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

Abstract

Due to the great therapeutic interest that involves the translation of mesenchymal stromal cells (MSCs) into clinical practice, they have been widely studied as innovative drugs, in order to treat multiple pathologies. MSC-based cell therapy involves the administration of MSCs either locally or systemically into the receptor body where they can traffic and migrate towards the affected tissue and participate in the process of healing. The therapeutic effects of MSCs compromise of different mechanisms such as the functional integration of differentiated MSCs into diseased host tissue after transplantation, their paracrine support, and their impact on the regulation of both the innate and the acquired immune system. Here, we establish and provide recent advances about the principal mechanisms of action through which MSCs can perform their activity and effect as a therapeutic tool. The purpose of this review is to examine and discuss the MSCs capacity of migration, their paracrine effect, as well as MSC-mediated modifications on immune cell responses.

Keywords: homing; immunomodulation; mechanism of action; mesenchymal stromal cells.

Figure 1

Homing and transendothelial migration of mesenchymal stromal cells (MSCs). MSCs can act both endogenously or exogenously, performing a homing process, by which they move towards the affected site following chemotactic signals in order to repair or contribute to the recovery of the damaged tissue. bFBF: basic fibroblast growth factor; FGFR: fibroblast growth factor receptors; VLA-4: very late antigen 4; VCAM-1: vascular cell adhesion molecule 1.

Figure 2

Transendothelial migration through the endothelial cells of the endothelium. Mesenchymal stromal cells (MSCs) develop a front pole through the joint action of the FROUNT protein and the C-C chemokine receptor type 2 (CCR2) in order to degrade endothelial cells and its basal membrane on its way to the damaged site.

Figure 3

Immune interactions (immunomodulation) of mesenchymal stromal cells (MSCs). MSCs have been proven to have influence over both adaptative cells, such as T and B cells, and innate immune cells, such as dendritic cells, natural killer (NK) cells, monocytes, and macrophages by secreting several molecular factors as indoleamine 2,3-dioxygenase (IDO) and different cytokines. BAFF: B cell activating factor.

Figure 4

Paracrine activity of mesenchymal stromal cells (MSCs). MSC-secreted factors can interact directly at different cellular processes, such as immunomodulation, chemoattraction, progenitor cell proliferation, angiogenesis and differentiation, remaining all of them essential to the correct function of MSCs within the body. HGF: hepatocyte growth factor; IGF: insulin-like growth factor 1; TSG6: tumor necrosis factor-inducible gene 6 protein; VEGF: vascular endothelial growth factor.

Figure 5

Mesenchymal stromal cell-secreted exosomes perform a role in cell-to-cell communication, as well as triggering therapeutic effects, by a reduction of oxidative stress, increasing cell live expectancy, and exhibiting an immunological tolerance through the reduction of activation and proliferation of adaptative immune cells and the differentiation of innate cells towards regulatory phenotypes.