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Engineered patches for cardiac repair

English title Engineered patches for cardiac repair
Applicant Marsano Anna
Number 172989
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Cardiovascular Research
Start/End 01.06.2017 - 31.05.2022
Approved amount 515'015.00
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All Disciplines (3)

Discipline
Cardiovascular Research
Cellular Biology, Cytology
Molecular Biology

Keywords (8)

CTGF; stromal vascular fraction; Pericytes; perfusion bioreactor; cardioprotection; cardiac ischemia; angiogenesis ; paracrine effects

Lay Summary (German)

Lead
Das Ziel des Projektes ist es, mit Zellen versehene Gewebe, um die chronische kardiale Ischämie zu behandeln. In dieser Studie wollen wir Gewebe aus adulten humanen mesenchymalen Vorläufer-/Stammzellen zu züchten, um eine normale und effiziente Angiogenese und die beschädigte Kardiomyozyten aufbewahren in ihrer umliegenden Umgebung zu fördern.
Lay summary
In dieser Studie verwendenwir hohen  vaskulogenischen menschlichen Zellquellen, nämlich die aus Fettgewebe stammenden Stromal-Vascular-Fraction (SVF) Zellen, um die Gefässneubildung/Gefässversorgung der bedeutend dicken Gewebe(Konstrukte) und der umliegenden Umgebung zu beschleunigen. SVF-zellbasierte Gewebe selbst entwickeln in einem perfusionsbasierten Bioreaktor-Kultur-System zur Förderung und Beschleunigung der in vivo Vaskularisation der Gewebe. Im vergangenen Jahr haben wir das angiogene Potential der SVF-Zellen untersucht, nachdem sich eine Kultur unter dynamischen Bedingungen in einem ektopischen rattenmodell gebildet hatte. Unsere wichtigsten Ergebnisse zeigen, dass die perfusionsbasierte Kultur die Vaskularisation in vivo beschleunigen der anderen Wachstumsfaktoren auf die Möglichkeit untersuchen, die Funktion der beschädigten Kardiomyozyten wiederherzustellen. Am Ende wollen wir die Wirkungen der Gewebe in einem rattenmodell der Her-Ischämie erforschen. Viele Studien benutzen die adulten humanen mesenchymalen Vorläufer-/Stammzellen für Herzregeneration, aber ihre Auswirkungen in vivo noch nicht erklärt ist. Von wissenschaftlichen und translationalen Standpunkte aus wird das Projekt unserer Verständnis von den mehreren Faktoren den SVF-Zellen voranbringen. SVF-Zellen; Herz-Ischämie, Angiogenese
Direct link to Lay Summary Last update: 18.05.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Fatty acid-based monolayer culture to promote in vitro neonatal rat cardiomyocyte maturation
Isu Giuseppe, Robles Diaz Diana, Grussenmeyer Thomas, Gaudiello Emanuele, Eckstein Friedrich, Brink Marijke, Marsano Anna (2019), Fatty acid-based monolayer culture to promote in vitro neonatal rat cardiomyocyte maturation, in Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 118561-118561.
Paracrine potential of adipose stromal vascular fraction cells to recover hypoxia-induced loss of cardiomyocyte function MYTSYK et al.
Mytsyk Myroslava, Isu Giuseppe, Cerino Giulia, Grapow Martin T. R., Eckstein Friedrich S., Marsano Anna (2019), Paracrine potential of adipose stromal vascular fraction cells to recover hypoxia-induced loss of cardiomyocyte function MYTSYK et al., in Biotechnology and Bioengineering, 116(1), 132-142.
A three-dimensional in vitro dynamic micro-tissue model of cardiac scar formation
Occhetta Paola, Isu Giuseppe, Lemme Marta, Conficconi Chiara, Oertle Philipp, Räz Christian, Visone Roberta, Cerino Giulia, Plodinec Marija, Rasponi Marco, Marsano Anna (2018), A three-dimensional in vitro dynamic micro-tissue model of cardiac scar formation, in Integrative Biology, 10(3), 174-183.
Engineering of an angiogenic niche by perfusion culture of adipose-derived stromal vascular fraction cells
Cerino Giulia, Gaudiello Emanuele, Muraro Manuele Giuseppe, Eckstein Friedrich, Martin Ivan, Scherberich Arnaud, Marsano Anna (2017), Engineering of an angiogenic niche by perfusion culture of adipose-derived stromal vascular fraction cells, in Scientific Reports, 7(1), 14252-14252.

Collaboration

Group / person Country
Types of collaboration
Marijke Brink Research group/DBM University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Attila Kiss research group/University of Vienna Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
9th CARDIOVASCULAR RESEARCH DAYS Poster Effects of different flow-derived shear stresses on three-dimensional culture of human stromal vascular fraction cells 16.01.2020 Weissensee, Austria Gili Solé Laia; Marsano Anna;
9th CARDIOVASCULAR RESEARCH DAYS Talk given at a conference In vitro biomimetic engineering of three dimensional niches with high angiogenesis potential 16.01.2020 Weissensee, Austria Fusco Deborah; Gili Solé Laia; Marsano Anna;
Jahrestagung für Chirurgische Forschung Talk given at a conference Dynamic culture enhances the angiogenic potential of human stromal vascular fraction-derived 3-dimensional engineered tissues in healthy rat hearts 14.11.2019 Vienna, Austria Marsano Anna; Gili Solé Laia;
TERMI_EU Talk given at a conference Silica Nanoparticle internalization by Human Mesenchymal Stem Cells enhances their adhesion properties in dynamic conditions 27.05.2019 Rhodes, Greece Isu Giuseppe; Marsano Anna; Gili Solé Laia; Fusco Deborah;


Associated projects

Number Title Start Funding scheme
149274 Engineering of a cell-loaded patch as a controlled VEGF-releasing device to treat cardiac ischemia 01.10.2013 Project funding (Div. I-III)

Abstract

Background. In chronic cardiac ischemia, the effective induction of microvascular networks is crucial to rescue the local hibernating cardiomyocytes and ultimately restore the cardiac function. The current surgical revascularization strategies restore mostly the macro-circulation and rarely the damaged micro-vasculature. Mesenchymal stem cell- (MSC) based therapies showed some benefits in stabilizing cardiac function in preclinical studies, but the outcomes of clinical trials are still controversial. The therapeutic potential of this approach is mainly related to paracrine effects and is strongly limited by the low in vivo cell survival associated to the cell delivery method (intra-myocardial injections). The implantation of cells previously organized in vitro in three-dimensional (3D) engineered tissues with a rapid vascularization potential could overcome this issue. The applicant main aim is to use 3D engineered patches generated by multiple cell types to improve their in vivo engraftment and sustain the release of key factors. Rationale. Among the investigated MSC, the stromal vascular fraction (SVF) freshly isolated from adipose tissue has recently gained interest since it is a unique source of relevant multiple cell types, including both mesenchymal stromal and endothelial/mural cells, with a wide secretion profile of relevant factors. Chronic ischemic heart treated with freshly generated SVF-sheets showed some promising results in improving angiogenesis and stabilizing the cardiac function, but donor variability is still a major drawback, holding back its real therapeutic potential. Our in vitro findings showed that, compared to static, perfusion culture of 8/8 SVF donors in 3D scaffolds reproducibly amplified a particular SVF subpopulation, namely the pericytes, and increased the release of pro-angiogenic factors and of the connective tissue growth factor (CTGF, 16 times higher). Pericytes might play a pivotal role in cardiac repair, since they are a key component of the cardiac unit and take a fundamental part in angiogenesis and possibly also in cardiac homeostasis and regeneration via -cytokine / -microRNA signaling. Moreover, CTGF might be a crucial factor (i) in the reproducible enrichment of in vitro patches during perfusion culture acting as mitogen for the pericytes; and (ii) in cardiac repair due to its possible involvement in cardiomyocyte hypertrophy/survival, vascular remodeling and fibrosis. In this project, we aim to investigate the molecular mechanisms underlying the pericyte growth during dynamic culture and to investigate the role of the pericytes and the paracrine SVF effects in angiogenesis, cardiomyocyte survival and fibrosis reduction. Specific aims. This proposal targets to investigate 1. the mechanisms at the molecular (CTGF role) and cellular (pericyte role) level possibly underlying the reproducible generation of SVF-patches with high angiogenic potential following perfusion culture (Aim 1); 2. the in vivo angiogenic dynamics (Aim 2); 3. the in vitro release of cardio-protective factors (Aim 3a) and their effects on 3D functional human cardiac in vitro models (Aim 3b) and 4. the overall efficacy on angiogenesis, fibrosis reduction and recovery of cardiac function in ischemic heart rat model of the pericyte-enriched SVF-based patches (Aim 4).Experimental design. The CTGF in vitro role will be assessed by using a CTGF neutralizing antibody during the in vitro culture. To investigate pericyte role, freshly isolated human SVF cells depleted or not of pericytes will be cultured on collagen scaffolds either in a perfusion-based bioreactor or in static conditions. The specific role of the perfusion will be investigated in terms of 1. angiogenesis induction in an ectopic site; 2. cardiomyocyte survival/phenotype and function in a relevant 3D human micro-engineered cardiac tissue model; and 3. fibrosis reduction, micro-circulation recovery, cardiomyocyte survival/phenotype and heart function in a cardiac ischemic rat model.Expected value of the proposed project. We expect to expand our scientific knowledge on the effects of SVF-based therapies and, in particular, on the role of pericytes in cardiac repair. The acquired insights will represent a significant step towards the sound clinical translation of this approach by understanding the mode of action of SVF-based patches, which is a pre-requisite to improve the standardization in their manufacture and reproducibility in their effectiveness.
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