Mesenchymal stromal cell-based therapy: Regulatory and translational aspects in gastroenterology

Abstract

The past decade has witnessed an outstanding scientific production focused towards the possible clinical applications of mesenchymal stromal cells (MSCs) in autoimmune and chronic inflammatory diseases. This raised the need of novel standards to adequately address quality, efficacy and safety issues of this advanced therapy. The development of a streamlined regulation is currently hampered by the complexity of analyzing dynamic biological entities rather than chemicals. Although numerous pieces of evidence show efficacy in reducing intestinal inflammation, some inconsistencies between the mechanisms of action of rodent vs human MSCs suggest caution before assigning translational value to preclinical studies. Preliminary evidence from clinical trials showed efficacy of MSCs in the treatment of fistulizing Crohn’s disease (CD), and preparations of heterologous MSCs for CD treatment are currently tested in ongoing clinical trials. However, safety issues, especially in long-term treatment, still require solid clinical data. In this regard, standardized guidelines for appropriate dosing and methods of infusion could enhance the likelihood to predict more accurately the number of responders and the duration of remission periods. In addition, elucidating MSC mechanisms of action could lead to novel and more reliable formulations such as those derived from the MSCs themselves (e.g., supernatants).

Keywords: Mesenchymal stromal cells, Mesenchymal stem cells, Inflammatory bowel diseases, Intestinal disorders, Translational medicine

Core tip: Mesenchymal stromal cells (MSCs) release immunomodulatory mediators upon inflammatory stimuli. This behavior is attractive for the development of advanced therapeutic strategies applied to several intestinal disorders where inflammation is a key pathophysiological feature. In order to assess quality, efficacy and safety of MSC-based therapy, a novel approach to pharmacokinetics/pharmacodynamics (PK/PD) is mandatory. This must rely on careful assessment of cell phenotype, signaling and homing mechanisms. In this regard, experimental models must take advantage of the most updated knowledge in order to reflect the PK/PD mechanisms in humans. Finally, an alternative approach to the “whole-cell treatment” applies MSC-derived mediators alone in order to avoid the hypothesized serious adverse events deriving from a biological entity mostly acting systemically.