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Developmental engineering of endochondral ossification from mesenchymal stem cells

English title Developmental engineering of endochondral ossification from mesenchymal stem cells
Applicant Martin Ivan
Number 136179
Funding scheme Sinergia
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Embryology, Developmental Biology
Start/End 01.10.2011 - 31.03.2015
Approved amount 1'600'000.00
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All Disciplines (2)

Discipline
Embryology, Developmental Biology
Other disciplines of Engineering Sciences

Keywords (2)

endochondral; developmental engineering

Lay Summary (English)

Lead
Lay summary

Title

Developmental Engineering of Endochondral Ossification from Mesenchymal Stem Cells

Background

Endochondral ossification refers to the process which, starting from the condensation of mesenchymal cells, leads to formation of cartilage templates and their remodelling into bone tissue. Understanding and controlling molecular events occurring during endochondral ossification has the potential to support the engineering/repair of cartilage and bone tissues. While certain aspects of endochondral ossification have been recapitulated by using mesenchymal (MSC) or embryonic stem cells, the spatio-temporally ordered organisation of cartilage templates as observed during long bone development has yet to be reproduced in vitro or in vivo.

 

Questions

The ultimate aim of the proposed research is to develop a process leading to spatially and temporally controlled formation of cartilage and bone tissues from adult MSC by endochondral ossification. The working hypothesis underlying the proposal is that the target can be achieved by mimicking and recapitulating the structural and molecular programs occurring during embryonic development (i.e., ‘developmental engineering’)

 

Methods

Different disciplines will be integrated to combine (i) systematic molecular analysis of human MSC in 3-dimensional (3D) culture systems, (ii) knowledge derived from genetically altered mice models, (iii) mathematical modelling and spatio-temporal simulations of molecular signalling networks, as well as (iv) development of polymeric delivery systems to reproduce spatial gradients of defined key signalling proteins.

 

Potential significance of the results

The proposed interdisciplinary research strategy will bring together the fields of tissue engineering, developmental and mouse molecular genetics, take advantage of the predictive power of mathematical modelling and incorporate material science to develop polymeric scaffolds for directed release of key signalling molecules. The activities will lead to the design of innovative models which, by recapitulating developmental processes, will advance the engineering of cartilage and bone tissue. The project will thus bridge the gap between fundamental and translational research, with medical potential for cartilage and bone repair.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
High-throughput microfluidic platform for 3D cultures of mesenchymal stem cells, towards engineering developmental processes
Occhetta Paola (2015), High-throughput microfluidic platform for 3D cultures of mesenchymal stem cells, towards engineering developmental processes, in Scientific reports, 5(10288), 1-12.
Priming 3D Cultures of Human Mesenchymal Stromal Cells Toward Cartilage Formation Via Developmental Pathways
Centola Matteo, Tonnarelli Beatrice, Schären Stefan, Glaser Nicolas, Barbero Andrea, Martin Ivan (2013), Priming 3D Cultures of Human Mesenchymal Stromal Cells Toward Cartilage Formation Via Developmental Pathways, in Stem Cells and Development, 22(21), 2849-2858.
Making sense-data-based simulations of vertebrate limb development
Iber Dagmar, Zeller Rolf (2012), Making sense-data-based simulations of vertebrate limb development, in Curr Opin Genet Dev, 22, 570-577.
Engineering developmental processes to instruct tissue regeneration
Tonnarelli Beatrice, Centola Matteo, Barbero Andrea, Zeller Rolf, Martin Ivan, Engineering developmental processes to instruct tissue regeneration, in Current Topics in Developmental Biology.
Inter-dependent tissue growth and Turing patterning in a model for long bone development
Tanaka Simon, Iber Dagmar, Inter-dependent tissue growth and Turing patterning in a model for long bone development, in Physical biology.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
CRS Annual Meeting 2013 Poster Gelatin-Based Controlled Release System for Long-Term Delivery of Proteins 21.07.2013 Honolulu, United States of America Christensen Jon; Ahrens Lucas; Shastri Venkatram Prasad;
eCM 2013 - Stem & Progenitor Cells for Musculoskeletal Regeneration Talk given at a conference Priming 3D Cultures of Human Mesenchymal Stromal Cells Toward Cartilage Formation Via Developmental Pathways 23.06.2013 Davos, Switzerland Martin Ivan; Tonnarelli Beatrice;
Gordon Conference in Cartilage Biology and Pathology Poster Towards developmental engineering: role of Wnt3a and FGF2 in priming human bone marrow-derived mesenchymal stromal cells 07.04.2013 Les Diablerets, Switzerland Tonnarelli Beatrice; Martin Ivan;


Associated projects

Number Title Start Funding scheme
133110 Engineering of large size grafts capable to generate bone tissue by endochondral ossification 01.10.2010 Project funding (Div. I-III)
156430 Developmental Engineering of Cartilage from Adult MSCs - Mimicking Differentiation of Limb Mesenchymal Progenitors 01.04.2015 Project funding (Div. I-III)
170930 A 3D Cell-Based Simulation Framework for Morphogenetic Problems 01.04.2017 Sinergia

Abstract

Endochondral ossification refers to the processes which, starting from the condensation of mesenchymal cells, leads to the formation of cartilage templates and their remodelling into bone tissue. Understanding and controlling the molecular events that occur during endochondral ossification has the potential to support the engineering/repair of cartilage and bone tissues by recapitulating developmental processes (the so-called ‘developmental engineering’ paradigm). While certain aspects of endochondral ossification have been reproduced in vitro and/or by ectopic implantation of mesenchymal stem/progenitor cells (MSC) or embryonic stem cells, the spatio-temporally ordered organisation of cartilage templates as observed during long bone development has not yet been reproduced either in culture or by regenerative approaches in vivo.Therefore, the major aim of the proposed research is to develop and implement a developmental engineering approach to endochondral ossification from MSC. The program will integrate the systematic molecular analysis of human MSC in 3-dimensional (3D) culture systems (Subproject A, I. Martin), the knowledge derived from MSC and mesenchymal progenitor cells of genetically altered mice (Subproject B, R. Zeller), the mathematical modelling and spatio-temporal simulations of molecular signalling networks (Subproject C, D. Iber), and the development of polymeric delivery systems to reproduce spatial gradients of defined soluble small molecules and recombinant proteins (Subproject D, P. Shastri). The recapitulation of endochondral ossification will rely on the controlled manipulation of the WNT and FGF pathways in order to maintain a proliferating pool of undifferentiated MSC, and of the IHH/PTHrP negative signalling feedback loop and BMPs to drive the directed chondrogenic development and differentiation of MSC. The signals released from polymeric systems, will initially be assessed for their dose-dependent effects in a spatially uniform environment and assess the effects using biological read-outs and sensors for signalling pathway activities (Workpackage I). Subsequently, these signals will be delivered from polymeric systems in the form of defined gradients in 3D culture models (Workpackage II) and ultimately assessed for their capacity to instruct orderly progression of cartilage and bone formation in vivo (Workpackage III). The proposed interdisciplinary research strategy will bring together the disciplines of tissue engineering, developmental and mouse molecular genetics, take advantage of the predictive power of mathematical modelling and incorporate material science to develop polymeric scaffolds for directed release of small molecules and proteins. The projects will bridge the gap between fundamental and translational research to progress towards the ultimate aims of (i) designing innovative models recapitulating developmental processes, and (ii) advancing the engineering of cartilage templates with medical potential for cartilage and bone repair
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