Soluble matrix protein is a potent modulator of mesenchymal stem cell performance

Abstract

We challenge the conventional designation of structural matrix proteins primarily as supporting scaffolds for resident cells. The extracellular matrix protein tropoelastin is classically regarded as a structural component that confers mechanical strength and resilience to tissues subject to repetitive elastic deformation. Here we describe how tropoelastin inherently induces a range of biological responses, even in cells not typically associated with elastic tissues and in a manner unexpected of typical substrate-dependent matrix proteins. We show that tropoelastin alone drives mesenchymal stem cell (MSC) proliferation and phenotypic maintenance, akin to the synergistic effects of potent growth factors such as insulin-like growth factor 1 and basic fibroblast growth factor. In addition, tropoelastin functionally surpasses these growth factors, as well as fibronectin, in allowing substantial media serum reduction without loss of proliferative potential. We further demonstrate that tropoelastin elicits strong mitogenic and cell-attractive responses, both as an immobilized substrate and as a soluble additive, via direct interactions with cell surface integrins αvβ3 and αvβ5. This duality of action converges the long-held mechanistic dichotomy between adhesive matrix proteins and soluble growth factors and uncovers the powerful, untapped potential of tropoelastin for clinical MSC expansion and therapeutic MSC recruitment. We propose that the potent, growth factor-like mitogenic and motogenic abilities of tropoelastin are biologically rooted in the need for rapid stem cell homing and proliferation during early development and/or wound repair.

Tendon‐derived extracellular matrix induces mesenchymal stem cell tenogenesis via an integrin/transforming growth factor‐β crosstalk‐mediated mechanism

“…ECM regulation of cell behavior, such as migration, adhesion, and differentiation are likely contributing factors in various biochemical and physical signaling phenomena, such as mechanotransduction and topographic influences 58‐61 . A recent study demonstrated an important role of soluble matrix protein, that is, tropoelastin, as an important regulator of MSC performance, such as proliferation and phenotypic maintenance 62 . This is in agreement with our study showing that soluble fraction of tendon ECM enhanced ASC proliferation and tenogenic committment.…”

Tropoelastin-Coated Tendon Biomimetic Scaffolds Promote Stem Cell Tenogenic Commitment and Deposition of Elastin-Rich Matrix

“…45,46 This is worthwhile because tropoelastin-integrin crosstalk activates the mechanosensing pathways that result in enhanced cell focal adhesion and cytoskeleton organization. 26 Still, these differences in AR were no longer observed after 14 days ( Figure 4B). While the AR of cells on TROPO remained unchanged from day 5 to 14, it significantly increased on uncoated and PDA-coated samples.…”

“…7,[18][19][20] In a tissue engineering perspective, TROPO has been incorporated as a bulk material to build highly elastic hydrogels, 21,22 films produced through casting 23 or electrospun fibrous scaffolds 24,25 to enhance cell adhesion, proliferation and migration, neo-vascularization and even direct stem cell commitment. 26 TROPO has also been covalently bounded to plasma activated surfaces to enhance cell attachment and potentiate integration within the body. 27,28 Based on the potential role of elastin over native tenocytes, here we propose a novel biomimetic strategy that combines the advantages of 3D nano-to-macro hierarchical and anisotropic scaffolds with the biological potential of TROPO.…”

Stem cell homing: From physiology to therapeutics

“…Which MMPs are involved is not entirely understood, but MMP‐1 has been found to have a role in tissue invasion by MSCs 114 . Matrix components such as tropoelastin have also been found to increase homing and proliferation of MSCs in development and in wound repair 115 . Last, as in HSPC homing, the MSCs must migrate to the site of injury guided by chemotactic signals such as PDGFα, 116 insulin growth factor‐1, 117 CXCL12, and other chemokines.…”