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.

Mesenchymal stromal cell‐derived small extracellular vesicles restore lung architecture and improve exercise capacity in a model of neonatal hyperoxia‐induced lung injury

“…In experimental BPD, we and others have noted that pulmonary macrophages (Mϕs) occupy an "M2like" phenotype, that can persist for several months following HYRX-exposure [18,30,49]. Considering the potent immunomodulatory actions of MEx [50][51][52], future studies should consider if modulating a persistently dysregulated monocyte/Mϕ phenotype can inhibit any further fibrosis and reprogramme the lung milieu to afford reparative actions. Furthermore, considering their diverse functions across multiple experimental models, the pursuit for a single active ingredient is arguably futile.…”

Exosomes Could Offer New Options to Combat the Long-Term Complications Inflicted by Gestational Diabetes Mellitus

“…Several studies suggest that MSC-exosomes regulate immune responses [195,196]; reinforcing this proposition, recent data suggests that macrophage (MΦ) immunomodulation is the 'gatekeeper' to the success of MSC-exosome therapies [197,198]. MSC-exosomes reportedly modulate MΦ phenotype, suppressing the proinflammatory M1-like state and shifting the M2-like MΦ to favor an anti-inflammatory, pro-regulatory phenotype both in vitro and in vivo [197,198]. However, exosomes extracted from cells cultured in cardiometabolic disease [199][200][201][202][203][204][205] mimicking conditions or from biological fluids of diabetic patients, produce pathogenic microangiopathic effects [201,202].…”

“…However, the mechanisms by which MSC-exosomes afford their beneficial actions remain incompletely understood. Several studies suggest that MSC-exosomes regulate immune responses [195,196]; reinforcing this proposition, recent data suggests that macrophage (MΦ) immunomodulation is the 'gatekeeper' to the success of MSC-exosome therapies [197,198]. MSC-exosomes reportedly modulate MΦ phenotype, suppressing the proinflammatory M1-like state and shifting the M2-like MΦ to favor an anti-inflammatory, pro-regulatory phenotype both in vitro and in vivo [197,198].…”

Peer Review #2 of "Conditioned medium from M2b macrophages modulates the proliferation, migration, and apoptosis of pulmonary artery smooth muscle cells by deregulating the PI3K/Akt/FoxO3a pathway (v0.1)"

“…For this reason, immunoregulatory approaches have also been considered. Moreover, stem cell and progenitor cell-based therapies, such as MSCs, induced pluripotent stem cells (iPSs), endothelial progenitor cells (EPCs), and human amniotic epithelial cells (AECs), have shown promise in experimental models for the treatment of PAH (Willis et al 2018). This cell-based approach is useful in providing protection, anti-inflammatory, regeneration, and improved function.…”