Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities

Abstract

Mesenchymal stromal cells (MSCs) have been the subject of clinical trials for more than a generation, and the outcomes of advanced clinical trials have fallen short of expectations raised by encouraging pre-clinical animal data in a wide array of disease models. In this Perspective, important biological and pharmacological disparities in pre-clinical research and human translational studies are highlighted, and analyses of clinical trial failures and recent successes provide a rational pathway to MSC regulatory approval and deployment for disorders with unmet medical needs.

Keywords: Crohn’s disease; FDA; biomarkers; clinical trials; efferocytosis; graft versus host disease; immune compatibility; mesenchymal stromal cells; thawing.

Conflict of interest statement

Declaration of interests

The authors declare no competing interests.

Copyright © 2018 Elsevier Inc. All rights reserved.

Figures

Figure 1.

MSC fitness, function, and fate theorem. Culture adapted “fit” MSCs express inflammation-suppressing paracrine factors that augment Treg function and M2-macrophage polarization as well as suppress effector lymphoid cell function. MSCs are also habilitated to produce morphogens and exosomes that promote tissular repair. The sum effect of these additive functionalities is to drive tissue regeneration. MSCs progressing to apoptosis express “eat-me” signals such as phosphatidylserine (PtS) and are susceptible to the alternate efferocytosis pathway where their engulfment by phagocytic macrophages leads to expression of immune tolerance factors. The reciprocal relationship between fitness and apoptosis dictates whether MSC metabolism or their efferocytosis, respectively, is responsible for their in vivo biological effects.