Concise Review: The Bystander Effect: Mesenchymal Stem Cell-Mediated Lung Repair

Abstract

Mesenchymal stem or stromal cells (MSCs), a heterogeneous subset of adult stem/progenitor cells, have surfaced as potential therapeutic units with significant clinical benefit for a wide spectrum of disease conditions, including those affecting the lung. Although MSCs carry both self-renewal and multilineage differentiation abilities, current dogma holds that MSCs mainly contribute to tissue regeneration and repair by modulating the host tissue via secreted cues. Thus, the therapeutic benefit of MSCs is thought to derive from so called bystander effects. The regenerative mechanisms employed by MSCs in the lung include modulation of the immune system as well as promotion of epithelial and endothelial repair. Apart from secreted factors, a number of recent findings suggest that MSCs engage in mitochondrial transfer and shedding of membrane vesicles as a means to enhance tissue repair following injury. Furthermore, it is becoming increasingly clear that MSCs are an integral component of epithelial lung stem cell niches. As such, MSCs play an important role in coupling information from the environment to stem and progenitor populations, such that homeostasis can be ensured even in the face of injury. It is the aim of this review to outline the major mechanisms by which MSCs contribute to lung regeneration, synthesizing recent preclinical findings with data from clinical trials and potential for future therapy.

Controlled delivery and minimally invasive imaging of stem cells in the lung

“…In particular, mesenchymal stem cells (MSCs) have been extensively tested in animal models and clinical trials 15,16 . Through a variety of paracrine actions, MSCs have been shown to induce cell proliferation and angiogenesis, and rescue near-apoptotic cells.…”

“…To enhance therapeutic efficacy, parameters such as the number of cells (i.e., cell dose), delivery mechanism, and delivery route (e.g., intravenous vs. intratracheal) need to be optimized for disease- and patient-specific applications 22 . For example, while the cell dosages used in clinical studies displayed good safety profiles with limited efficacy, increasing total cell number may enhance therapeutic outcomes 16 , a dose-response effect that has yet to be fully elucidated. Unlike intravenous cell injection – where most cells are trapped in the pulmonary microvasculature due to their large size and surface-adhesion receptors – administration of MSCs through the trachea via liquid bolus (i.e., intratracheal administration) could increase the chance for the cells to reach targeted lung regions and augment therapeutic effects 23 .…”

Best of Milan 2017—repair of the emphysematous lung: mesenchymal stromal cell and matrix

“…As an example, BM derived-MSCs are able to inhibit the release of pro-inflammatory cytokines and stimulate the functional activity of regulatory T-lymphocytes (10,11). On the other hand, lung derived-MSCs express several basement membrane proteins and growth factors which seem to amplify their retention in the injured tissue (12).…”

Regulation of mesenchymal stem cell function by TGFβ-1 on mast cell extracellular vesicles – role of endosomal retention

“…After first round of ultracentrifugation, first two fractions (green and red, Supplementary Fig. 9a) were collected and bottom loaded on two separate tubes with different iodixanol density (18,20,22,22,24,26,28,30,35, and 50 %) for second round of ultracentrifugation (182,300 × g, SW40-Ti Rotor, 16 hours, 4°C). Later the fractions were collected from top to bottom (1 ml each for 10 factions) and subjected for the western blotting analysis of lysosomes (LAMP1) and endosomes (EEA1) enrichment markers to defining the distribution of density.…”

“…It has been shown that mesenchymal stem cells (MSCs) can regulate immune responses (18)(19)(20)(21)(22), which has made them attractive therapeutic candidates in several inflammatory diseases, including multiple sclerosis, rheumatoid diseases, tissue transplant rejection and inflammatory respiratory disorders (23)(24)(25). It is known that cytokines can alter the MSC phenotype in numerous ways (26)(27)(28)(29), but very little is known whether or how EVs can influence MSC functions, and exactly by which mechanism this may be induced.…”