HGF-Modified Dental Pulp Stem Cells Mitigate the Inflammatory and Fibrotic Responses in Paraquat-Induced Acute Respiratory Distress Syndrome

Abstract

Paraquat (PQ) poisoning can cause acute lung injury and progress to pulmonary fibrosis and eventually death without effective therapy. Mesenchymal stem cells (MSCs) and hepatocyte growth factor (HGF) have been shown to partially reverse this damage. MSCs can be derived from bone marrow (BM-MSCs), adipose tissue (AD-MSCs), umbilical cord (UC-MSCs), dental pulp (DPSCs), and other sources. The biological characteristics of MSCs are specific to the tissue source. To develop an effective treatment for PQ poisoning, we compared the anti-inflammatory and antifibrotic effects of UC-MSCs and DPSCs and chose and modified a suitable source with HGF to investigate their therapeutic effects in vitro and in vivo. In this study, MSCs’ supernatant was beneficial to the viability and proliferation of human lung epithelial cell BEAS-2B. Inflammatory and fibrosis-related cytokines were analyzed by real-time PCR. The results showed that MSCs’ supernatant could suppress the expression of proinflammatory and profibrotic cytokines and increase the expression of anti-inflammatory and antifibrotic cytokines in BEAS-2B cells and human pulmonary fibroblast MRC-5. Extracellular vesicles (EVs) derived from MSCs performed more effectively than MSCs’ supernatant. The effect of DPSCs was stronger than that of UC-MSCs and was further strengthened by HGF modification. PQ-poisoned mice were established, and UC-MSCs, DPSCs, and DPSCs-HGF were administered. Histopathological assessments revealed that DPSCs-HGF mitigated lung inflammation and collagen accumulation more effectively than the other treatments. DPSCs-HGF reduced lung permeability and increased the survival rate of PQ mice from 20% to 50%. Taken together, these results indicated that DPSCs can suppress inflammation and fibrosis in human lung cells better than UC-MSCs. The anti-inflammatory and antifibrotic effects were significantly enhanced by HGF modification. DPSCs-HGF ameliorated pulmonitis and pulmonary fibrosis in PQ mice, effectively improving the survival rate, which might be mediated by paracrine mechanisms. The results suggested that DPSCs-HGF transplantation was a potential therapeutic approach for PQ poisoning.

Heme Oxygenase-1-Modified Bone Marrow Mesenchymal Stem Cells Combined with Normothermic Machine Perfusion Repairs Bile Duct Injury in a Rat Model of DCD Liver Transplantation via Activation of Peribiliary Glands through the Wnt Pathway

“…Mesenchymal stem cells (MSCs) have been shown to contribute to tissue repair regeneration through secreting cytokines and extracellular vesicles [5][6][7][8]. However, the ability of MSCs to "home" to injured tissue is controversial, because most MSCs are actually trapped in pulmonary capillaries after intravenous administration [5].…”

Extracellular vesicles in the pathogenesis and treatment of acute lung injury

“…For example, human umbilical cord MSCs secrete EVs enriched with miR-377-3p, which can attenuate LPS-induced ALI by down-regulating mammalian target of rapamycin (mTOR) to inhibit the expression of inflammatory factors and induce autophagy, both in vivo and in vitro [ 127 ]. Another study found that DPSCs, particularly DPSCs modified to overexpress hepatocyte growth factor (HGF), had a stronger effect than umbilical cord MSCs to inhibit lung inflammation and fibrosis and improve the survival rate of a paraquat poisoning-induced ALI/ARDS mice model [ 128 ]. Similarly, MSC-EV treatment prevented AEC injury caused by mitochondrial gene damage in cigarette-exposed mice by transferring mitochondrial DNA with functional copies [ 129 ].…”

Recent advances in the therapeutic efficacy of hepatocyte growth factor gene‐modified mesenchymal stem cells in multiple disease settings

“…Fibrosis is defined by the accumulation of excess ECM components, which can affect any organ and is responsible for up to 45% of all deaths in the industrialized world. 70 It has been reported that HGF/MSCs could reduce fibrosis efficiently in various diseased organs, including the heart, 68 , 71 lung, 29 , 55 , 72 , 73 , 74 liver, 47 , 52 , 56 , 75 , 76 , 77 , 78 kidney, 45 , 49 bladder, 79 bone 48 and skin. 62 Collagen (COL) is the most important component of ECM, hydroxyproline is the most important component of COL, and fibronectin (FN) is the most important non‐collagenous component of ECM.…”