Mesenchymal Stromal Cell Homing: Mechanisms and Strategies for Improvement

Abstract

Mesenchymal stromal cells (MSCs) have been widely investigated for their therapeutic potential in regenerative medicine, owing to their ability to home damaged tissue and serve as a reservoir of growth factors and regenerative molecules. As such, clinical applications of MSCs are reliant on these cells successfully migrating to the desired tissue following their administration. Unfortunately, MSC homing is inefficient, with only a small percentage of cells reaching the target tissue following systemic administration. This attrition represents a major bottleneck in realizing the full therapeutic potential of MSC-based therapies. Accordingly, a variety of strategies have been employed in the hope of improving this process. Here, we review the molecular mechanisms underlying MSC homing, based on a multistep model involving (1) initial tethering by selectins, (2) activation by cytokines, (3) arrest by integrins, (4) diapedesis or transmigration using matrix remodelers, and (5) extravascular migration toward chemokine gradients. We then review the various strategies that have been investigated for improving MSC homing, including genetic modification, cell surface engineering, in vitro priming of MSCs, and in particular, ultrasound techniques, which have recently gained significant interest. Contextualizing these strategies within the multistep homing model emphasizes that our ability to optimize this process hinges on our understanding of its molecular mechanisms. Moving forward, it is only with a combined effort of basic biology and translational work that the potential of MSC-based therapies can be realized.

Advances in Analysis of Biodistribution of Exosomes by Molecular Imaging

“…MSC-exosomes have also been reported to be effective for kidney diseases in various animal models [108]. Since MSCs are known to accumulate in damaged tissues through the interactions of receptors on the MSCs and target tissues [109,110], it is highly probable that MSC-exosomes are also localized in damaged tissues due to these receptor interactions. Similarly, exosomes from endothelial progenitor cells showed accumulation in ischemic kidney to prevent ischemic injury through CXCR4-SDF-1α interaction [91].…”

Improved therapeutics of modified mesenchymal stem cells: an update

“…On the basis of enhancing MSC migration, the induction of CXC chemokine receptors 1, 4 and 7 overexpression has been employed [26]. While CXCR4 and CXCR7 serves as specific receptors for one of the most powerful chemokines concerned with cellular migratory processes, which is the stromal cell-derived factor 1 (SDF-1) [27][28][29], CXCR1 is rather a receptor for interleukin-8 (IL-8) [30]. These studies report that the overexpression of CXCR4/CXCR7 in the adipose tissue-derived MSCs, promotes their paracrine, proliferative and migratory abilities.…”

Role of Mesenchymal Stromal Cells as Therapeutic Agents: Potential Mechanisms of Action and Implications in Their Clinical Use

“…Despite the evidence about MSCs direct differentiation and cell replacement, recent studies strongly suggest that the most remarkable MoA of MSCs are attributed to their capacity of migration [17] and paracrine effect [30,31], as well as the modifications that MSCs can cause over the immune system (immunomodulation) [32,33].…”

“…However, MSCs exhibit a remarkable tendency to get located in non-specific tissues, such as the microvasculature and the capillary network, regardless of the presence or absence of an specific injury and the multiple surface leukocyte-like receptors, which intervene in MSC homing [23,35]. MSCs must approach the damaged site through the vascular system and then pass through the endothelial wall in order to keep moving towards the lesion [17].…”