Microtissues in Cardiovascular Medicine: Regenerative Potential Based on a 3D Microenvironment

Abstract

More people die annually from cardiovascular diseases than from any other cause. In particular, patients who suffer from myocardial infarction may be affected by ongoing adverse remodeling processes of the heart that may ultimately lead to heart failure. The introduction of stem and progenitor cell-based applications has raised substantial hope for reversing these processes and inducing cardiac regeneration. However, current stem cell therapies using single-cell suspensions have failed to demonstrate long-lasting efficacy due to the overall low retention rate after cell delivery to the myocardium. To overcome this obstacle, the concept of 3D cell culture techniques has been proposed to enhance therapeutic efficacy and cell engraftment based on the simulation of an in vivo-like microenvironment. Of great interest is the use of so-called microtissues or spheroids, which have evolved from their traditional role as in vitro models to their novel role as therapeutic agents. This review will provide an overview of the therapeutic potential of microtissues by addressing primarily cardiovascular regeneration. It will accentuate their advantages compared to other regenerative approaches and summarize the methods for generating clinically applicable microtissues. In addition, this review will illustrate the unique properties of the microenvironment within microtissues that makes them a promising next-generation therapeutic approach.

Spheroid three-dimensional culture enhances Notch signaling in cardiac progenitor cells

“…The supplementary material for this article can be found at https://doi.org/10.1557/mrc.2017.82 spheroid culture provides improved cell-cell and cell-ECM contact and gradients of oxygen and nutrients, [9,26] more similar to the in vivo environment. This results in enhanced Notch activation and might thus lead to: (b) CPC proliferation and maintenance of the stem cell pool and of niche homeostasis (20% O 2 ); or (c) cardiac differentiation, increased ECM production and modulation, mechanical integration and ultimately to a cardioprotective effect and cardiac regeneration (5% O 2 ).…”

“…These model systems recapitulate key features of the endogenous cell niche, such as improved cellcell and cell-extracellular matrix (ECM) contacts, as well as gradients of oxygen and nutrients between periphery and core of the spheroid. [8][9][10][11] Improved knowledge on the mechanisms that regulate CPC behavior and functions, such as survival, proliferation, and differentiation, is needed. In particular, the interaction of CPCs with the niche in which they reside is of pivotal importance to ultimately direct their behavior toward cardiac regeneration.…”

Inspiration from heart development: Biomimetic development of functional human cardiac organoids

“…Despite the increasing progress in other organ systems, few studies have focused on the development of a human cardiac organoid (8, 9). Recapitulation of the 3D multicellular structure and function of the developing myocardium remains a challenge for the development and application of human cardiac organoids (10). …”

Cardiac Regenerative Medicine: The Potential of a New Generation of Stem Cells

“…Their more physiological 3D environment is supposed to recapitulate the stem cell niche. 3D-MTs can also serve as new tools for coculture of multiple cell types [54]. They can contain mixed cell types, be coated with a different cell type, or be fused to produce Janus spheroids [55].…”