Superior protective effects of PGE2 priming mesenchymal stem cells against LPS-induced acute lung injury (ALI) through macrophage immunomodulation

Hezam, Kamal; Wang, Chen; Fu, Enze; Zhou, Manqian; Liu, Yue; Wang, Hui; Zhu, Lihong; Han, Zhibo; Han, Zhongchao; Chang, Ying; Li, Zongjin

doi:10.1186/s13287-023-03277-9

Cited by 14 publications

(6 citation statements)

References 82 publications

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“…The KEGG pathway enrichment analysis revealed that both WT-LPS vs. WT-PBS and TRPC6 -/--LPS vs. WT-LPS were associated with multiple immune-related pathways, including cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, TNF signaling pathway, and cell adhesion molecule signaling pathway in the case of WT-LPS vs. WT-PBS. These findings suggest that the model construction of acute lung injury triggered an immune system response in the organism, which is consistent with previous literature [25]. In TRPC6 -/--LPS versus WT-LPS, the differentially expressed genes were primarily involved in signaling pathways such as cell adhesion molecules, Th1 and Th2 cell differentiation, Th17 cell differentiation, and NF-kappa B signaling pathway.…”

Section: Discussionsupporting

confidence: 90%

TRPC6 Deletion Enhances eNOS Expression and Reduces LPS—Induced Acute Lung Injury

Wang,

Zhang,

Guo

et al. 2023

IJMS

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Acute lung injury (ALI) is characterized by endothelial barrier disruption and associated inflammatory responses, and transient receptor potential cation channel 6 (TRPC6)—mediated Ca2+ influx is critical for endothelial hyperpermeability. In this study, we investigated the role of TRPC6 in LPS—induced ALI, analyzed gene expression in WT and TRPC6-/- lungs using RNA sequencing, and explored the effects of TRPC6 in the LPS—induced hyperpermeability in human umbilical vein endothelial cells (HUVECs) to elucidate the underlying mechanisms. Intratracheal instillation of LPS caused edema in the mouse lungs. Deletion of TRPC6 reduced LPS—induced lung edema and decreased cell infiltration. RNA sequencing analysis suggested that downregulated cell adhesion molecules in TRPC6-/- lungs may be responsible for their resistance to LPS—induced injury. In addition, downregulation of TRPC6 significantly alleviated the LPS—induced decrease in eNOS expression in lung tissue as well as in HUVECs. Moreover, inhibition of TRPC6 with the channel antagonist larixyl led to a decrease in LPS—induced hyperpermeability and ROS production in HUVECs, which could be reversed by blocking eNOS. Our findings suggest that inhibition of TRPC6 ameliorates LPS—induced ALI, which may be achieved by acting on the cell adhesion molecule signaling pathway and participating in the regulation of eNOS levels in endothelial cells.

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Section: Discussionsupporting

confidence: 90%

TRPC6 Deletion Enhances eNOS Expression and Reduces LPS—Induced Acute Lung Injury

Wang,

Zhang,

Guo

et al. 2023

IJMS

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“…Macrophages are important immune cells in lungs which play a vital role in defense functions including phagocytosis, immunity, and cytokine secretion 69 . From the perspective of mechanism, it is more convincing that UC‐MSCs improved the regeneration microenvironment by reducing inflammatory cytokine secretion of macrophage, or promoting M2 macrophage polarization and enhanced immunosuppressive factor secretion, which meet the previous studies between MSCs transplantation and endogenous macrophage behaviors in acute lung injury, 70–74 rather than caused by the xenogenic effects. In addition, macrophages might also regulate the degradation of collagen scaffolds with the formation of alveolar‐like structures.…”

Section: Discussionmentioning

confidence: 64%

Biomimetic scaffold‐based stem cell transplantation promotes lung regeneration

Wang

Feng

Zhao

et al. 2023

Bioengineering & Transla Med

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Therapeutic options are limited for severe lung injury and disease as the spontaneous regeneration of functional alveolar is terminated owing to the weakness of the inherent stem cells and the dyscrasia of the niche. Umbilical cord mesenchymal-derived stem cells (UC-MSCs) have been applied to clinical trials to promote lung repair through stem cell niche restruction. However, the application of UC-MSCs is hampered by the effectiveness of cell transplantation with few cells homing to the injury sites and poor retention, survival, and proliferation in vivo. In this study, we constructed an artificial three-dimensional (3D) biomimetic scaffold-based MSCs implant to establish a beneficial regeneration niche for endogenous stem cells in situ lung regeneration. The therapeutic potential of 3D biomimetic scaffold-based MSCs implants was evaluated by 3D culture in vitro. And RNA sequencing (RNA-Seq) was mapped to explore the gene expression involved in the niche improvement. Next, a model of partial lung resection was established in rats, and the implants were implanted into the operative region. Effects of the implants on rat resected lung injury repair were detected. The results revealed that UC-MSCs loaded on biomimetic scaffolds exerted strong paracrine effects and some UC-MSCs migrated to the lung from scaffolds and had long-term retention to suppress inflammation and fibrosis in residual lungs and promoted vascular endothelial cells and alveolar type II epithelial cells to enter the scaffolds. Then, under the guidance of the ECM-mimicking structures of scaffolds and the stimulation of the remaining UC-MSCs, vascular and alveolar-like structures were formed in the scaffold region. Moreover, the general morphology of the operative lung was also restored. Taken together, the artificial 3D biomimetic scaffold-based MSCs implants induce in situ lung regeneration and recovery after lung destruction, providing a promising direction for tissue engineering and stem cell strategies in lung regeneration.

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“…With MSCs’ existence, pro-inflammatory macrophages secrete anti-inflammatory factors and pro-inflammatory cytokines were downregulated, consequently resulting in the enhancement of phagocytic properties and macrophage type switch ( 47 ). In an experiment in mice, a significant reduction in inflammatory cell and alveolar hemorrhage were observed, and the total number of macrophages and neutrophils, respectively, were remarkably decreased ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

Successful salvage of a severe COVID-19 patient previously with lung cancer and radiation pneumonitis by mesenchymal stem cells: a case report and literature review

Huang,

Tan,

Xie

et al. 2024

Front. Immunol.

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During the COVID-19 pandemic, elderly patients with underlying condition, such as tumors, had poor prognoses after progressing to severe pneumonia and often had poor response to standard treatment. Mesenchymal stem cells (MSCs) may be a promising treatment for patients with severe pneumonia, but MSCs are rarely used for patients with carcinoma. Here, we reported a 67-year-old female patient with lung adenocarcinoma who underwent osimertinib and radiotherapy and suffered from radiation pneumonitis. Unfortunately, she contracted COVID-19 and that rapidly progressed to severe pneumonia. She responded poorly to frontline treatment and was in danger. Subsequently, she received a salvage treatment with four doses of MSCs, and her symptoms surprisingly improved quickly. After a lung CT scan that presented with a significantly improved infection, she was discharged eventually. Her primary disease was stable after 6 months of follow-up, and no tumor recurrence or progression was observed. MSCs may be an effective treatment for hyperactive inflammation due to their ability related to immunomodulation and tissue repair. Our case suggests a potential value of MSCs for severe pneumonia that is unresponsive to conventional therapy after a COVID-19 infection. However, unless the situation is urgent, it needs to be considered with caution for patients with tumors. The safety in tumor patients still needs to be observed.

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Superior protective effects of PGE2 priming mesenchymal stem cells against LPS-induced acute lung injury (ALI) through macrophage immunomodulation

Cited by 14 publications

References 82 publications

TRPC6 Deletion Enhances eNOS Expression and Reduces LPS—Induced Acute Lung Injury

TRPC6 Deletion Enhances eNOS Expression and Reduces LPS—Induced Acute Lung Injury

Biomimetic scaffold‐based stem cell transplantation promotes lung regeneration

Successful salvage of a severe COVID-19 patient previously with lung cancer and radiation pneumonitis by mesenchymal stem cells: a case report and literature review

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