largely absent from studies based on healthy pregnancies, additional experiments of this nature using clinically relevant model systems are essential for further development of this technology and its eventual clinical application.
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Affiliation(s)
- Haruo Usuda
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Western Australia, Australia; Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan.
| | - Shimpei Watanabe
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Masatoshi Saito
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Western Australia, Australia; Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Hideyuki Ikeda
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Shota Koshinami
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Shinichi Sato
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Gabrielle C Musk
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Western Australia, Australia; Animal Care Services, The University of Western Australia, Crawley, Western Australia, Australia
| | - Erin Fee
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Western Australia, Australia
| | - Sean Carter
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Western Australia, Australia
| | - Yusaku Kumagai
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Tsukasa Takahashi
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Western Australia, Australia; Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Yuki Takahashi
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Western Australia, Australia; Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan
| | | | - Takushi Hanita
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Shigeo Kure
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Nobuo Yaegashi
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - John P Newnham
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Western Australia, Australia; School of Veterinary and Life Sciences, Murdoch University, Western Australia, Australia
| | - Matthew W Kemp
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Western Australia, Australia; Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan; School of Veterinary and Life Sciences, Murdoch University, Western Australia, Australia
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Tung CL, Hsieh DJY, Baskaran R, Ban B, Dung TD, Ju DT, Viswanadha VP, Day CH, Yeh YL, Huang CY. LPS-enhanced IGF-IIR pathway to induce H9c2 cardiomyoblast cell hypertrophy was attenuated by Carthamus tinctorius extract via IGF-IR activation. ENVIRONMENTAL TOXICOLOGY 2020; 35:145-151. [PMID: 31714667 DOI: 10.1002/tox.22850] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 08/13/2019] [Accepted: 08/14/2019] [Indexed: 06/10/2023]
Abstract
The use of herbs as alternative cardiovascular disease treatment has attracted a great deal of attention owing to their lower toxicity. Whether Carthamus tinctorius extract prevent cardiomyoblast cell hypertrophy remains unclear. The present study was performed to investigate the effect of C tinctorius extract (CTF) on rat cardiomyoblast cell H9c2 and the possible molecular mechanisms. H9c2 cells were treated with lipopolysaccharide (LPS; 2 μg/mL) for 12 hours, subsequently treated with CTF (1-25 μg/mL) The incubation continued for another 24 hours, and the cells were analyzed with actin staining assay, western blot analysis, and siRNA transfection assays. In the present study, the increased cell size induced by LPS was significantly decreased by pretreating at a concentration of 1-25 μg/mL CTF. It was found that CTF could inhibit cardiac hypertrophy induced by LPS and decrease hypertrophic proteins calcineurin, p-GATA-4, GATA-4, atrial natriuretic peptide, and B-type natriuretic peptide levels in H9c2 cells. Additionally, LPS-induced insulin-like growth factor-II receptor (IGF-IIR) hypertrophy pathway was downregulated by CTF. Moreover, IGF-IR siRNA or inhibitors both reversed the CTF effects, confirming that CTF activates IGF-1R to prevent LPS-induced H9c2 cardiomyoblast cell hypertrophy. The current findings indicate that CTF activates IGF-IR to inhibit IGF-IIR signaling pathway which resulted in reducing H9c2 cardiomyoblast cell hypertrophy induced by LPS.
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Affiliation(s)
- Chum-Liang Tung
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
- Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City, Taiwan
| | - Dennis Jine-Yuan Hsieh
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Rathinasamy Baskaran
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
| | - Bo Ban
- Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Tran Duc Dung
- School of Chinese Medicine, Viet Nam Academy of Traditional Medicine, Ha Noi, Viet Nam
| | - Da-Tong Ju
- Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | | | | | - Yu-Lan Yeh
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
| | - Chih-Yang Huang
- Department of Biotechnology, Asia University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Cardiovascular Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan
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Ghanipoor-Samami M, Javadmanesh A, Burns BM, Thomsen DA, Nattrass GS, Estrella CAS, Kind KL, Hiendleder S. Atlas of tissue- and developmental stage specific gene expression for the bovine insulin-like growth factor (IGF) system. PLoS One 2018; 13:e0200466. [PMID: 30001361 PMCID: PMC6042742 DOI: 10.1371/journal.pone.0200466] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 06/27/2018] [Indexed: 01/04/2023] Open
Abstract
The insulin-like growth factor (IGF) axis is fundamental for mammalian growth and development. However, no comprehensive reference data on gene expression across tissues and pre- and postnatal developmental stages are available for any given species. Here we provide systematic promoter- and splice variant specific information on expression of IGF system components in embryonic (Day 48), fetal (Day 153), term (Day 277, placenta) and juvenile (Day 365–396) tissues of domestic cow, a major agricultural species and biomedical model. Analysis of spatiotemporal changes in expression of IGF1, IGF2, IGF1R, IGF2R, IGFBP1-8 and IR genes, as well as lncRNAs H19 and AIRN, by qPCR, indicated an overall increase in expression from embryo to fetal stage, and decrease in expression from fetal to juvenile stage. The stronger decrease in expression of lncRNAs (average ―16-fold) and ligands (average ―12.1-fold) compared to receptors (average ―5.7-fold) and binding proteins (average ―4.3-fold) is consistent with known functions of IGF peptides and supports important roles of lncRNAs in prenatal development. Pronounced overall reduction in postnatal expression of IGF system components in lung (―12.9-fold) and kidney (―13.2-fold) are signatures of major changes in organ function while more similar hepatic expression levels (―2.2-fold) are evidence of the endocrine rather than autocrine/paracrine role of IGFs in postnatal growth regulation. Despite its rapid growth, placenta displayed a more stable expression pattern than other organs during prenatal development. Quantitative analyses of contributions of promoters P0-P4 to global IGF2 transcript in fetal tissues revealed that P4 accounted for the bulk of transcript in all tissues but skeletal muscle. Demonstration of IGF2 expression in fetal muscle and postnatal liver from a promoter orthologous to mouse and human promoter P0 provides further evidence for an evolutionary and developmental shift from placenta-specific P0-expression in rodents and suggests that some aspects of bovine IGF expression may be closer to human than mouse.
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Affiliation(s)
- Mani Ghanipoor-Samami
- Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- JS Davies Epigenetics and Genetics Group, Davies Research Centre, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, South Australia, Australia
| | - Ali Javadmanesh
- Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- JS Davies Epigenetics and Genetics Group, Davies Research Centre, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, South Australia, Australia
| | - Brian M. Burns
- Centre for Animal Science, Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, Rockhampton, Queensland, Australia
| | - Dana A. Thomsen
- Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- JS Davies Epigenetics and Genetics Group, Davies Research Centre, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, South Australia, Australia
| | - Greg S. Nattrass
- Livestock Systems, South Australian Research and Development Institute (SARDI), Roseworthy, South Australia, Australia
| | - Consuelo Amor S. Estrella
- Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- JS Davies Epigenetics and Genetics Group, Davies Research Centre, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, South Australia, Australia
| | - Karen L. Kind
- JS Davies Epigenetics and Genetics Group, Davies Research Centre, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, South Australia, Australia
| | - Stefan Hiendleder
- Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- JS Davies Epigenetics and Genetics Group, Davies Research Centre, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, South Australia, Australia
- * E-mail:
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Pierce J, Jacobson P, Benedetti E, Peterson E, Phibbs J, Preslar A, Reems JA. Collection and characterization of amniotic fluid from scheduled C-section deliveries. Cell Tissue Bank 2016; 17:413-25. [PMID: 27460879 DOI: 10.1007/s10561-016-9572-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 07/15/2016] [Indexed: 02/06/2023]
Abstract
Amniotic fluid (AF) possesses anti-inflammatory, anti-microbial and regenerative properties that make it attractive for use in clinical applications. The goals of this study were to assess the feasibility of collecting AF from full-term pregnancies and to evaluate non-cellular and cellular properties of AF for clinical applications. Donor informed consent and medical histories were obtained from pregnant women scheduled for C-sections and infectious disease testing was performed the day of collection. AFs were evaluated for total volume, fluid chemistries, total protein, and hyaluronic acid (HA) levels. AF was also assessed with quantitative antibody arrays, cellular content and for an ability to support angiogenesis. Thirty-six pregnant women consented and passed donor screening to give birth tissue. AF was successfully collected from 17 individuals. Median AF volumes were 70 mL (range 10-815 mL; n = 17). Fluid chemistries were similar, but some differences were noted in HA levels and cytokine profiles. Cytokine arrays revealed that an average of 304 ± 20 of 400 proteins tested were present in AF with a majority of cytokines associated with host defense. AF supported angiogenesis. Epithelioid cells were the major cell type in AF with only a minor population of lymphoid cells. Cultures revealed a highly proliferative population of adherent cells capable of producing therapeutic doses of mesenchymal stromal cells (MSCs). These findings showed that significant volumes of AF were routinely collected from full-term births. AF contained a number of bioactive proteins and only a rare population of MSCs. Variations noted in components present in different AFs, warrant further investigations to determine their relevance for specific clinical applications.
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Affiliation(s)
- Jan Pierce
- Cell Therapy and Regenerative Medicine Facility, University of Utah, 676 Arapeen Drive, Suite 300, Salt Lake City, UT, 84108, USA
| | - Pam Jacobson
- Cell Therapy and Regenerative Medicine Facility, University of Utah, 676 Arapeen Drive, Suite 300, Salt Lake City, UT, 84108, USA
| | - Eric Benedetti
- Cell Therapy and Regenerative Medicine Facility, University of Utah, 676 Arapeen Drive, Suite 300, Salt Lake City, UT, 84108, USA
| | - Emily Peterson
- Cell Therapy and Regenerative Medicine Facility, University of Utah, 676 Arapeen Drive, Suite 300, Salt Lake City, UT, 84108, USA
| | - Jessica Phibbs
- Cell Therapy and Regenerative Medicine Facility, University of Utah, 676 Arapeen Drive, Suite 300, Salt Lake City, UT, 84108, USA
| | - Amber Preslar
- Cell Therapy and Regenerative Medicine Facility, University of Utah, 676 Arapeen Drive, Suite 300, Salt Lake City, UT, 84108, USA
| | - Jo-Anna Reems
- Cell Therapy and Regenerative Medicine Facility, University of Utah, 676 Arapeen Drive, Suite 300, Salt Lake City, UT, 84108, USA. .,Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA.
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Dasgupta S, Jain SK. Importance of Amniotic Fluid in Gastrointestinal Development. Neoreviews 2016; 17:e367-e376. [DOI: 10.1542/neo.17-7-e367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
Amniotic fluid (AF) is a bioactive medium containing various trophic factors and other nutrients that are necessary for fetal growth and organogenesis. Many trophic factors present in AF are responsible for the development of the fetal gastrointestinal tract. Development and maturation of the gastrointestinal tract is a complex cascade that begins before birth and continues during infancy and childhood by breastfeeding. Many factors, such as genetic preprogramming, local and systemic endocrine secretions, and many trophic factors from swallowed AF, modulate the development and growth of the gastrointestinal tract. Studies are currently examining a potential role of stem cells in AF as a protective agent against the development of necrotizing enterocolitis in preterm infants. Preliminary studies suggest that simulated AF may be a possible means of reducing feeding intolerance. In this article, the authors review the various functions of AF and its importance in fetal gastrointestinal tract development. They also examine possible future uses of this extremely important bioactive fluid.
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Affiliation(s)
- Soham Dasgupta
- Department of Pediatrics, University of Texas Medical Branch, Galveston, TX
| | - Sunil K. Jain
- Department of Pediatrics, University of Texas Medical Branch, Galveston, TX
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Dasgupta S, Arya S, Choudhary S, Jain SK. Amniotic fluid: Source of trophic factors for the developing intestine. World J Gastrointest Pathophysiol 2016; 7:38-47. [PMID: 26909227 PMCID: PMC4753188 DOI: 10.4291/wjgp.v7.i1.38] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 12/22/2015] [Accepted: 01/05/2016] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal tract (GIT) is a complex system, which changes in response to requirements of the body. GIT represents a barrier to the external environment. To achieve this, epithelial cells must renew rapidly. This renewal of epithelial cells starts in the fetal life under the influence of many GIT peptides by swallowing amniotic fluid (AF). Development and maturation of GIT is a very complex cascade that begins long before birth and continues during infancy and childhood by breast-feeding. Many factors like genetic preprogramming, local and systemic endocrine secretions and many trophic factors (TF) from swallowed AF contribute and modulate the development and growth of the GIT. GIT morphogenesis, differentiation and functional development depend on the activity of various TF in the AF. This manuscript will review the role of AF borne TF in the development of GIT.
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The effects of human amniotic fluid and different bone grafts on vertebral fusion in an experimental rat model. Curr Ther Res Clin Exp 2015; 77:35-9. [PMID: 25737745 PMCID: PMC4339529 DOI: 10.1016/j.curtheres.2015.01.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2015] [Indexed: 12/04/2022] Open
Abstract
Objective The high risk of nonunion represents a challenge in vertebral surgery, thus stimulating new strategies to improve fusion rates. We investigated the effect of 2 different bone grafts and amniotic fluid application on radiologically and histologically evaluated vertebral fusion in an experimental rat model. Materials and methods Forty-eight 24-week-old Sprague Dawley rats were included and assigned into 1 of 4 groups: allograft group, allograft plus human amniotic fluid group, demineralized bone matrix (DBM) group, or DBM plus human amniotic fluid group. After decortication and L4–L6 spinal fusion, study treatments were applied. Fusion in each rat was examined radiologically and histologically 8 weeks after the intervention. Results The group that received only allograft had better radiologic scores (median = 3.5; range = 3–4) when compared with the group that received only DBM (median = 2; range = 1–4) (P = 0.002); however, histologic scores did not differ. When amniotic fluid was added to the grafting, allograft-based treatments performed better than DBM-based treatments both on radiologic (median = 4; range = 3–4 vs median = 3; range = 3–4; P = 0.003) and histologic (median = 7; range = 6–7 vs median = 5; range = 3–6; P < 0.001) evaluation. Addition of amniotic fluid did not result in better outcomes in the rats that received DBM-based treatments but based on histologic evaluation, rats that received allograft-based treatments benefited from this application. Conclusions Amniotic fluid seems to have an enhancing effect on posterior spinal fusion, particularly when combined with allograft.
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Chaiworapongsa T, Romero R, Kusanovic JP, Savasan ZA, Kim SK, Mazaki-Tovi S, Vaisbuch E, Ogge G, Madan I, Dong Z, Yeo L, Mittal P, Hassan SS. Unexplained fetal death is associated with increased concentrations of anti-angiogenic factors in amniotic fluid. J Matern Fetal Neonatal Med 2010; 23:794-805. [PMID: 20199197 PMCID: PMC3016945 DOI: 10.3109/14767050903443467] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Angiogenesis is critical for successful pregnancy. An anti-angiogenic state has been implicated in preeclampsia, fetal growth restriction and fetal death. Increased maternal plasma concentrations of the anti-angiogenic factor, soluble vascular endothelial growth factor receptor (sVEGFR)-1, have been reported in women with preeclampsia and in those with fetal death. Recent observations indicate that an excess of sVEGFR-1 and soluble endoglin (sEng) is also present in the amniotic fluid of patients with preeclampsia. The aim of this study was to determine whether fetal death is associated with changes in amniotic fluid concentrations of sVEGFR-1 and sEng, two powerful anti-angiogenic factors. Study design. This cross-sectional study included patients with fetal death (n = 35) and controls (n = 129). Fetal death was subdivided according to clinical circumstances into: (1) unexplained (n = 25); (2) preeclampsia and/or placental abruption (n = 5); and (3) chromosomal/congenital anomalies (n = 5). The control group consisted of patients with preterm labor (PTL) who delivered at term (n = 92) and women at term not in labor (n = 37). AF concentrations of sVEGFR-1 and sEng were determined by ELISA. Non-parametric statistics and logistic regression analysis were applied. Results. (1) Patients with a fetal death had higher median amniotic fluid concentrations of sVEGFR-1 and sEng than women in the control group (p < 0.001 for each); (2) these results remained significant among different subgroups of stillbirth (p < 0.05 for each); and (3) amniotic fluid concentrations of sVEGFR-1 and those of sEng above the third quartile were associated with a significant risk of unexplained preterm fetal death (adjusted OR = 10.8; 95%CI 1.3-89.2 and adjusted OR 87; 95% CI 2.3-3323, respectively). Conclusion. Patients with an unexplained fetal death at diagnosis are characterized by an increase in the amniotic fluid concentrations of sVEGFR-1 and sEng. These observations indicate that an excess of anti-angiogenic factors in the amniotic cavity is associated with unexplained fetal death especially in preterm gestations.
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Affiliation(s)
- Tinnakorn Chaiworapongsa
- Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
| | - Roberto Romero
- Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI
| | - Juan Pedro Kusanovic
- Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
| | - Zeynep Alpay Savasan
- Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
| | - Sun Kwon Kim
- Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, MI, United States
| | - Shali Mazaki-Tovi
- Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
| | - Edi Vaisbuch
- Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
| | - Giovanna Ogge
- Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, MI, United States
| | - Ichchha Madan
- Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
| | - Zhong Dong
- Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, MI, United States
| | - Lami Yeo
- Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
| | - Pooja Mittal
- Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
| | - Sonia S Hassan
- Perinatology Research Branch, NICHD, NIH, DHHS, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
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13
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Kerimoğlu S, Livaoğlu M, Sönmez B, Yuluğ E, Aynacı O, Topbas M, Yarar S. Effects of Human Amniotic Fluid on Fracture Healing in Rat Tibia. J Surg Res 2009; 152:281-7. [DOI: 10.1016/j.jss.2008.02.028] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2007] [Revised: 01/24/2008] [Accepted: 02/12/2008] [Indexed: 11/26/2022]
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Abstract
Nutrition plays a major role in the modulation of the evolving human gut influencing all the main components of the intestinal ecosystem. The regulatory role of nutrition is particularly crucial in the early postnatal period but it continues also in subsequent ages when the development of the gastrointestinal tract is completed. Recent data support the hypothesis that nutrition can affect some inherited disorders of gastrointestinal tract. These "epigenetic" mechanisms are involved in the development of intestinal enzymes, hormones, transporters, and immunity. This is an expanding research area related to the possible nutritional intervention in selected clinical condition. This paper is focused on the main components and mechanisms of action of the nutritional modulation on intestinal development.
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15
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Host factors in amniotic fluid and breast milk that contribute to gut maturation. Clin Rev Allergy Immunol 2008; 34:191-204. [PMID: 18330727 DOI: 10.1007/s12016-007-8032-3] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The gut represents a complex organ system with regional differences, which reflect selective digestive and absorptive functions that change constantly in response to bodily requirements and the outside milieu. As a barrier to the external environment, gut epithelium must be renewed rapidly and repeatedly. Growth and renewal of gut epithelial cells is dependent on controlled cell stimulation and proliferation by a number of signaling processes and agents, including gut peptides-both endogenous and exogenous sources. This cascade of events begins during fetal development; with the ingestion of amniotic fluid, this process is enhanced and continued during infancy and early childhood through the ingestion of human milk. Events influenced by amniotic fluid during fetal development and those influenced by human milk that unfold after birth and early childhood to render the gut mature are presented.
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16
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Donovan SM. Role of human milk components in gastrointestinal development: Current knowledge and future NEEDS. The journal The Journal of Pediatrics 2006. [DOI: 10.1016/j.jpeds.2006.06.052] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Tisi DK, Liu XJ, Wykes LJ, Skinner CD, Koski KG. Insulin-like growth factor II and binding proteins 1 and 3 from second trimester human amniotic fluid are associated with infant birth weight. J Nutr 2005; 135:1667-72. [PMID: 15987847 DOI: 10.1093/jn/135.7.1667] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The developing fetus begins to swallow amniotic fluid (AF) early in gestation, a process that results in ingestion of numerous growth factors. Our objectives were 2-fold: 1) to assess the concentration and distribution of insulin-like growth factor II (IGF II) and its binding proteins (BP) 1 and 3 in 2nd trimester amniotic fluid using ELISA, and 2) to establish whether concentrations of AF IGF II and its binding proteins IGF BP1 and 3, measured early in pregnancy, were associated with and predictive of infant birth weight. Birth weights were categorized using recently developed birth-weight-for-gestational-age percentiles for fetal growth in which infants < 10% were classified as SGA (small-for-gestational-age) and those > 90% as LGA (large-for-gestational-age). AF samples were collected after routine genetic testing (15.1 +/- 0.04 wk, range 12-20 wk) from 543 mother-infant pairs in Montreal, QC, Canada. Maternal and fetal characteristics were obtained from questionnaires and medical chart review. Multivariate regression analysis that controlled for maternal height, prepregnancy weight, smoking behavior, infant gender, gestational age, parity, as well as amniocentesis week showed that higher AF IGF BP1 was associated with lower birth weight (partial r2 = 0.0062). Regression analyses revealed that AF IGF BP3 was positively associated with birth weight within LGA and macrosomia subpopulations (partial r2 = 0.0283 and 0.0404, respectively). These results show that 2nd trimester AF IGF BP1, BP3, and IGF II may emerge as early indicators of fetal growth.
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Affiliation(s)
- Daniel K Tisi
- School of Dietetics and Human Nutrition, McGill University, Montreal, Canada
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18
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Strodtbeck F. The pathophysiology of prolonged periods of no enteral nutrition or nothing by mouth. ACTA ACUST UNITED AC 2003. [DOI: 10.1016/s1527-3369(03)00005-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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19
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Ozgenel GY, Filiz G. Effects of human amniotic fluid on peripheral nerve scarring and regeneration in rats. J Neurosurg 2003; 98:371-7. [PMID: 12593625 DOI: 10.3171/jns.2003.98.2.0371] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECT Peripheral nerve repair surgery is still replete with challenges. Despite technical improvements in microsurgery, classic methods of nerve repair have failed to provide satisfactory results. The purpose of this study was to investigate the effects of amniotic fluid from humans on peripheral nerve scarring and regeneration in rats. METHODS Forty adult Sprague-Dawley rats were used in this study. After the right sciatic nerve in each rat was transected and repaired using an epineural suture procedure, the nerves were divided into two groups according to the solution applied around the repair site: experimental group, 0.3 ml human amniotic fluid (HAF); and control group, 0.3 ml saline. Macroscopic and histological evaluations of peripheral nerve scarring were performed 4 weeks postsurgery. Nerves treated with HAF demonstrated a significant reduction in the amount of scar tissue surrounding the repair site (p < 0.05). No evidence of a reaction against HAF was noted. Functional nerve regeneration was measured once every 2 weeks by using a sciatic function index until 12 weeks postsurgery. Functional recovery in nerves treated with amniotic fluid occurred significantly faster than that in nerves treated with saline (p < 0.05). Peripheral nerve regeneration was evaluated histomorphologically at 12 weeks postsurgery. Nerves treated with amniotic fluid showed significant improvement with respect to the indices of fiber maturation (p < 0.05). CONCLUSIONS Preliminary data show that HAF enhances peripheral nerve regeneration. The preventive effect of HAF on epineural scarring and the rich content of neurotrophic and neurite-promoting factors possibly contribute to this result.
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Affiliation(s)
- Güzin Yeşim Ozgenel
- Departments of Plastic and Reconstructive Surgery, and Pathology, Uludağ University Medical School, Bursa, Turkey.
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20
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Hirai C, Ichiba H, Saito M, Shintaku H, Yamano T, Kusuda S. Trophic effect of multiple growth factors in amniotic fluid or human milk on cultured human fetal small intestinal cells. J Pediatr Gastroenterol Nutr 2002; 34:524-8. [PMID: 12050579 DOI: 10.1097/00005176-200205000-00010] [Citation(s) in RCA: 114] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To evaluate the role of growth factors in amniotic fluid and in human milk on gastrointestinal adaptation of the fetus and very low-birth-weight infants, the effects of these fluids and multiple growth factors were investigated in a human fetal small intestinal cell line (FHs 74 Int). METHODS After FHs 74 Int cells were incubated with amniotic fluid, human milk, or recombinant growth factors, growth-promoting activity was measured by [3H]-thymidine incorporation into cells. RESULTS Incubating cells with amniotic fluid or human milk promoted growth dose dependently. Genistein almost completely inhibited growth-promoting activity in amniotic fluid P = 0.002), and growth was partially inhibited by antibodies against epidermal growth factor (EGF) (P = 0.047), insulin-like growth factor-1 (IGF-1, P = 0.047), or fibroblast growth factor (FGF, P = 0.014). This activity in human milk was inhibited almost completely by genistein (P < 0.0001) and partially inhibited by antibodies against EGF (P = 0.036), IGF-1 (P = 0.009), FGF (P = 0.004), hepatocyte growth factor (HGF, P = 0.001), or transforming growth factor-alpha (TGF-alpha, P = 0.001). Although recombinant EGF, IGF-1, FGF, HGF, and TGF-alpha elicited a synergistic trophic response on cultured cells, the response was much less than with amniotic fluid or with human milk. CONCLUSION In aminiotic fluid and in human milk, EGF, IGF-1, FGF, HGF, and TGF-alpha have a strong trophic effect on immature intestinal cells and may be involved in perinatal gastrointestinal adaptation.
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Affiliation(s)
- Chie Hirai
- Department of Pediatrics, Osaka City University Graduate School of Medicine, Japan
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21
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Ozgenel GY. The influence of human amniotic fluid on the potential of rabbit ear perichondrial flaps to form cartilage tissue. BRITISH JOURNAL OF PLASTIC SURGERY 2002; 55:246-50. [PMID: 12041980 DOI: 10.1054/bjps.2002.3811] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Since several experimental and clinical studies demonstrated the chondrogenic potential of perichondrium, there has been great interest in examining factors that might promote neochondrogenesis from perichondrium. Human amniotic fluid contains hyaluronic acid, growth factors and extracellular macromolecules, and may, therefore, have a stimulating effect on cartilage regeneration. This experimental study investigated the effect of human amniotic fluid on cartilage regeneration from rabbit ear perichondrial flaps, using 96 ears of 48 New Zealand young rabbits. A perichondrial flap was elevated and a cartilage defect measuring 20 mm x 15 mm was created on the dorsum of each ear, then the perichondrial flap was sutured in place. The ears were divided into two groups according to the solution injected underneath the perichondrial flap. The right ears, which were injected with 0.2 ml human amniotic fluid, formed the experimental group, and the left ears, which were injected with 0.2 ml saline, formed the control group. Macroscopic and histological progression of neochondrogenesis were evaluated at 2, 4, 6 and 8 weeks after surgery. Macroscopically, the cartilage in the experimental group was generated quickly and had a similar appearance to the surrounding cartilage tissue, whereas in the control group minimal cartilage formation was observed at 4 weeks. Histologically, the neocartilage was significantly thicker in the experimental group than in the control group at 8 weeks (P < 0.05, Student's t -test). It can be concluded that human amniotic fluid enhances new cartilage formation from rabbit ear perichondrial flaps. The preventive effect of human amniotic fluid on scar formation and the rich content of growth factors and extracellular matrix precursors may play a role in this result.
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Affiliation(s)
- G Y Ozgenel
- Department of Plastic and Reconstructive Surgery, Uludae University, Görükle, Bursa, Turkey
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Bloomfield FH, Breier BH, Harding JE. Fate of (125)I-IGF-I administered into the amniotic fluid of late-gestation fetal sheep. Pediatr Res 2002; 51:361-9. [PMID: 11861943 DOI: 10.1203/00006450-200203000-00016] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Large amounts of amniotic fluid (AF) are swallowed in late gestation. AF is the most accessible fetal compartment and provides a possible paraplacental route for the therapeutic administration of hormones and nutrients to the fetus. We therefore wished to investigate the fate of the predominant fetal growth factor, IGF-I, administered into AF of late-gestation ovine fetuses. Seven chronically catheterized fetuses at 124 d gestation had approximately 800 x 10(6) dpm of (125)I-IGF-I injected into the AF. AF and blood samples were withdrawn for up to 6 d. At 131 d gestation a postmortem examination was performed. All AF, blood, and tissue samples were counted. Selected samples of AF, blood, and gut contents underwent size-separation chromatography. (125)I-IGF-I was rapidly mixed in AF, with a significant difference in counts from different regions of the cavity persisting for only 3 h (p < 0.05). In vivo binding of (125)I-IGF-I in AF correlated highly with AF IGF binding protein 3 concentrations (r(2) = 0.93, p < 0.0001). In some animals, free (125)I-IGF-I persisted in AF and in plasma for the duration of the experiments. Chromatography of plasma samples demonstrated that intact (125)I-IGF-I was taken up from the fetal gut. Only fetal gut and thyroid contained appreciable counts at postmortem examination. Gut contents had more counts than gut wall, and the number of counts in gut contents increased distally (p < 0.05 for colon contents versus other regions). We conclude that there is sustained delivery of (125)I-IGF-I from the AF to the gut and systemic circulation of the ovine fetus after a single intraamniotic injection.
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Affiliation(s)
- Frank H Bloomfield
- Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand
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Bloomfield FH, Bauer MK, van Zijl PL, Gluckman PD, Harding JE. Amniotic IGF-I supplements improve gut growth but reduce circulating IGF-I in growth-restricted fetal sheep. Am J Physiol Endocrinol Metab 2002; 282:E259-69. [PMID: 11788356 DOI: 10.1152/ajpendo.00200.2001] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Insulin-like growth factor I (IGF-I) is an important regulator of fetal growth, and circulating concentrations are reduced in intrauterine growth-restricted (IUGR) fetuses. We investigated whether IGF-I administered into amniotic fluid could ameliorate IUGR in fetal sheep. Fetuses were assigned to control (n = 9), IUGR+saline (n = 12), or IUGR+IGF-I groups (daily intra-amniotic IGF-I injections of 20 microg, n = 13). IUGR was induced by placental embolization from 114 to 120 days. Treatment was from 120 to 130 days of gestation. Embolization produced asymmetrically IUGR fetuses with decreased body weight and lighter, thinner-walled guts. Fetal plasma and amniotic IGF-I levels were reduced. During treatment, fetal plasma, but not amniotic, IGF-I levels recovered in the saline group but remained depressed in the IGF-I-treated group. IGF-I treatment restored gut weight and wall thickness to control levels and increased the number of crypt mitoses. Fetal weight was similar to that of controls, but spleen, liver, and thymic weights were reduced by 30-37%, and placentome growth was altered. Amniotic fluid IGF-I supplementation may provide the basis of future therapeutic approaches to IUGR, but the systemic effects require further investigation.
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Affiliation(s)
- Frank H Bloomfield
- Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand
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Kong W, Yee LF, Mulvihill SJ. Hepatocyte growth factor stimulates fetal gastric epithelial cell growth in vitro. J Surg Res 1998; 78:161-8. [PMID: 9733635 DOI: 10.1006/jsre.1997.5230] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND The growth and development of the fetal gastrointestinal tract is likely mediated, in part, by peptide growth factors. We compared the mitogenic effects of graded doses of hepatocyte growth factor (HGF) to epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and insulin-like growth factor-1 (IGF-1) on fetal rabbit gastric epithelial cells. MATERIALS AND METHODS Fetal rabbit gastric epithelial cells were purified by mechanical dissociation and selected culture and grown in short-term (24 h) and long-term (12 days) culture. Stimulation of fetal gastric epithelial cell growth in response to individual peptide growth factors was measured by [3H]thymidine incorporation and cell counting. RESULTS In short-term culture, HGF stimulated [3H]thymidine incorporation in a dose-dependent manner from a threshold at 10 pM to a maximum at 100 pM. For EGF and TGF-alpha, maximal stimulation occurred at 100 pM. For HGF, maximal [3H]thymidine incorporation was 3.6 +/- 0.7 times basal. For EGF and TGF-alpha, maximal [3H]thymidine incorporation was 4.3 +/- 0.4, and 3.6 +/- 0.4 times basal, respectively. For IGF-1, maximal [3H]thymidine incorporation was only 70% of the maximal effect observed for the other growth factors tested. Rabbit amniotic fluid increased [3H]thymidine uptake in a dose-dependent manner. In long-term culture, purification to greater than 90% epithelial cells was attained after 12 days treatment. For HGF, EGF, TGF-alpha, and 20% rabbit amniotic fluid, significant increases in cell number above control (P < 0.05) were observed at 1 nM concentrations. None of these individual factors, however, increased cell growth as significantly as that of 10% fetal bovine serum. CONCLUSIONS Our results suggest that: (1) HGF stimulates [3H]thymidine uptake and cell proliferation in fetal rabbit gastric epithelial cells in vitro, and (2) HGF's mitogenic effect on fetal rabbit gastric epithelial cell growth is comparable to that observed for EGF and TGF-alpha, but superior to the effect observed for IGF-1.
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Affiliation(s)
- W Kong
- Department of Surgery, University of California at San Francisco, 533 Parnassus Avenue, San Francisco, California, 94143-0788, USA
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Zgleszewski SE, Blewett CJ, Cilley RE, Krummel TM, Chinoy MR. Esophageal/pyloric ligation enhances development of the murine fetal stomach in organ culture. J Pediatr Surg 1998; 33:433-41. [PMID: 9537553 DOI: 10.1016/s0022-3468(98)90084-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE The authors hypothesized that increased intraluminal pressure in the fetal stomach would enhance development in a murine organ culture model. METHODS Gestation day 14 (Gd14) fetal stomachs from time-dated pregnant CD-1 mice (term, 20 days) were maintained in organ culture for 7 days. Some stomachs were ligated at the gastroesophageal (GE) and pyloroduodenal (PD) junctions. Others were left unligated. Gd14, Gd16, and Gd18 stomachs were taken as well to compare organogenesis in vivo. Tissues were processed for histological, morphometric, and immunohistochemical analysis, as well as total protein and DNA determination. RESULTS The ligated stomachs were visibly distended compared with unligated stomachs in organ culture after 7 days. The length and width of the 7-day in vitro ligated stomachs were significantly increased compared with unligated (2.97+/-0.04 mm v 2.48+/-0.05 mm and 2.14+/-0.04 mm v 1.57+/-0.08 mm, respectively, P < .05). Mucosal epithelial cells showed nuclear polarization, and there was a distinct outer muscle layer in the ligated stomachs, but not in the unligated stomachs, which demonstrated pseudostratified epithelial cells in the mucosa. The ligated stomachs had increased in mucosal thickness compared with unligated (31.4+/-1.3 microm vs 24.9+/-0.9 microm, p < 0.05). The ligated stomachs also had significantly increased protein and DNA content when compared with unligated stomachs (65.8+/-3.1 microg and 23.3+/-1.2 microg v 55.0+/-2.7 microg and 19.0+/-1.2 microg, respectively, P < .05). However, there were no significant differences noted between the protein to DNA ratios. Immunohistochemical staining for proliferating cell nuclear antigen (PCNA), a marker for cell proliferation, demonstrated increased proliferative activity of the mucosal epithelial cells in the ligated stomachs. CONCLUSIONS Esophageal and pyloric ligation enhanced the development of the fetal stomach in vitro in comparison with unligated stomachs cultured under similar conditions. Developmental characteristics of the ligated stomachs paralleled that of Gd16 stomachs in vivo.
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Affiliation(s)
- S E Zgleszewski
- Department of Surgery, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey 17033, USA
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Abstract
Skin wound healing has been shown to be a different process in the fetus than in the adult animal. Some of these differences have been attributed to the unique fetal environment (i.e., amniotic fluid). The aim of the present study is to compare fetal skin healing in intraamniotic and extraamniotic wounds. A fetal rabbit model has been used in which three types of skin wounds were induced on 23-day-old fetuses in contact with either amniotic fluid or maternal peritoneal fluid. The wounds consisted of a sutured skin incision, a nonsutured incision, and an electrocautery burn. Seven days later all wounds were examined mechanically (scar resistance), biochemically (collagen and noncollagen protein concentration), and histologically. Biochemical and growth factor studies of both environments, the amniotic and the peritoneal fluids, were also conducted. The results showed excellent healing by first intention and absence of healing by second intention in both environments, greater scar resistance in the intraperitoneally positioned fetal wounds, and a higher concentration of insulin-like growth factor-1 (IGF-1) in the peritoneal fluid than in the amniotic fluid. It can be concluded that fetal skin wounds in contact with peritoneal fluid show the same healing pattern as in the natural fetal environment (amniotic fluid). The higher concentration of IGF-1 in the peritoneal fluid suggests that this growth factor, through its relationship with the growth hormone, plays a role in increasing the scar resistance of fetal skin wounds in contact with maternal peritoneal fluid.
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Affiliation(s)
- M A Sancho
- Servicio de Cirugia Pediatrica, Hospital Sant Joan de Deu, Universidad de Barcelona, Spain
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Trahair JF, Wing SJ, Horn JL. Failure of short-term luminal IGF-I to protect against atrophy in a model of fetal esophageal atresia. J Pediatr Surg 1995; 30:1564-70. [PMID: 8583326 DOI: 10.1016/0022-3468(95)90158-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Short-term luminal infusion in utero (3 days) of insulin-like growth factor I (IGF-I) failed to protect the fetal small intestine against atrophy induced by ablation of swallowing. Human recombinant IGF-1 (or vehicle) was infused into the duodenum of fetal sheep at 125 days' gestation for 3 days (day 1, 0.025 mg; day 2, 0.25 mg: day 3, 2.5 mg). Fetal swallowing was prevented by esophageal ligation, and a carotid catheter was implanted for blood sampling. There were no changes in body growth of in major organ growth. Small intestinal (SI) weight (corrected for body weight) was significantly lower for IGF-I treated fetuses. Villus height decreased significantly in proximal regions. Villus enterocyte cellularity was reduced significantly in the proximal regions. The percentage of crypt cells labeled with a 4-hour pulse of tritiated thymidine (as assessed by autoradiography) decreased significantly in the proximal SI only, from 16.14% (1.06% SEM) to 13.28% (1.05% SEM) (P < .05). Plasma levels of IGF-1 increased in the treated fetuses by an average of 76%. IGF-1 immunoreactivity was detected in the apical endocytic complex of enterocytes from proximal SI. This study shows that wasting of fetal intestinal tissues in the absence of enteral input cannot be prevented by IGF-1 delivered luminally.
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Affiliation(s)
- J F Trahair
- Department of Anatomy & Histology, University of Adelaide, Australia
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Lewitt MS, Scott FP, Clarke NM, Baxter RC. Developmental regulation of circulating insulin-like growth factor-binding proteins in normal pregnancies and in pre-eclampsia. PROGRESS IN GROWTH FACTOR RESEARCH 1995; 6:475-80. [PMID: 8817692 DOI: 10.1016/0955-2235(95)00030-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The insulin-like growth factors (IGFs) and their binding properties (IGFBPs) are believed to play important roles in the growth and development of the human fetus. They have been implicated in the pathophysiology of pre-eclampsia. In this study we have characterized the developmental regulation, in normal and pre-eclamptic pregnancies, of IGFs and IGFBPs in maternal serum, neonatal serum and amniotic fluid. In neonatal cord serum IGFBP-1, -2 and -6 decreased with increasing gestational age. In contrast, the ternary complex and its components, IGF-I, IGFBP-3 and ALS increased with gestation. We show that while ALS is an important limiting factor for ternary complex formation in the fetal circulation, there is a fraction of IGFBP-3 which is unable to form this complex. IGFs and IGFBPs in the maternal and fetal circulation were similar in normal and pre-eclamptic pregnancies.
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Affiliation(s)
- M S Lewitt
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia
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Trahair JF, Rodgers HF, Cool JC, Ford WD. Altered intestinal development after jejunal ligation in fetal sheep. VIRCHOWS ARCHIV. A, PATHOLOGICAL ANATOMY AND HISTOPATHOLOGY 1993; 423:45-50. [PMID: 8212533 DOI: 10.1007/bf01606431] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Experimental obstruction of the fetal small intestine resulted in massive hypertrophy of the segment proximal to the site of obstruction. Villus morphology was grossly abnormal. Enterocytes developed many irregular features, most notably cytoplasmic extensions (pseudopods, or blebs) from their apical surface. Distal to the site of obstruction, morphological anomalies which resembled those seen after experimental oesophageal ligation were found. These included delayed disappearance of the apical endocytic network, disrupted or absent microvilli, glycogen accumulation and inappropriate cell extrusion. Proximal to the obstruction, where stasis of swallowed fluid occurs, distension and abnormal intestinal development ensues. Distal to the obstruction where the intestine develops in the absence of swallowed fluid, development is also abnormal. The anomalies resemble those noted after oesophageal ligation in utero, and possibly are the results of reduced cellular nutrition. These results suggest that fetal ingestion provides the developing gastrointestinal tract with an important stimulus for normal growth.
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Affiliation(s)
- J F Trahair
- Child Health Research Institute, Women's and Children's Hospital, Adelaide, Australia
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Trahair JF. Is fetal enteral nutrition important for normal gastrointestinal growth?: a discussion. JPEN J Parenter Enteral Nutr 1993; 17:82-5. [PMID: 8437331 DOI: 10.1177/014860719301700182] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Long-term total parenteral nutrition results in atrophy of small intestinal structure and function. Maintenance or re-establishment of enteral nutrition can prevent or redress this loss. Paradoxically, the fetus develops in a total parenteral nutrition environment, but at the same time must achieve appropriate levels of gastrointestinal maturation in readiness for enteral feeding soon after birth. The fetus swallows large amounts of fluid during life in utero and growth is arrested if fetal ingestion is impaired. It is possible therefore that enteral nutrition provided by fetal swallowing is just as important in ensuring normal gastrointestinal homeostasis and growth in the fetus as it is in the adult.
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Affiliation(s)
- J F Trahair
- Child Health Research Institute, Adelaide Medical Centre for Women & Children, Australia
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Wathen NC, Wang HS, Cass PL, Campbell DJ, Chard T. Insulin-like growth factor-1 and insulin-like growth factor binding protein-1 in early human pregnancy. Early Hum Dev 1992; 28:105-10. [PMID: 1375140 DOI: 10.1016/0378-3782(92)90105-p] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-1 (IGFBP-1) were measured in amniotic fluid, extraembryonic coelomic fluid and maternal serum from 23 women with apparently normal first trimester pregnancies prior to termination. The levels of IGF-1 and IGFBP-1 were significantly higher in coelomic fluid than amniotic fluid (IGF-1, P = 0.006; IGFBP-1, P = 0.0008 (paired t-test)). The levels of IGFBP-1 were lower in amniotic fluid than in maternal serum (P = 0.017), a finding in sharp contrast to the situation in the second and third trimesters of pregnancy. There was a significant relation between levels of IGF-1 and IGFBP-1 in amniotic fluid (r = 0.43; P = 0.04) and in coelomic fluid (r = 0.81; P less than 0.001) but not in maternal serum. The finding that both the absolute levels of IGFBP-1 and the ratio to IGF-1 were low in amniotic fluid implies that there is a very high level of unbound, biologically active IGF-1 in this compartment in the first trimester. Thus, the regulatory role of IGFBP-1 may change as pregnancy advances.
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Affiliation(s)
- N C Wathen
- Combined Academic Departments of Obstetrics, Homerton Hospital, West Smithfield, London, U.K
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Yeh J, Danehy FT, Osathanondh R, Villa-Komaroff L. mRNAs for insulin-like growth factor-II (IGF-II) and variant IGF-II are co-expressed in human fetal ovary and uterus. Mol Cell Endocrinol 1991; 80:75-82. [PMID: 1955083 DOI: 10.1016/0303-7207(91)90144-h] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Insulin-like growth factor-II (IGF-II) is postulated to have autocrine and/or paracrine functions in developing fetal tissues, but has never been reported in human fetal reproductive organs. The forms of IGF-II found in normal human serum include a 67 amino acid form and a variant form resulting from alternate splicing of the mRNA such that Ser-29 is replaced by four other amino acid residues. We studied the expression of mRNA encoding IGF-II in human fetal ovaries and uteruses of 10, 15, 19 and 22 weeks of gestation. By reverse transcription followed by polymerase chain reaction (PCR), we identified the co-expression of two mRNAs encoding IGF-II in all developmental stages of fetal ovaries and uteruses tested. One of the PCR amplified fragments was 9 nucleotides larger than the other. The PCR amplified ovarian and uterine DNA fragments were mapped by digestion with the restriction endonucleases AvaII and PvuII and both the IGF-II fragment and the larger IGF-II fragment produced the anticipated DNA patterns by gel electrophoresis. The PCR amplified DNA fragments were cloned and sequenced to confirm that the expressed mRNAs encoded IGF-II and variant IGF-II. We conclude that IGF-II and variant IGF-II mRNA co-expression occurs in the human fetal female genital tract and that the two forms of the growth factors may have physiologic roles in reproductive tract development.
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Affiliation(s)
- J Yeh
- Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, MA 02115
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Frunzio R, Chiariotti L, Brown AL, Graham DE, Rechler MM, Bruni CB. Structure and expression of the rat insulin-like growth factor II (rIGF-II) gene. rIGF-II RNAs are transcribed from two promoters. J Biol Chem 1986. [DOI: 10.1016/s0021-9258(19)76010-4] [Citation(s) in RCA: 91] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Abstract
Insulin-like growth factors (IGF) in serum from 3 patients with nonislet cell tumors and hypoglycemia were measured by radioimmunoassay and by means of a rat liver membrane assay (specific for IGF II). The concentration of IGF II by receptor assay was greater than normal when the samples were initially assayed, but subsequently decreased 48% to 80% over the next 8 to 15 weeks. In the same serum samples, concentrations of both IGF I and IGF II by radioimmunoassay were consistently less than normal. In all 3 patients growth hormone (GH) responses to intravenous arginine were depressed and in 2 of the 3 patients, a GH-dependent 150 K serum protein carrier of IGF was absent. None of these abnormalities were seen in 7 patients with insulinomas and chronic hypoglycemia. The data suggest that some patients with nonislet cell tumors and hypoglycemia produce a receptor-active, nonimmunoreactive IGF-II-like material. This material appears (a) more labile than normal IGF II and (b) capable of inhibiting GH secretion. The latter effect may decrease immunoreactive IGF I and II, as well as decrease the GH-dependent 150 K protein carrier of these factors. The extreme lability of the IGF-II-like material produced by tumors probably explains the previous contradictory reports on this topic.
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Congote LF. Similarities in structure and function of bovine serum erythrotropin and human insulin-like growth factor II: two fetal erythroid cell stimulating factors. Biochem Biophys Res Commun 1985; 126:653-9. [PMID: 3883999 DOI: 10.1016/0006-291x(85)90234-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Serum erythrotropin (ET) was isolated from fetal bovine serum. Partial sequence analysis of the N-terminal portion of the peptide indicated that the first 20 amino acids were practically identical to those found in human insulin-like growth factor II (IGF II). The effect of IGF II on [3H] thymidine incorporation in cell cultures of fetal bovine liver was similar to the effect of ET. Both factors acted synergistically with erythropoietin but not with platelet derived growth factor. The stimulation of thymidine incorporation by ET and IGF II on cell cultures of fetal liver erythroid cells was at least 15 times higher than their effects on cultures of fetal calf intestine, lung and kidney cells.
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