Mesenchymal Stromal Cell Therapy: Does the Source Matter?*

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Acute respiratory distress syndrome (ARDS), an acute inflammatory lung injury, is a major contributor to mortality and morbidity of patients admitted to ICUs. It is a hypoxemic respiratory failure characterized by an increase in lung endothelial and epithelial permeability (1). It can develop in response to multiple factors including infection (pneumonia or systemic sepsis) and trauma (2).
Despite advances in care, the morbidity and mortality of ARDS remains high. Investigators have begun to explore cell-based therapies for ARDS, including the use of mesenchymal stromal cells (MSCs) (3). MSCs are known to have immunomodulatory properties making them an ideal candidate for this type of therapy. They are a heterogeneous population of cells, originally discovered in the bone marrow stromal compartment (4) and subsequently identified in other organs and tissues, including adipose tissue, dental pulp, placenta, amniotic fluid, and umbilical cord (5, 6). MSCs have been shown to play important roles in mediating both the innate and adaptive immune responses and homing to sites of injury in order to contribute to tissue repair (7). A critical property of MSCs is modulation of the immune response and promotion of resolution of inflammation (8). In addition, MSCs have been shown to enhance bacterial clearance in preclinical models of infection (9). The concept of cellular therapeutics for ARDS is easily translatable, as a recent phase 1 clinical trial in humans demonstrated the safety and tolerability of administering MSCs to patients with ARDS (10). Furthermore, a phase 2a trial is currently in progress (11). In regard to ARDS, our comments will focus on the use of allogeneic MSCs for therapy (12). Although autologous cells are certainly being considered for a number of disease processes, the ability to use autologous MSCs in an acute disease (unless previously harvested and expanded) may not be feasible. In addition, autologous MSCs may not be optimal for therapeutic purposes when isolated from patients with underlying systemic diseases, or individuals of older age, due to intrinsic abnormalities of the cells. Therefore, we will limit our discussion to the use of allogeneic MSCs, typically harvested from young healthy donors, for patients with ARDS.
Despite their potential as a cell-based therapy, there is no consensus of an optimal tissue source for the procurement of MSCs. MSCs can exhibit different potential for clinical applications according to their origin. The cell source becomes more important as we consider the doses and number of cells needed for large-scale clinical applications. Bone marrow, adipose, and umbilical cord have the most experimental data to support them (13). There are two published phase 1 clinical trials using allogeneic MSCs for ARDS, with one using adipose-derived (14) and the other using bone marrow–derived MSCs (10). Other clinical trials for pulmonary disorders such as interstitial pulmonary fibrosis (15, 16) and bronchopulmonary dysplasia (17) have used allogeneic sources such as placental-derived, bone marrow–derived, and umbilical cord–derived MSCs, respectively.
In this issue of Critical Care Medicine, Silva et al (18) compared MSCs derived from three sources (bone marrow, adipose, and lung tissues) in an in vivo model of endotoxin-induced lung injury, as well as in vitro coculture experiments. MSCs from different sources led to variable responses in lungs and distal organs in this endotoxin model, with both bone marrow–derived as well as adipose-derived MSCs yielding greater beneficial effects than lung MSCs. Additionally, MSCs presented different immunomodulatory effects when cocultured with macrophages and lipopolysaccharide depending on their source (18). The authors presented important concepts regarding identifying an optimal source of MSCs, which has direct relevance to our ability to translate MSC therapy to patients.
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