Project leader : Jean-Daniel Malcor
Participant : Marielle Pasdeloup, Frédéric Mallein-Gerin, Jérôme Lafont
Cartilage is an avascular tissue which possesses poor intrinsic healing properties. As osteoarthritis is a growing source of infirmity worldwide, cartilage repair represents an increasingly important clinical challenge. Our goal is to develop biomaterials for cartilage tissue engineering. These biomaterials are made from collagen or fibrin, and are designed to host chondrocytes, the cellular component of cartilage, or mesenchymal stem cells (MSCs) derived from adipose tissue or dental pulp, due to their high proliferative abilities and versatile differentiation potential (into chondrocytes, adipocytes, osteocytes, etc.).
Biomaterials must also provide cells with the correct biological and mechanical cues to direct cellular response (including cell adhesion, survival, proliferation, function and, in the case of MSCs, differentiation). In cartilage, the extracellular matrix (ECM), principally made of collagen type II, plays a dominant role in providing a biological and structural support for chondrocytes. We aim to replicate the key characteristics of the ECM in biomaterials seeded with chondrocytes or MSCs, and to produce a cellular microenvironment suitable with the formation of artificial engineered cartilage.
Our approach is to employ triple-helical peptides (THPs), a family of biomimetic peptides that spontaneously assemble in solution to adopt the triple helix conformation of native collagen. We use THPs to model cell interactions with collagen and address key cell-surface receptors. Using THPs containing specific sequences that are ligands for collagen-binding receptors (such as the collagen-binding integrins α1β1, α2β1, α10β1 and α11β1, or the discoidin domain receptors 1 and 2), we investigate how cell-collagen interactions precisely affect MSC fate and chondrocyte activity.
This fundamental insight will enable us to decorate biomaterials with the appropriate THPs to drive chondrogenesis and cartilage ECM production. We are especially interested in developing a convenient protocol to selectively retain chondrogenic MSCs and prompt their differentiation into chondrocytes using THPs that target the α10β1 integrin. THP-functionalized cell-laden biomaterials will constitute, on the one hand, a platform to model cartilage in vitro and to conveniently study pathologies associated with cartilage (such as osteoarthritis) at a reduced cost; and on the other hand, patches destined to be implanted on damaged cartilage in vivo, to contribute to the repair of articular cartilage following traumatic injury.
- J-D. Malcor, V. Juskaite, D. Gavriilidou, E.J. Hunter, N. Davidenko, S. Hamaia, S. Sinha, R.E. Cameron, S.M. Best, B. Leitinger, R.W. Farndale, Coupling of a specific photoreactive triple-helical peptide to crosslinked collagen films restores binding and activation of DDR2 and VWF, Biomaterials 182 (2018) 21-34.
- J-D. Malcor, D. Bax, S.W. Hamaia, N. Davidenko, S. Best, R. Cameron, R. Farndale, D. Bihan, The synthesis and coupling of photoreactive collagen-based peptides to restore integrin reactivity to an inert substrate, chemically-crosslinked collagen, Biomaterials 85 (2016) 65-77.
- J-D. Malcor, E. Hunter, N. Davidenko, B. Bax, S. Best, R. Cameron, S. Sinha, R. Farndale, Collagen scaffolds functionalized with triple-helical peptides support 3D HUVEC culture, Regenerative Biomaterials 5 (2020) 7 471-481.
- M. Colzani, J.D. Malcor, E.J. Hunter, S. Bayraktar, M. Polkinghorne, R. Cameron, S. Best, S. Sinha, R. Farndale, Modulating hESC-derived cardiomyocyte and endothelial cell function with triple-helical peptides for heart tissue engineering, Biomaterials 269 (2021) 120612.