Mechanics and mechanobiology of mesenchymal stem cell-based engineered cartilage

Abstract

OverviewThe intent of this manuscript is to review recent advances in the use of mesenchymal stem cells (MSCs) for the engineering of functional cartilage replacement tissues. Mesenchymal stem cells are a multipotent cell type capable of differentiating toward a number of lineages of the musculoskeletal system, including bone, cartilage and fat (Baksh et al. 2004). This multipotential capacity was first described over three decades ago (Friedenstein et al. 1974), and since then, the potential use of MSCs for regenerative therapies has generated tremendous excitement and focus. The attractiveness of MSCs for tissue repair is self-evident: in addition to their ability to take on multiple phenotypes, MSCs are readily expandable in culture and retain their multipotential characteristics with expansion; further, MSCs and other similar progenitor cells can be isolated from a wide variety of tissue sources, thereby avoiding further damage to diseased/injured tissues.In this review, we outline seminal and recent work highlighting the potential of these unique cells in producing cartilage-like tissue equivalents. Specific focus is placed on the mechanical properties of engineered MSC-based cartilage and how these properties relate to that of engineered cartilage based on primary chondrocytes and to native tissue properties. We discuss current limitations and/or concerns that must be addressed for the clinical realization of MSCbased cartilage therapeutics, and provide some insight into potential underpinnings for the observed deviations from chondrocyte-based engineered constructs. We posit that these differences reveal specific deficits in terms of our description of chondrogenesis, and suggest that new benchmarks must be developed towards this end. Further, we describe the growing body of literature on the mechanobiology of MSC-based cartilage, highlighting positive findings with regards to the furtherance of the chondrogenic phenotype. We likewise discuss the failure of early successes to translate directly into engineered constructs with improved

Expansion in the presence of FGF-2 enhances the functional development of cartilaginous tissues engineered using infrapatellar fat pad derived MSCs

“…Therefore identifying expansion and differentiation conditions that promote a more chondrogenic phenotype is critical to enhancing their utility for cartilage tissue engineering applications. Differentiation conditions that have been shown to promote the chondrogenic potential of MSCs include a low oxygen (5%) microenvironment (Khan et al 2007;Buckley et al 2010a;Meyer et al 2010), various combinations of growth factors (Mastrogiacomo et al 2001;Sakimura et al 2006;Hennig et al 2007;Diekman et al 2010;Buxton et al 2011) and mechanical signals (Huang et al 2005;Mauck et al 2007;Huang et al 2010a;Huang et al 2010b;Kelly and Jacobs 2010;Li et al 2010; Thorpe et al 2010;Haugh et al 2011). …”

Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis

“…The multipotent differentiation of MSCs is tightly regulated by both soluble and physical cues present in the pericellular microenvironment, including cell-cell and cell-matrix interactions, cues that can be engineered into a variety of natural and synthetic biomaterial scaffolds (3). These materials may be either permissive to chondrogenesis (inert materials including agarose and PEG) or inductive to chondrogenesis by mimicking components of the natural pericellular microenvironment (4,5).…”

Computational investigation of in situ chondrocyte deformation and actin cytoskeleton remodelling under physiological loading

“…This would suggest that in order to induce the chondrocyte phenotype in mesenchymal stem cells, dynamic loading and hence continuous actin cytoskeleton dissociation is required. Additionally, dynamic loading has been demonstrated to be important for the generation of stem cell-based engineered cartilage constructs [73,74]. The current approach for the design of tissue-engineered cartilage constructs is focused on parameters such as cell source, scaffolds and mechanical stimulation [75].…”