Stem Cell Based Approaches to Modulate the Matrix Milieu in Vascular Disorders

Abstract

The extracellular matrix (ECM) represents a complex and dynamic framework for cells, characterized by tissue-specific biophysical, mechanical, and biochemical properties. ECM components in vascular tissues provide structural support to vascular cells and modulate their function through interaction with specific cell-surface receptors. ECM-cell interactions, together with neurotransmitters, cytokines, hormones and mechanical forces imposed by blood flow, modulate the structural organization of the vascular wall. Changes in the ECM microenvironment, as in post-injury degradation or remodeling, lead to both altered tissue function and exacerbation of vascular pathologies. Regeneration and repair of the ECM are thus critical toward reinstating vascular homeostasis. The self-renewal and transdifferentiating potential of stem cells (SCs) into other cell lineages represents a potentially useful approach in regenerative medicine, and SC-based approaches hold great promise in the development of novel therapeutics toward ECM repair. Certain adult SCs, including mesenchymal stem cells (MSCs), possess a broader plasticity and differentiation potential, and thus represent a viable option for SC-based therapeutics. However, there are significant challenges to SC therapies including, but not limited to cell processing and scaleup, quality control, phenotypic integrity in a disease milieu in vivo, and inefficient delivery to the site of tissue injury. SC-derived or -inspired strategies as a putative surrogate for conventional cell therapy are thus gaining momentum. In this article, we review current knowledge on the patho-mechanistic roles of ECM components in common vascular disorders and the prospects of developing adult SC based/inspired therapies to modulate the vascular tissue environment and reinstate vessel homeostasis in these disorders.

Keywords: ECM; cardiovascular; collagen; elastin; exosomes; regenerative repair.

Figure 1

Anatomical structure of blood vessel from transverse (A) and longitudinal (B), (C) views. Tunica media of blood vessel shows aligned circumference of SMCs following herringbone helical arrangement, and tunica intima form straight cell alignment. FBs, fibroblasts; SMCs, smooth muscle cells; ECs, endothelial cells. Double-headed arrow, blood flow direction. Reprinted from Wang et al. (14), with permission from IOP Publishing Ltd.

Figure 2

Key elements of the arterial wall and vascular extracellular matrix components. Reprinted from Barallobre-Barreiro et al. (5), with permission from Elsevier.

Figure 3

Tropoelastin synthesis, binding with elastin-binding protein (EBP), transport, release of EBP, assembly with fibulins, binding to microfibrils, lysyl oxidase-mediated cross-linking, and final formation of an elastic fiber with microfibrils.

Figure 4

Transmission electron micrographs showing significantly greater density of forming elastic fibers in cBM-SMC cultures, and less so in rBM-SMC cultures relative to RASMC cultures. The elastic fibers were composed of fibrillin microfibrils (white arrows) laid down as a prescaffold onto which amorphous elastin (red arrows) was deposited and crosslinked. The RASMC cultures contained mainly amorphous elastin deposits. Very few amorphous elastin deposits and no fiber-like structures were seen in EaRASMC cultures. Reprinted from Dahal et al. (117), with permission from Mary Ann Liebert, Inc.

Figure 5

Schematic summarizing a stem cell inspired approach for vascular elastic matrix repair involving delivery of stem cell exosomes.

Figure 6

Effects of EV(exosomes)/conditioned media (CCM)/conditioned media depleted with exosome (CCM-D) treatment on elastic fiber ultrastructure. Transmission electron micrographs showing elastic fiber formation (red arrows) in EaRASMC cultures treated with EVs/CCM/CCM-D. TC and CCM-D treated cell layers contained very few sporadic deposits of elastin and no fibers. Reprinted from Sajeesh et al. (148), with permission from Elsevier.