Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension?

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by remodeling of the pulmonary arteries, increased pulmonary infiltrates, loss of vascular cross-sectional area, and elevated pulmonary vascular resistance. Despite recent advances in the management of PAH, there is a pressing need for the development of new tools to effectively treat and reduce the risk of further complications. Dysregulated immunity underlies the development of PAH, and macrophages orchestrate both the initiation and resolution of pulmonary inflammation, thus, manipulation of lung macrophage function represents an attractive target for emerging immunomodulatory therapies, including cell-based approaches. Indeed, mesenchymal stem cell (MSC)-based therapies have shown promise, effectively modulating the macrophage fulcrum to favor an anti-inflammatory, pro-resolving phenotype, which is associated with both histological and functional benefits in preclinical models of pulmonary hypertension (PH). The complex interplay between immune system homeostasis and MSCs remains incompletely understood. Here, we highlight the importance of macrophage function in models of PH and summarize the development of MSC-based therapies, focusing on the significance of MSC exosomes (MEx) and the immunomodulatory and homeostatic mechanisms by which such therapies may afford their beneficial effects.

Keywords: MSC exosomes (MEx); bronchopulmonary dysplasia (BPD); exosomes; extracellular vesicles (EVs); inflammation; macrophages; mesenchymal stem cells (MSCs); pulmonary arterial hypertension (PAH); pulmonary hypertension (PH).

Figure 1

Mesenchymal stem/stromal cell-exosomes (MEx). (Left panel) Transmission electron microscopy (TEM) image of human umbilical Wharton’s jelly-derived MEx. Scale bar = 500 nm. (Right panel) Schematic representation of MEx composition. MEx contain molecules associated with the pathways of their biogenesis, such as small G-proteins RABs, tumor susceptibility gene 101 (TGS101), programmed cell death 6 interacting protein (Alix), Syntenin, Annexins, and Flotillin 1 (FLOT1). MEx’s cargo includes small non-coding RNAs, but also macromolecular modules, growth factors, and metabolic enzymes. Although heterogenous by nature, typically, exosomes have a diameter of 35–150 nm. Adapted from Willis et al. [96] and Willis et al. [28]. Multivesicular bodies (MVB); endosomal sorting complexes required for transport (ESCRT); glyceraldehyde 3-phosphate dehydrogenase (GAPDH); lysosome-associated membrane glycoprotein (LAMPs).

Figure 2

Modulation of macrophage function by mesenchymal stem cell (MSC)-exosomes (MEx): implications in pulmonary hypertension (PH). A diagrammatic illustration of the pulmonary vascular changes in pulmonary arterial hypertension (PAH) (left) and mechanisms by which MEx may afford their beneficial effects (right). In patients with PAH, pulmonary vessels are characterized by phenotypically altered, hyperproliferative smooth muscle cells (SMCs). Simultaneously, the blood vessels in PAH become decorated with an influx of inflammatory cells including, but not limited to, lymphocytes, monocytes, and proinflammatory macrophages. These invading inflammatory cells augment the inflammatory cascade by the secretion of pro-inflammatory and pro-fibrotic cytokines. MEx modulate macrophage phenotypes away from the pro-inflammatory phenotype towards that of a pro-resolving, anti-inflammatory state. Endothelial cell (EC); interleukin- (IL-); tumor necrosis factor alpha (TNF-α); arginase-1 (Arg-1); resistin-like alpha (Retnla); chitinase 3-like 3 (Chi3L3).