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Effects of Sex Steroids on Adult Stem/Progenitor Cell-Mediated Cardiovascular Regeneration

Applicant Dubey Raghvendra K.
Number 142213
Funding scheme Romanian-Swiss Research Programme (RSRP)
Research institution Klinik für Reproduktions-Endokrinologie Departement Frauenheilkunde Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Cardiovascular Research
Start/End 01.01.2013 - 30.06.2016
Approved amount 362'821.00
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All Disciplines (5)

Discipline
Cardiovascular Research
Molecular Biology
Pathophysiology
Cardiovascular Diseases
Endocrinology

Keywords (11)

Menopause; Andropause; ageing; Sex hormones; stem cells; progenitor cells; endothelium; tissue regeneration; cardiovascular disease; heart disease; coronary artery disease

Lay Summary (German)

Lead
Hypothesis: Sex Hormones, play a key role in directly modulating adult stem cell induced tissue repair & regeneration following myocardial infarction, moreover, decreases in estrogen & androgen levels in ageing men & women may be associated with decreased potential for stem cell mediated repair of cardiovascular tissue. Since patients receiving stem cells for cardiovascular repair are older, low endogenous levels of sex hormones would decrease the potential of stem cell mediated tissue repair.
Lay summary
Sowohl bei  Frauen und Männern korrelieren Herz- Kreislauf- Erkrankungen mit dem Alter und werden mit den  Östrogen-Spiegel bei Frauen  und  Androgen-Spiegel bei Männern, welche mit dem  Einsetzen der Wechseljahre sinken, in Zusammenhang gebracht.  Die niedrige Konzentration an Östrogenen und Androgenen könnte der Grund für die erhöhte Todesursache Herzinfarkt bei menopausalen Frauen und andropausalen Männern sein. Sexualhormone beeinflussen die  normale Funktion von Blutgefässen, aber wichtiger ist deren Rolle bei Zellprozessen in denen altersbedingte Membranschäden repariert werden. Zum Beispiel aktivieren Sexualhormone endotheliale Stammzellen und führen so zur Reparatur der Membran.  In diesem Projekt  wird untersucht, ob Sexualhormone (Östrogene und Androgene) eine Schlüsselrolle in der Reparatur und Regeneration von Herzgewebe, induziert durch adulte Stammzellen, nach einem Herzinfarkt spielen. Weiters wird untersucht ob der niedrige Östrogen- und Androgenspiegel in älteren Frauen und Männern in direkten  Zusammenhang mit dem niedrigen Regenerationspotential von Stammzellen auf  Herzgewebe steht.  Der Grossteil der Patienten, die Stammzelltherapie erhalten um Herzgewebe zu regenerieren, ist älter und verfügt daher über  niedrige Konzentration an Sexualhormonen, was zu einem erniedrigten Potential dieser Therapieform führen könnte. Die Resultate aus dieser vorgeschlagenen Studie können die Bedeutung von Sexualhormonen in Stammzellen vermittelter Herzgewebereparatur und – regeneration untermauern und so zur Optimierung der klinischen Stammzelltherapie führen. Wenn Sexualhormone einen gewebereparierenden Prozess induzieren, könnten sie zusätzlich zur Stammzelltherapie verabreicht werden und somit deren Effekt potenzieren.
Direct link to Lay Summary Last update: 22.11.2012

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Mechanism of 17β-estradiol stimulated integration of human mesenchymal stem cells in heart tissue
Mihai Maria Cristina, Popa Mirel Adrian, Suica Viorel Iulian, Antohe Felicia, Jackson Edwin K., Simionescu Maya, Dubey Raghvendra K. (2019), Mechanism of 17β-estradiol stimulated integration of human mesenchymal stem cells in heart tissue, in Journal of Molecular and Cellular Cardiology, 133, 115-124.
Mechanism of 17β-estradiol stimulated integration of human mesenchymal stem cells in heart tissue
Mihai Maria Cristina, Popa Mirel Adrian, Suica Viorel Iulian, Antohe Felicia, Jackson Edwin K., Simionescu Maya, Dubey Raghvendra K. (2019), Mechanism of 17β-estradiol stimulated integration of human mesenchymal stem cells in heart tissue, in Journal of Molecular and Cellular Cardiology, 133, 115-124.
Effect of androgenic hormones on mesenchymal stromal / progenitor cells involved in cardiovascular regeneration
PopaMirel (2018), Effect of androgenic hormones on mesenchymal stromal / progenitor cells involved in cardiovascular regeneration, Institute of Biology and Pathology "Nicolae Simionescu", George Emil Palade Hall of Institute of Cellular Biology and Pathology.
Dihydrotestosterone induces pro-angiogenic factors and assists homing of MSC into the cardiac tissue
Popa Mirel-Adrian Constantin Alina Sulca Vlorel Tucureanu Catalin Costache, Antohe Felicia Dubey Raghvendra K Simionescu Maya (2018), Dihydrotestosterone induces pro-angiogenic factors and assists homing of MSC into the cardiac tissue, in Journal of Molecular Endocrinology, 60, 1-15.
Role of G-protein Coupled Estrogen Receptor in Mediating the Vasoprotective actions of Estradiol
Unterleutner Elisabeth (2016), Role of G-protein Coupled Estrogen Receptor in Mediating the Vasoprotective actions of Estradiol, ETH-Zurich, Zurich.
Testosterone stimulates proliferation and preserves stemness of human adult mesenchymal stem cells and endothelial progenitor cells
Corotchi MC Popa MA Simionescu M (2016), Testosterone stimulates proliferation and preserves stemness of human adult mesenchymal stem cells and endothelial progenitor cells, in Rom J Morphol Embryol, 57(1), 75-80.
The osteoinductive potential of collagen based scaffolds for human mesenchymal stromal cells depends on scaffold composition and on the source of the cells; the need for pesonalized tests.
Pruna V, Titorencu I, Albu MG , Lungu A, Jinga VV, Radulescu R, Simionescu M (2016), The osteoinductive potential of collagen based scaffolds for human mesenchymal stromal cells depends on scaffold composition and on the source of the cells; the need for pesonalized tests., in Annals of the Romanian Society for Cell Biology, XX(2), 20-28.
2-Methoxyestradiol blocks RhoA/ROCK1 Pathway in Human Aortic Smooth Muscle Cells.
Rigassi L Bozzola FB Lucchinetti Zaugg M Jürgen Fingerle Jackson EK Rosselli M Imthurn B Dub (2015), 2-Methoxyestradiol blocks RhoA/ROCK1 Pathway in Human Aortic Smooth Muscle Cells., in Am J Physiol Endocrinol & Metab, 309, E995-E1007.
An in vitro method for adhesion of fresh adult murine heart slices on Collagen - coated surfaces
Popa MA Corotchi MC (2015), An in vitro method for adhesion of fresh adult murine heart slices on Collagen - coated surfaces, in Annals of the Romanian Society for Cell Biology, XX(1), 35-39.
Pre-stimulation with FGF-2 increases in vitro functional coupling of mesenchymal stem cells with cardiac cells.
Preda MB Rosca AM Tutuianu R Burlacu A (2015), Pre-stimulation with FGF-2 increases in vitro functional coupling of mesenchymal stem cells with cardiac cells., in Biochem Biophys Res Commun, 464(2), 667-673.
Defining the role of androgens in vascular remodeling associated with cardiovascular disease
Plutino Yulia (2014), Defining the role of androgens in vascular remodeling associated with cardiovascular disease, ETH Zurich PhD Thesis , Zurich.
CO2 laser increases the regenerative capacity of human adipose derived - stem cells by a mechanism involving the redox state and enhanced secretion of pro-angiogenic molecules.
Constantin A Dumitrescu M Corotchi C Jianu D Simionescu M, CO2 laser increases the regenerative capacity of human adipose derived - stem cells by a mechanism involving the redox state and enhanced secretion of pro-angiogenic molecules., in Lasers in Medical Science .
Mechanism of 17B-estradiol stimulated integration of human mesenchymal stem cells in heart tissue
MihaiCristina, PopaMirel-Adrian, SuicaViorel, AntoheFelicia, JacksonEdwin, SimonescuMaya, DubeyRaghvendra, Mechanism of 17B-estradiol stimulated integration of human mesenchymal stem cells in heart tissue, in Journal of Molecular and Cellular Cardiology.
Micro-RNA contribute to the protective actions of 17-B-Estradiol on the vascular system
Rigassi Lisa, Micro-RNA contribute to the protective actions of 17-B-Estradiol on the vascular system, ETH Zurich, Zurich.

Collaboration

Group / person Country
Types of collaboration
Mr. M. B. Preda, Institute of Cellular Biology & Pathology, Bucharest Romania (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Maya Simionescu, Institute of Cellular Biology and Pathology Romania (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Mr. Mirel A Popa, Institute of Cellular Biology & Pathology, Bucharest Romania (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Ms. M.C. Corotchi, Institute of Cellular Biology & Pathology, Bucharest Romania (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
8th National Congress with International Participation and 34th Annual Scientific Session of Romanian Society for Cell Biology Poster MMPs are involved in migration and chemotaxis of DHT-stimulated mesenchymal stem cells toward heart tissue sections 08.06.2016 Oradea, Romania Simionescu Maya;
8th National Congress with International Participation and 34th Annual Scientific Session of Romanian Society for Cell Biology”, Poster -BETA ESTRADIOL STIMULATES MIGRATION AND INTEGRATION OF MESENCHYMAL STEM CELLS INTO HEART TISSUE BY A MECHANISM INVOLVING EMMPRIN AND MMP-9 08.06.2016 Oradea, Romania Simionescu Maya;
10th Annual Congress of the Romanian Medical Association Poster Testosterone treatment enhances proliferation and preserves stemness of human stem cells 25.04.2016 Bucharest, Romania Simionescu Maya;
10th Annual Congress of the Romanian Medical Association Poster In vitro adhesion of fresh adult murine heart slices on Collagen - coated surfaces 25.04.2016 Bucharest, Romania Simionescu Maya;
International AHA council for Hypertension Meeting Poster Inhibition of MicroRNA-221 by estradiol contributes to its differential effects on smooth muscle growth and endothelial cell capillary formation 16.09.2015 Washington DC, United States of America Rigassi Lisa; Dubey Raghvendra K.;
International AHA Council for Hypertension Meeting Poster G-Protein Coupled Estrogen Receptor Stimulates Capillary Formation by Human Umbilical Vein Endocthelial Cells via ALK1-SMAD 1/5/8 Pathway activation 16.09.2015 Washington DC, United States of America Dubey Raghvendra K.; Rigassi Lisa;
7th National Congress with International Participation and 33th Annual Scientific Session of Romanian Society for Cell Biology Poster Chemoattraction of human Wharton's Jelly derived mesenchymal stem cells mediated by 17-beta estradiol in cardiac integration 11.06.2015 Baia-Mare, Romania Simionescu Maya;
14th Day of Clinical Research, University Zurich Individual talk Differential role of AKT-pathway in mediating the growth effects of GPER in Human Coronary Artery Smooth Muscle Cells and Human Umbilical Vein Endothelial Cells. 09.04.2015 Zurich, Switzerland Dubey Raghvendra K.; Rigassi Lisa;
7th Santorini Conference Biologie Prospective Poster Effects of 17-beta estradiol on proliferation and cardiac integration of human Wharton’s jelly-derived mesenchymal stem cells 25.09.2014 Santorini, Greece Simionescu Maya;
7th Santorini Conference Biologie Prospective Poster Effect of dihydrotestosterone on adult stem cells derived from human post-natal cord blood and matrix 25.09.2014 Santorini, Greece Simionescu Maya;
6th National Congress with International Participation and 32th Annual Scientific Session of Romanian Society for Cell Biology Poster Effects of 17-beta estradiol on proliferation of human mesenchymal stem cells 04.06.2014 Targu-Mures, Romania Simionescu Maya;
6th National Congress with International Participation and 32th Annual Scientific Session of Romanian Society for Cell Biology Poster Effects of dihydrotestosterone on proliferation of adult stem cells derived from fetal tissue 04.06.2014 Targu-Mures, Romania Simionescu Maya;
International Scientific Conference on Arteriosclerosis, Thrombosis and Vascular Biology in USA Poster Capillary Formation and Autologous Regulation of Androgen Receptor Expression in Endothelial Progenitor Cells (EPCs) by DHT: Potential Implications for EPC Mediated Cardiovascular Repair in Men. 01.05.2014 Toronto, Canada Dubey Raghvendra K.;


Communication with the public

Communication Title Media Place Year

Awards

Title Year
Best Poster Award to the Poster entitled " G-Protein Coupled Estrogen Receptor Mediates capillary formation" at the 10th ZIHP Symposium in University Zurich. 2014

Associated projects

Number Title Start Funding scheme
64040 Estrogen(s) and cardiovascular protection in postmenopausal women: Defining the cellular and biochemical mechanisms. 01.10.2001 Project funding (Div. I-III)

Abstract

Summary Ageing is associated with a significant increase in cardiovascular disease and mortality in both men and women. Because, onset of menopause in women, and andropause in men is associated with a significant decrease in the levels of estrogen and androgens, respectively, it is hypothesized that sex hormones importantly contribute to the increase in cardiovascular mortality in postmenopausal women and men in andropause. Epidemiological/observational studies provide strong evidence that estrogen protects women against cardiovascular disease, moreover, data from the clinical trials EPAT demonstrated cardiovascular protection (reduced intimal thickening) additionally, data from large randomized clinical trial (WHI) suggests that estrogen protects younger menopausal women treated with estrogen within 10 years of menopause. In contrast to estrogens, the link between androgens and cardiovascular disease remains controversial with clinical and animal data supporting both deleterious and protective actions. Since estrogens and androgens interact dynamically with cells (smooth muscle cells, SMCs and endothelial cells, ECs) within the vascular wall, it is feasible that decreased levels of these sex hormones contribute to the vascular remodeling processes leading to vaso-occlusive disorders. Recent scientific advances in regenerative medicine suggest that adult stem cells [progenitor endothelial cells (EPCs) and mesenchymal cells (MSCs)] can serve as therapeutic tools to repair and heal dead heart tissue following myocardial infarction. The fact that estrogen potentiates EPC induced vessel formation in a mouse model for ischemic injury suggests that sex hormones can importantly influence progenitor stem cell-induced tissue repair, however, whether they would mimic similar repair processes in humans remains unknown, moreover, the mechanisms involved remain undefined. The above findings, together with the fact that estrogens induce the number of circulating EPCs in women and EPC number are decreased in postmenopausal women, we hypothesize that Sex Hormones, estrogens and androgens play a key role in directly modulating adult stem cell induced tissue repair and regeneration following myocardial infarction, moreover, decreases in estrogen and androgen levels in ageing men and women may be associated with a decreased potential for stem cell mediated repair of cardiovascular tissue. Moreover, since most patients receiving stem cells for cardiovascular repair are older, the low endogenous levels of sex hormones would decrease the potential of stem cell mediated tissue repair. Hence, using human adult stem cells [cord blood derived progenitor endothelial cells (EPCs) and Wharton jelly derived mesenchymal cells (MSCs)] separately and in a novel co-culture system of EPCs, MSCs or EPCs plus MSCs with human viable cardiac slices (organ cultures), the objective of this proposal is to assess the effects of sex steroids on adult stem cell-induced tissue regeneration and define the cellular and molecular mechanisms involved. In this context, the effects of estradiol and dihydroxytestosterone (DHT) on capillary formation (2-D gel system), cell growth (DNA synthesis, cell number), adhesion under dynamic flow conditions (parallel flow chambers) and tissue integration and regeneration (EPC/MNC co-cultured with cardiac slices) will be tested. Molecular (Immunostaining, western blotting, microarrays, gene silencing) and biochemcal approaches will be employed to dissect the key mechanisms.Several publications from our laboratory provide evidence that estradiol interacts with vascular SMCs and endothelial cells and activates cellular and molecular processes that protect against vaso-occlusive disorders. More recently, we demonstrated that estradiol induces capillary and tube formation by EPCs via estrogen receptor a. Recent papers by our Romanian collaborator demonstrate the use of murine ventricular slices to assess integration and repair by EPCs and MSCs. Hence using the strengths of each partner we will assess the mechanisms by which sex hormones may influence repair/regeneration in human tissues. Here we will investigate and compare the effects of estradiol and DHT on: EPCs mediated capillary formation and the role of key angiogenic pathways (HIF-1, Akt-P?Hemeoxygenase-1?VEGF?CO?VASP; TGF-ß?ALK1/ALK5?Smad1/5 2/3; and NOTCH pathway) in mediating these effects; molecules involved in adhesion and homing in of EPCs and MNCs (MMPs and integrin a4 and 5, VCAM-1, ICAM-1 and CXCR-4) under dynamic flow conditions. The impact of sex steroids on EPC and MSC growth will be assessed by mitogen-activated protein kinase (ERK1/2), the protein kinase C (PKC) pathway, Akt-phosphorylation, cyclin dependent kinases (cdc2/cdk1, cdk2); cyclins A and E, and cdk-inhibitors (p21/p27). Moreover, we will study whether estradiol and DHT induce on the growth of MNCs and the adhesion of both EPCs and MNCs to monolayers of endothelial cells and cardiac fibroblasts under dynamic conditions (flow). Microscopy and immunostaining with specific markers (as described before) will be employed to assess the impact of sex steroids on the integration of EPCs and MSCs in slices. Differentially labeled EPCs and MSCs will be used to track their contribution to regenerative process in heart slices. Finally, using human microarray gene chips we will screen and document the genes that are influenced by estradiol and DHT.Potential Implications: Findings from proposed study will shed light on the impact of Sex steroids on stem cell mediated tissue repair and regeneration. The use of in vitro transplantation model to assess the contribution of EPCs and MSCs in repairing damaged cardiac tissue in presence of sex steroids will importantly contribute to the current knowledge on the biology of human adult progenitor cells and contribute to optimizing protocols for stem cell therapy in a clinical setting. If sex steroids induce tissue repair process, they could be co-administered with stem cells to potentiate tissue repair.
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