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Review
. 2014 Oct;20(5):365-80.
doi: 10.1089/ten.TEB.2013.0537. Epub 2013 Dec 13.

Three-dimensional aggregates of mesenchymal stem cells: cellular mechanisms, biological properties, and applications

Sébastien Sart  1 , Ang-Chen Tsai, Yan Li, Teng Ma
Affiliations
Review

Three-dimensional aggregates of mesenchymal stem cells: cellular mechanisms, biological properties, and applications

Sébastien Sart et al. Tissue Eng Part B Rev. 2014 Oct.

Abstract

Mesenchymal stem cells (MSCs) are primary candidates in cell therapy and tissue engineering and are being tested in clinical trials for a wide range of diseases. Originally isolated and expanded as plastic adherent cells, MSCs have intriguing properties of in vitro self-assembly into three-dimensional (3D) aggregates reminiscent of skeletal condensation in vivo. Recent studies have shown that MSC 3D aggregation improved a range of biological properties, including multilineage potential, secretion of therapeutic factors, and resistance against ischemic condition. Hence, the formation of 3D MSC aggregates has been explored as a novel strategy to improve cell delivery, functional activation, and in vivo retention to enhance therapeutic outcomes. This article summarizes recent reports of MSC aggregate self-assembly, characterization of biological properties, and their applications in preclinical models. The cellular and molecular mechanisms underlying MSC aggregate formation and functional activation are discussed, and the areas that warrant further investigation are highlighted. These analyses are combined to provide perspectives for identifying the controlling mechanisms and refining the methods of aggregate fabrication and expansion for clinical applications.

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Figures

<b>FIG. 1.</b>
FIG. 1.
Proposed mechanisms for mesenchymal stem cell (MSC) aggregation and ultrastructure organization. (A) MSCs are heterogeneous population containing cells expressing various levels of integrins and cadherins. Initial MSC aggregation is mediated by cadherin–cadherin interactions. Minimizing the free energy, cadherin low/integrin high MSCs sort out at the edge of the aggregates. Mechanical polarization and the increased aggregate compactness are mediated through cadherins. Cadherins act as anchoring point for the cytoskeleton and mediate the increased cortical tension at the medium-aggregate interface. As a consequence of increased cortical tension and integrin–extracellular matrix (ECM) interactions, MSCs at the edge of aggregate display spindle shape and organize the actin as stress fibers. (B) In homotypic cell-to-cell contacts, the interfacial tension (γ) is increased by the cortical tension (T) and decreased by the adhesion energy (J). Since the cells at the interface with the medium are not associated with cell–cell adhesion complexes, the interfacial tension (γ) is equal to the cortical tension (T). As a consequence, the surface tension is increased by cell–cortex tension (T), leading to increase actin polymerization at the edge of the aggregates. Color images available online at www.liebertpub.com/teb
<b>FIG. 2.</b>
FIG. 2.
Methods to generate and cultivate MSC aggregates. MSC aggregates can be generated by (A) spontaneous self-assembly; (B) gravity-induced aggregation in hanging drops; or in (C) confined space of 96-well plates. Applied centrifugal forces induce MSC aggregation in (D) tubes or (E) AggreWell. (F) MSC aggregates form on chitosan membranes through the increased cell motility. (G) Thermal lifting liberates MSC-ECM complexes to form aggregates. Long-term culture of MSC aggregates in (H) low attachment plates, (I) stirred bioreactors, or (J) semisolid gels. Color images available online at www.liebertpub.com/teb
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