Cardiac Progenitor Cells and the Interplay with Their Microenvironment

Abstract

The microenvironment plays a crucial role in the behavior of stem and progenitor cells. In the heart, cardiac progenitor cells (CPCs) reside in specific niches, characterized by key components that are altered in response to a myocardial infarction. To date, there is a lack of knowledge on these niches and on the CPC interplay with the niche components. Insight into these complex interactions and into the influence of microenvironmental factors on CPCs can be used to promote the regenerative potential of these cells. In this review, we discuss cardiac resident progenitor cells and their regenerative potential and provide an overview of the interactions of CPCs with the key elements of their niche. We focus on the interaction between CPCs and supporting cells, extracellular matrix, mechanical stimuli, and soluble factors. Finally, we describe novel approaches to modulate the CPC niche that can represent the next step in recreating an optimal CPC microenvironment and thereby improve their regeneration capacity.

Figure 1

The cardiac progenitor cell resident microenvironment. (a) The simplified representation shows some of the key players of the healthy CPC niche: (1) cellular elements (CPCs and supporting cells: cardiomyocytes, endothelial cells, smooth muscle cells, stromal cells, and immune cells) and cell-cell interactions such as signaling via Notch; (2) extracellular matrix (ECM); (3) mechanical stimuli, such as the cyclic strain provided by the beating heart; and (4) soluble factors, such as cytokines, oxygen gradients, and growth factors. (b) Simplified representation of the infarcted heart, where the microenvironment is altered and the niche components modified: (1) cardiomyocyte death and infiltration of myofibroblasts and immune cells; (2) excessive and disordered formation of ECM; (3) increased ECM stiffness and thus altered mechanical behavior; and (4) increased secretion of growth factors and cytokines.

Figure 2

The CPC microenvironments. For therapeutic application, CPCs can be isolated from their resident niche and (a) cultured in an in vitro niche, prior to transplantation into the infarcted heart, or (b) the local microenvironment can be modulated in order to recruit CPCs to the injured area. The aim of both approaches is to regenerate the myocardium thanks to CPC proliferation and differentiation into cardiomyocytes.

Figure 3

Cell-cell interactions in the CPC niche. CPCs interact with each other and with supporting cells (cardiomyocytes, fibroblasts, endothelial cells, smooth muscle cells, and immune cells), both via direct cell-cell signaling (such as the Notch pathway) and paracrine signaling.

Figure 4

CPCs migrate toward lower oxygen concentration in an oxygen gradient device. (a) In a PDMS device (showed in the schematic representation) where 20% or 95% O₂ was applied at one end, and 1% O₂ at the other end, an increasing number of CPCs were observed at the lower oxygen side after 24 hours. Representative images show the increased amount of cells (nuclei stained with Hoechst 33342, blue). (b) The quantification of cell number (normalized to the initial value after seeding) is reported as mean ± SD (n = 4; ^∗P < 0.05; ^∗∗P < 0.01).

Figure 5

In vitro approaches to modulate the CPC niche. Strategies to optimize the regenerative potential of CPCs by modulating their microenvironment include (clockwise) the following: engineering the ECM with synthetic or naturally derived polymers with the right composition and physical properties; recreating a niche-like environment by growing cells as multicellular spheroids; applying electrical pacing and/or cyclic strain; co- and multiculture of different cell types to optimize cell-cell interactions, with or without surrounding ECM; and modulating the cell recruiting potential held by gradients of oxygen and cytokines and growth factors.