Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat

Abstract

Background Bone-marrow derived mesenchymal stem cells (MSCs) reduce the severity of evolving acute lung injury (ALI), but their ability to repair the injured lung is not clear. A study was undertaken to determine the potential for MSCs to enhance repair after ventilatorinduced lung injury (VILI) and elucidate the mechanisms underlying these effects. Methods Anaesthetised rats underwent injurious ventilation which produced severe ALI. Following recovery, they were given an intravenous injection of MSCs (2310 6 cells) or vehicle immediately and a second dose 24 h later. The extent of recovery following VILI was assessed after 48 h. Subsequent experiments examined the potential for non-stem cells and for the MSC secretome to enhance VILI repair. The contribution of specific MSC-secreted mediators was then examined in a wound healing model. Results MSC therapy enhanced repair following VILI. MSCs enhanced restoration of systemic oxygenation and lung compliance, reduced total lung water, decreased lung inflammation and histological lung injury and restored lung structure. They attenuated alveolar tumour necrosis factor a concentrations while increasing concentrations of interleukin 10. These effects were not seen with non-stem cells (ie, rat fibroblasts). MSCsecreted products also enhanced lung repair and attenuated the inflammatory response following VILI. The beneficial effect of the MSC secretome on repair of pulmonary epithelial wounds was attenuated by prior depletion of keratinocyte growth factor. Conclusion MSC therapy enhances lung repair following VILI via a paracrine mechanism that may be keratinocyte growth factor-dependent.

Hepatocyte Growth Factor Is Required for Mesenchymal Stromal Cell Protection Against Bleomycin-Induced Pulmonary Fibrosis

“…The presence of KGF in the MSC secretome has been associated with attenuation of Escherichia coli-induced lung injury [47] and in ventilator induced lung injury [48]. A partial role has been identified for VEGF in MSC protection against a cigarette smoke induced lung injury model [49].…”

Lung Extracellular Matrix and Fibroblast Function

“…Mesenchymal stromal cells (MSCs), resident within lung tissue, appear to represent a viable pool of progenitor cells (reviewed in Reference 37) and have been investigated in animal models of lung disease (38)(39)(40). These studies demonstrate the reparative potential of MSCs and have led to a wave of clinical trials of MSC therapy in patients with various lung disorders (e.g., ARDS, IPF, and COPD).…”

Antisense Oligonucleotide Treatment Enhances the Recovery of Acute Lung Injury through IL-10–Secreting M2-like Macrophage-Induced Expansion of CD4+ Regulatory T Cells

“…The development of ALI, including lung injury recovery, is a complex process requiring a series of integrated steps, including conversion in the balance of proinflammatory and anti-inflammatory cytokines, as well as clearance of inflammatory cells from inflammation sites of lung (4,5). Although extensive investigation explored some pathogenetic factors of ALI, the effect of various approaches including gene therapy, cell therapy and cell-based gene therapy to treat disease remains limited because of the complex process of development of ALI (6)(7)(8). Thus, new strategies are still required for achieving effective treatment of ALI, which might ultimately aid the clinical therapy for patients with ALI.…”