Lung injury and fibrosis represent the most significant outcomes of severe and acute lung disorders, including COVID-19. However, there are still no effective drugs to treat lung injury and fibrosis. In this study, we report the generation of clinical-grade human embryonic stem cells (hESCs)-derived immunity-and matrix-regulatory cells (IMRCs) produced under good manufacturing practice requirements, that can treat lung injury and fibrosis in vivo. We generate IMRCs by sequentially differentiating hESCs with serumfree reagents. IMRCs possess a unique gene expression profile distinct from that of umbilical cord mesenchymal stem cells (UCMSCs), such as higher expression levels of proliferative, immunomodulatory and anti-fibrotic genes. Moreover, intravenous delivery of IMRCs inhibits both pulmonary inflammation and fibrosis in mouse models of lung injury, and significantly improves the survival rate of the recipient mice in a dose-dependent manner, likely through paracrine regulatory mechanisms. IMRCs are superior to both primary UCMSCs and the FDA-approved drug pirfenidone, with an excellent efficacy and safety profile in mice and monkeys. In light of public health crises involving pneumonia, acute lung injury and acute respiratory distress syndrome, our findings suggest that IMRCs are ready for clinical trials on lung disorders.

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34Lung injury and fibrosis represent the most significant outcomes of severe and acute lung disorders, 35including COVID-19. However, there are still no effective drugs to treat lung injury and fibrosis. In this 36 study, we report the generation of clinical-grade human embryonic stem cells (hESCs)-derived 37 immunity-and matrix-regulatory cells (IMRCs) manufactured under good manufacturing practice (GMP) 38 requirements, that can treat lung injury and fibrosis in vivo. We generate IMRCs through sequentially 39 differentiating hESCs with xeno-free reagents. IMRCs possess a unique gene expression profile distinct 40 from umbilical cord mesenchymal stem cells (UCMSCs), such as higher levels of proliferative, 41 immunomodulatory and anti-fibrotic genes. Moreover, intravenous delivery of IMRCs inhibits both 42 pulmonary inflammation and fibrosis in mouse models of lung injury, and significantly improves the 43 survival rate of the recipient mice in a dose-dependent manner, likely through their paracrine functions. 44IMRCs are superior to both primary UCMSCs and FDA-approved pirfenidone, with an excellent efficacy 45 and safety profile in mice, monkeys and two severely ill COVID-19 patients in our pilot study. In light 46 of recent public health crises involving pneumonia, acute lung injury (ALI) and acute respiratory distress 47 alveolar epithelial cells and capillary endothelial cells caused by various direct and indirect injury factors, 54 resulting in diffuse pulmonary interstitial and alveolar edema, and acute hypoxic respiratory insufficiency. 55Pathophysiologically, its characteristics include decreased lung volume, decreased lung extensibility and 56 imbalance of the ventilation / blood flow ratio. When ALI develops into the severe stage (oxygenation 57 index < 200), it is called acute respiratory distress syndrome (ARDS). Globally, there are more than 3 58 million patients with ARDS annually, accounting for 10% of intensive care unit (ICU) admissions 2 . ALI 59 / ARDS patients have an average mortality rate of 35-46% 3,4 . In late ARDS, pulmonary fibrosis (PF) 60 develops due to persistent alveolar injury, repeated destruction, repair, reconstruction and over-61 deposition of extracellular matrix (ECM) 5 , leading to progressive lung scars and common interstitial 62 pneumonia. In general, idiopathic pulmonary fibrosis (IPF) patients show very poor prognosis, with a 63 median survival time of 3-5 years after diagnosis 6 . It has also been reported that the degree of pulmonary 64 fibrosis is closely related to the mortality of ARDS 7,8 . Importantly, there are still no effective FDA-65 approved drugs to treat ALI, ARDS or IPF hitherto, and most of the experimental drugs are still in Phase 66 II or Phase III studies 2, 9,10 . 67Stem cell therapy is an emerging treatment modality being used to cure various inflammatory and/or 68 degenerative diseases, including ALI and PF. In particular, mesenchymal stem cells (MSCs) have been 69 tested as an intravenous infusion therapy for ALI and PF 11,12 . Preclinical and cl...

Background Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. Whether extracellular vesicles are effective in treating IPF and what is the optimal administrative route is not clear. Our previous studies have shown that immunity and matrix regulatory cells (IMRCs) derived from human embryonic stem cells can safely treat lung injury and fibrosis in mouse models, and its mechanism of action is related to the paracrine effect. In this study, we investigated the therapeutic effects of IMRC-derived extracellular vesicles (IMRC-EVs) on a bleomycin-induced pulmonary fibrosis mouse model and explored the optimal route of administration. Methods To study the biodistribution of IMRC-EVs after administration via different routes, NIR labeled-IMRC-EVs were delivered by intratracheal (IT) or intravenous (IV) route, and in vivo imaging was acquired at different time points. The therapeutic effects of IMRC-EVs delivered by different routes were analyzed by assessing histology, lung function, cytokines levels, and transcriptome profiling. RNA-seq of lung tissues was performed to investigate the mechanisms of EV treatment through IT or IV administrations. Results IMRC-EVs mainly reserved in the liver and spleen when administrated via IV route; and mainly retained in the lungs via the IT route. IMRC-EVs administrated via both routes demonstrated a therapeutic effect as attenuated pulmonary fibrosis, improved lung function, and histological parameters. Based on our RNA-seq results, different pathways may be affected by IMRC-EVs administrated via IT or IV routes. In addition, in vitro experiments showed that IMRC-EVs inhibited epithelial-to-mesenchymal transition induced by TGF-β. Conclusion IMRC-EVs administrated via IT or IV routes generate different biodistributions, but are both effective for the treatment of bleomycin-induced pulmonary fibrosis. The therapeutic mechanisms of IMRC-EVs administrated via different routes may be different.

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Silicosis is one of the potentially fatal occupational diseases characterized by respiratory dysfunction, chronic interstitial inflammation, and fibrosis, for which treatment options are limited. Previous studies showed that a novel N-arylpyridone compound named AKEX0011 exhibited anti-inflammatory and anti-fibrotic effects in bleomycin-induced pulmonary fibrosis; however, it is unknown whether it could also be effective against silicosis. Therefore, we sought to investigate the preventive and therapeutic roles of AKEX0011 in a silicosis rodent model and in a silica-stimulated macrophage cell line. In vivo, our results showed that AKEX0011 ameliorated silica-induced imaging lung damages, respiratory dysfunction, reduced the secretion of inflammatory and fibrotic factors (TNF-α, IL-1β, IL-6, TGF-β, IL-4, and IL-10), and the deposition of fibrosis-related proteins (collagen I, fibronectin, and α-SMA), regardless of early or advanced therapy. Specifically, we found that AKEX0011 attenuated silicosis by inhibiting apoptosis, blocking the ASK1-p38 MAPK signaling pathway, and regulating polarization of macrophages. In vitro, AKEX0011 inhibited macrophages from secreting inflammatory cytokines and inhibited apoptosis of macrophages in pre-treated and post-treated models, concurrent with blocking the ASK1-p38 pathway and inhibiting M1 polarization. Collectively, AKEX0011, as a novel N-arylpyridone compound, exerted protective effects for silica-induced pulmonary inflammation and fibrosis both in vivo and in vitro, and hence, it could be a strong drug candidate for the treatment of silicosis.

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