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Developmental Engineering of Cartilage from Adult MSCs - Mimicking Differentiation of Limb Mesenchymal Progenitors

English title Developmental Engineering of Cartilage from Adult MSCs - Mimicking Differentiation of Limb Mesenchymal Progenitors
Applicant Martin Ivan
Number 156430
Funding scheme Project funding (Div. I-III)
Research institution Kantonsspital Basel Departement Chirurgie und Forschung Inst. für Chirurgische Forschung (ICFS)
Institution of higher education University of Basel - BS
Main discipline Biomedical Engineering
Start/End 01.04.2015 - 30.06.2018
Approved amount 625'000.00
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All Disciplines (2)

Discipline
Biomedical Engineering
Embryology, Developmental Biology

Keywords (10)

Human MSC; Endochondral bone development; Signaling; Mouse MSC; Mesenchymal stromal/stem cells; Cartilage; Tissue engineering; Chondrogenesis; Limb bud; Regenerative Medicine

Lay Summary (German)

Lead
Verletzungsbedingte und degenerative skeletale Krankheiten, die derzeit meist chirurgisch behandelt werden, könnten auch mit funktionellen skeletalen Ersatzgeweben behandelt werden. Durch die Nutzung von genetischen Modellen der Maus und den Vergleich des Maustranskriptoms von mesenchymalen Vorläuferzellen der Gliedmassen (LMP) mit Maus- und humanen MSCs, wollen wir (i) die gemeinsame moleculare Signatur zwischen LMP und MSCs identifizieren, (ii) die Marker für die Selektion von MSCs mit robustem chondrogenem Potential definieren, und (iii) eine entwicklungsinspirierte Strategie zur Züchtung von Knorpeltemplates entwickeln. Dadurch wird könnte es möglich sein Subpopulationen mit definierten funktionellen Eigenschaften zu identifizieren und stabile Protokolle für die Gewebezüchtung zu etablieren.
Lay summary

Verletzungsbedingte und degenerative skeletale Krankheiten gehören zu den häufigsten Leiden und werden derzeit oft chirurgisch behandelt. Es werden momentan grosse Anstrengungen unternommen, um funktionelle skeletale Ersatzgewebe aus adulten humanen mesenchymalen Vorläufer-/Stammzellen (hMSCs) zu züchten. Ein Hauptnachteil ist, dass die chondrogene Kapazität der hMSCs stark variert abhängig von der Art der Isolierung und die Induktion der Chondrogenese derzeit noch nach der trial-and-error-Methode stattfindet.

Durch die Nutzung von genetischen Modellen der Maus und den Vergleich des Maustranskriptoms von mesenchymalen Vorläuferzellen der Gliedmassen (LMP) mit Maus- und humanen MSCs, wollen wir (i) die gemeinsame moleculare Signatur zwischen LMP und MSCs identifizieren, (ii) die Marker für  die Selektion von MSCs mit robustem chondrogenem Potential definieren, und (iii) eine entwicklungsinspirierte Strategie zur Züchtung von Knorpeltemplates entwickeln.

Wir sind überzeugt, dass die Resultate dieser Studie nicht nur eine fundamentale Einsicht in die grundlegenden molekularen Mechanismen und den Entwicklungsursprung der MSCs geben, sondern auch relevant sind, um die Anwendung von molekular kontrollierten, aus adulten MSCs gezüchteten Knorpel in klinischen Applikationen voranzubringen.

Die Kombination von Technologien und Modellen einerseits und Gewebezüchtung und entwicklungsbiologischen Gebieten andererseits wird eine starke wissenschaftliche und translationale Relevanz haben. Vom wissenschaftlichen Standpunkt aus wird das Projekt unser Verständnis vom Ursprung der MSCs in Erwachsenen voranbringen und das Ausmass mit dem sie  Phenotyp und funktionelle Eigenschaften mit dem embryonalen Mesenchym teilen. Vom translationalen Standpunkt aus, wird das Projekt der Schlüssel sein, um den Mangel an Signaturmarkern zur Identifikation von Subpopulationen mit definierten funktionellen Eigenschaften und suboptimalen Protokollen für die Induktion von MSC Differenzierung zu beheben.  

Direct link to Lay Summary Last update: 01.10.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Developmentally inspired programming of adult human mesenchymal stromal cells toward stable chondrogenesis
Occhetta Paola, Pigeot Sebastien, Rasponi Marco, Dasen Boris, Mehrkens Arne, Ullrich Thomas, Kramer Ina, Guth-Gundel Sabine, Barbero Andrea, Martin Ivan (2018), Developmentally inspired programming of adult human mesenchymal stromal cells toward stable chondrogenesis, in Proceedings of the National Academy of Sciences, 201720658-201720658.
Ontogenic Identification and Analysis of Mesenchymal Stromal Cell Populations during Mouse Limb and Long Bone Development
Nusspaumer Gretel, Jaiswal Sumit, Barbero Andrea, Reinhardt Robert, Ishay Ronen Dana, Haumer Alexander, Lufkin Thomas, Martin Ivan, Zeller Rolf (2017), Ontogenic Identification and Analysis of Mesenchymal Stromal Cell Populations during Mouse Limb and Long Bone Development, in Stem Cell Reports, 9(4), 1124-1138.

Collaboration

Group / person Country
Types of collaboration
Dr. Marco Rasponi, Dept. Electronics, Information and Bioengineering, Politecnico di Milano Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Dr. Sabine Guth, Novartis Institutes for BioMedical Research Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Robert Ivanek, Bioinformatics, Dept. Biomedicine, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Christian Beisel, Quantitative Genomics Facility, D-BSSE ETH Zürich, 4058 Basel Switzerland (Europe)
- Research Infrastructure

Communication with the public

Communication Title Media Place Year

Associated projects

Number Title Start Funding scheme
146248 Signaling systems during limb bud development: integrating inputs into dynamic gene regulation 01.04.2013 Project funding (Div. I-III)
166685 Bonus-of-Excellence: Signaling systems during limb bud development: integrating inputs into dynamic gene regulation 01.05.2016 Project funding (Div. I-III)
183068 Direct 3D Bioprinting strategies to study articular cartilage development and regenerative therapy for osteoarthritis 01.03.2019 Bilateral programmes
136179 Developmental engineering of endochondral ossification from mesenchymal stem cells 01.10.2011 Sinergia
133110 Engineering of large size grafts capable to generate bone tissue by endochondral ossification 01.10.2010 Project funding (Div. I-III)
164085 Subcellular targeting microscopy - Signaling in Development and Oncology 01.06.2016 R'EQUIP

Abstract

Trauma-related and degenerative skeletal diseases are among the most frequent medical conditions and are currently treated surgically. In particular, dysfunctional bones and joints are replaced by non-biological implants with a limited lifespan. Therefore, major efforts are underway to engineer functional skeletal replacement tissues from adult human mesenchymal stem/progenitor cells (hMSC) isolated from the patients and/or compatible donors. The promise of using hMSC for engineering of skeletal tissues stems from the fact that culturing them at high density in the presence of specific signalling factors results in formation cartilaginous templates, which undergo endochondral ossification upon implantation into animal models. However, one major drawback is that the chondrogenic capacity of hMSCs is variable across different preparations and that induction of chondrogenic differentiation depends currently rather on trial and error than directed approaches. This may be a consequence of the heterogeneity among donors or MSCs consisting of mixed progenitor populations. In addition, the available ex vivo chondrogenic approaches likely do not mimic well the signaling and gene regulatory inputs that control progression of chondrogenesis in embryos. Therefore, the groups of I. Martin and R. Zeller are joining forces to define (i) the molecular signatures required to select MSCs with robust chondrogenic potential and to (ii) devise a stepwise, developmental inspired (SDI) tissue-engineering strategy for cartilage templates that mimics limb long bone development. The proposed research takes advantage of the mouse as a superb experimental and genetic model to identify and study the origin of MSCs and to develop a knowledge-based SDI strategy that allows controlled ex vivo generation of robust cartilage templates from limb mesenchymal progenitors (LMPs) and MSCs. In addition, clonal populations and freshly isolated hMSC from different donors will be analysed in comparison to mouse LMPs and MSCs (mMSCs) to identify the shared molecular signature of progenitors with the best chondrogenic proliferation and differentiation potential. We will use FACS analysis in combination with immunohistochemistry to identify the origin of MSCs during mouse limb skeletal development and to characterise the different MSC subpopulations in comparison to LMPs. RNAseq analysis of the transcriptome of selected hMSC, mMSC and LMP subpopulations will be used to define shared and divergent gene expression signatures. This analysis aims to identify additional signature markers defining and distinguishing multi-potent and chondrogenic progenitors. LMPs are the embryonic standard to develop an SDI protocol that allows induction of proliferative expansion while retaining the progenitor potential of MSCs, and subsequent chondrogenic differentiation to give rise to growing cartilage templates (i.e. avoid premature hypertrophy). In addition to conventional high-density (3D) cultures, we will use a novel microfluidics approach to expose LMPs and MSCs to different concentrations of the relevant signals in a high throughput and temporally controlled manner. Finally, the fate of these ex vivo generated cartilage templates will be tested in vivo by ectopic transplantation into nude mice and the lineage potential of MSCs after in vitro expansion will be assessed by their engraftment into developing mouse limb buds.Taken together, the proposed research aims to reproducibly and robustly generate cartilage templates from MSCs for subsequent in vivo engraftment using a development inspired and controlled approach. We are confident that the results of these studies will not only provide fundamental insights into the underlying molecular mechanisms and developmental origin of MSCs, but be relevant to taking the molecularly controlled, faithful engineering of cartilage from adult MSCs a significant step further toward clinical application.
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