Table 1.

Preclinical studies (in vitro and in vivo) of MSC treatment in lung conditions.

Preclinical Model	Intervention (MSCs/EVs)	Outcome	Mechanism	References
Human-monocyte-derived Mφs in noncontact co-culture with hMSCs.	Stimulation of co-cultured cells with LPS or BALF from patients with ARDS.	MSCs suppressed pro-inflammatory cytokine production by Mφ.	Increased M2 Mφ marker expression and augmented phagocytic capacity of Mφs.	[44] Morrison et al., 2017
MSCs cultured under different temperatures in vitro in co-culture with Mφ.	hBM-MSCs and Mφ.	MSCs cultured at higher temperatures induce more IL-10 and less TNFα production in Mφs (M2-like phenotype).	Nuclear translocation of HSF-1 and induction of COX2/PGE2 pathways by hyperthermia in MSCs promoted M2-like Mφ phenotype change.	[56] McClain-Caldwell et al., 2018
Polymicrobial sepsis-induced lung injury in mice and in vitro.	Murine MSCs or MSC-conditioned media.	Attenuation of sepsis and TNF-induced miR- 193b-5p upregulation.	miR-193b-5p was decreased by MSCs while its target gene OCLN was increased in lungs from septic mice and in vitro.	[51] DosSantos et al., 2022
Escherichia coli (E. coli)-induced ARDS in rats.	hUC-MSCs and hBM-MSCs.	Improved animal survival, systemic oxygenation, and lung compliance by both hUC- and BM-MSCs.	Decrease in pro-inflammatory cytokines in BALF, increase in IL-10, and ROS reduction in lung tissue.	[43] Curley et al., 2017
LPS-induced ALI in mice.	Adoptive transfer of AMφs pretreated with hMSC-derived EVs.	Reduced inflammation and lung injury in LPS mice.	Mφ changes induced by mitochondrial transfer from EVs to AMφs during pretreatment.	[44] Morrison et al., 2017
LPS-induced ALI in mice.	MSC-EVs derived from young and aging MSCs.	Young MSC-EVs alleviated LPS-ALI, while aging MSC-EVs did not.	Aging MSC-EVs failed to be internalized and did not induce Mφ phenotypic change.	[45] Huang et al., 2019
LPS-induced ALI in mice.	MSC-EVs.	EVs reduce lung injury.	Restoration of mitochondrial respiration in the lung tissue.	[46] Dutra Silva 2021
Ventilator-induced ALI in rats.	Rodent BM-MSCs or their secretome.	Restored systemic oxygenation, lung function, and structure by both MSCs and their secretome.	Decreased lung inflammation (TNFα, IL-6), and increase in IL-10; role of KGF in lung repair.	[47] Curley et al., 2012
Ventilator-induced ALI in mice.	Murine BM-MSCs.	Lungs were protected from injury.	Improved lung function and reduced oxidative stress and collagen-1 expression.	[48] Islam et al., 2019
Ventilator-induced ALI in rats.	Rodent BM-MSCs or their secretome.	MSCs were more effective in reducing lung injury than their secretome.	Improved oxygenation; reduction in lung edema, alveolar inflammation, and IL-6 levels.	[49] Hayes et al., 2015
Polymicrobial sepsis-induced lung injury in mice.	Murine MSCs.	MicroRNA (miRNA) and transcriptome analysis of septic mouse lungs showed that MSCs induced a shift in transcription profiles favoring reconstitution of ‘sham-like’ expression patterns.	MSCs downregulated miR-27a-5p and upregulated its target gene VAV3 in septic lungs.	[50] Younes et al., 2020
Ventilator-induced ALI in rats.	hBM-MSCs, naïve and cytokine-pre-activated (with IL-1β, TNF-α, IFN-γ).	Cytokine pre-activation enhanced the capacity of MSCs to promote injury resolution.	Mechanism dependent on KGF secreted by MSCs.	[52] Horie et al., 2020
Radiation-induced pneumonia and late fibrosis in mice.	Murine BM-MSCs cultured in normoxic and hypoxic environment.	Therapeutic effect of MSCs exposed to hypoxia was more pronounced compared to MSCs exposed to normoxia.	Hypoxia-treated MSCs were more viable and resistant to hypoxia decreasing oxidative stress in lungs by HIF1-α.	[54] Li et al., 2017
Chronic asthma mouse model—challenged with ovalbumin (OVA).	hUC-MSCs-derived EVs from MSCs cultured in normoxic (Nor-EVs) and hypoxic (Hypo-EVs) conditions.	Hypo-EVs were more effective than Nor-EVs in attenuation of chronic asthma.	TGFβ1 pathway was decreased and miR-146-5p increased. The effect was more pronounced if Hypo-EVs were used.	[55] Dong et al., 2021
E. coli-induced pneumonia in rats.	EVs from naïve or interferon (IFN)-γ-primed hUC-MSCs.	EVs from IFN-γ-primed hUC-MSCs more effectively attenuated lung injury than EVs from naïve MSCs.	Enhancements of Mφ phagocytosis and bacterial killing.	[53] Varkouhi et al., 2019
E. coli-induced ARDS.	Naïve and IL-10 over-expressing hUC-MSCs.	IL-10-UC-MSCs were more efficient in decreasing structural lung injury compared to naïve UC-MSC or vehicle therapy.	AMφs from naïve and especially from IL-10-UC-MSC-treated rats enhanced Mφ phagocytosis via increased Mφ HO-1, an effect blocked by PGE2 and LXA4 inhibition.	[58] Jerkic et al., 2019
Acid-primed lung injury in mice.	Murine BM-MSCs, environment correction, or MSC-carrying human IL-10 or HGF gene.	MSCs worsened acid-primed lung injuries associated with fibrosis and high levels of ROS and IL-6.	Correction of oxidative stress with GPx-1, or treatment with MSCs carrying IL-10 or HGF after injury reversed the detrimental effects of naïve MSCs.	[48] Islam et al., 2019
COPD rat cigarette smoke model.	hUC-MSCs and hUC-EVs.	Both transplantation of hUC-MSCs and application of EVs reduced lung inflammation and ameliorated the loss of alveolar septa and their thickening.	Both hUC-MSCs and EVs decreased mononuclear infiltration and reduced the levels of NF-κB subunit p65 in COPD lungs.	[63] Ridzuan et al., 2021
Hyperoxia-induced bronchopulmonary dysplasia (BPD) in rats.	hUC-MSC-EVs.	EVs ameliorated the impaired alveolarization and pulmonary artery remodeling.	MSC-EV prevented hyperoxia-induced reduction in CD163-positive (M2-like) Mφ both in alveolar and interstitial compartment.	[64] Porzionato et al., 2021
Mouse-bleomycin-induced pulmonary fibrosis.	hUC-MSCs.	MSCs attenuated pulmonary fibrosis and promoted lung repair by interacting with Mφs.	Mφs interferon-sensitive sub-cluster induced by MSC infusion caused T-regulatory cell recruitment by CXCL9/10. Number of CD206 Mφs involved in fibrosis was reduced.	[65] Tang et al., 2021