Keratinocyte Growth Factor Gene Delivery via Mesenchymal Stem Cells Protects against Lipopolysaccharide-Induced Acute Lung Injury in Mice

Chen, Jie; Li, Chunsun; Gao, Xiaofang; Li, Chonghui; Liang, Zhixin; Yu, Ling; Li, Yanqin; Xiao, Xiaoyi; Chen, Liangan

doi:10.1371/journal.pone.0083303

Cited by 57 publications

(46 citation statements)

References 44 publications

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“…Several studies have suggested a paracrine/endocrine mechanism in stem cell-mediated lung repair [ 6 , 8 , 12 , 13 ]. However, the nature of the factors that are responsible for the beneficial paracrine/endocrine effect of stem cells has remained elusive.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Lee and colleagues [ 8 ] demonstrated that treatment with human MSC-CM reduced extravascular lung water, improved lung endothelial barrier permeability, and restored alveolar fluid clearance in an ex vivo perfused human lung that was injured by endotoxin. Several studies have demonstrated that the protective effect of MSCs in ALI depends on secreted factors [ 7 , 8 , 11 , 13 , 16 ], such as keratinocyte growth factor (KGF) [ 8 , 13 ], angiopoietin-1 (Ang1) [ 16 ], and insulin-like growth factor (IGF-I) [ 11 ]. KGF gene and Ang1 gene silencing limited the protective effect of MSCs on lung endothelial permeability, and recombinant IGF-I partially reproduced the protective effect of MSC-CM on lungs in ALI.…”

Section: The Paracrine/endocrine Effect Of Mscs In Lung Regeneratimentioning

confidence: 99%

“…This conclusion is drawn from the observation that MSCs can produce bioactive soluble factors that are known to reduce the permeability of the alveolocapillary membrane, inhibit apoptosis and fibrosis, decrease inflammation, and enhance tissue repair [ 5 , 8 – 10 ]. MSC-secreted bioactive molecules may act as paracrine or endocrine mediators that interact with neighboring cells, modulate immune responses, and promote self-repair from cells that survive injury [ 11 – 13 ]. In this context, microvesicles (MVs) that are released from stem cells may account for a reciprocal communication between stem and injured tissue cells.…”

Section: Introductionmentioning

confidence: 99%

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The Role of Microvesicles Derived from Mesenchymal Stem Cells in Lung Diseases

Chen

2015

BioMed Research International

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Microvesicles (MVs) are membrane vesicles that are released by many types of cells and have recently been considered important mediators of cell-to-cell communication. MVs serve as a vehicle to transfer proteins and messenger RNA and microRNA (miRNA) to distant cells, which alters the gene expression, proliferation, and differentiation of the recipient cells. Several studies have demonstrated that mesenchymal stem cells (MSCs) have the capacity to reverse acute and chronic lung injury in different experimental models through paracrine mechanisms. This paracrine action may be partially accounted for by MVs that are derived from MSCs. MSC-derived MVs may confer a stem cell-like phenotype to injured cells with the consequent activation of self-regenerative programmers. In this review, we summarize the characteristics and biological activities of MSC-derived MVs, and we describe their potential in novel therapeutic approaches in regenerative medicine to repair damaged tissues. Additionally, we provide an overview of studies that have assessed the role of MSC-derived MVs in lung diseases, including the mechanisms that may account for their therapeutic potential. Finally, we discuss the clinical use of MSC-derived MVs with several suggestions for enhancing their therapeutic efficiency.

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Section: Discussionmentioning

confidence: 99%

Section: The Paracrine/endocrine Effect Of Mscs In Lung Regeneratimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Role of Microvesicles Derived from Mesenchymal Stem Cells in Lung Diseases

Chen

2015

BioMed Research International

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“…VEGF activates tyrosine phosphorylation of Tie2 in endothelial cells (26), and may positively modulate Ang1-Tie2 signaling to enhance endothelial barrier function (30). Furthermore, PRP also contains various other growth factors, such as keratinocyte growth factor and epidermal growth factor, that stimulate lung repair after damage by endotoxin (31,32). Thus, multiple factors contained in PRP extract may interact with each other to prevent LPS-induced pulmonary edema in vivo.…”

Section: Discussionmentioning

confidence: 99%

Platelet-Rich Plasma Extract Prevents Pulmonary Edema through Angiopoietin-Tie2 Signaling

Mammoto

Jiang

et al. 2015

Am J Respir Cell Mol Biol

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Increased vascular permeability contributes to life-threatening pathological conditions, such as acute respiratory distress syndrome. Current treatments for sepsis-induced pulmonary edema rely on low-tidal volume mechanical ventilation, fluid management, and pharmacological use of a single angiogenic or chemical factor with antipermeability activity. However, it is becoming clear that a combination of multiple angiogenic/chemical factors rather than a single factor is required for maintaining stable and functional blood vessels. We have demonstrated that mouse platelet-rich plasma (PRP) extract contains abundant angiopoietin (Ang) 1 and multiple other factors (e.g., platelet-derived growth factor), which potentially stabilize vascular integrity. Here, we show that PRP extract increases tyrosine phosphorylation levels of Tunica internal endothelial cell kinase (Tie2) and attenuates disruption of cell-cell junctional integrity induced by inflammatory cytokine in cultured human microvascular endothelial cells. Systemic injection of PRP extract also increases Tie2 phosphorylation in mouse lung and prevents endotoxin-induced pulmonary edema and the consequent decreases in lung compliance and exercise intolerance resulting from endotoxin challenge. Soluble Tie2 receptor, which inhibits Ang-Tie2 signaling, suppresses the ability of PRP extract to inhibit pulmonary edema in mouse lung. These results suggest that PRP extract prevents endotoxin-induced pulmonary edema mainly through Ang-Tie2 signaling, and PRP extract could be a potential therapeutic strategy for sepsis-induced pulmonary edema and various lung diseases caused by abnormal vascular permeability.

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“…Other MSC‐derived cues include keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) . Using a human ex vivo lung model, KGF was shown to be essential for the beneficial effect of human MSCs on alveolar epithelial fluid transport .…”

Section: Regenerative Mechanisms Employed By Mscsmentioning

confidence: 99%

Concise Review: The Bystander Effect: Mesenchymal Stem Cell-Mediated Lung Repair

et al. 2016

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Mesenchymal stem or stromal cells (MSCs), a heterogeneous subset of adult stem/progenitor cells, have surfaced as potential therapeutic units with significant clinical benefit for a wide spectrum of disease conditions, including those affecting the lung. Although MSCs carry both self-renewal and multilineage differentiation abilities, current dogma holds that MSCs mainly contribute to tissue regeneration and repair by modulating the host tissue via secreted cues. Thus, the therapeutic benefit of MSCs is thought to derive from so called bystander effects. The regenerative mechanisms employed by MSCs in the lung include modulation of the immune system as well as promotion of epithelial and endothelial repair. Apart from secreted factors, a number of recent findings suggest that MSCs engage in mitochondrial transfer and shedding of membrane vesicles as a means to enhance tissue repair following injury. Furthermore, it is becoming increasingly clear that MSCs are an integral component of epithelial lung stem cell niches. As such, MSCs play an important role in coupling information from the environment to stem and progenitor populations, such that homeostasis can be ensured even in the face of injury. It is the aim of this review to outline the major mechanisms by which MSCs contribute to lung regeneration, synthesizing recent preclinical findings with data from clinical trials and potential for future therapy.

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Keratinocyte Growth Factor Gene Delivery via Mesenchymal Stem Cells Protects against Lipopolysaccharide-Induced Acute Lung Injury in Mice

Cited by 57 publications

References 44 publications

The Role of Microvesicles Derived from Mesenchymal Stem Cells in Lung Diseases

The Role of Microvesicles Derived from Mesenchymal Stem Cells in Lung Diseases

Platelet-Rich Plasma Extract Prevents Pulmonary Edema through Angiopoietin-Tie2 Signaling

Concise Review: The Bystander Effect: Mesenchymal Stem Cell-Mediated Lung Repair

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