Mesenchymal Stem Cells Overexpressing Angiotensin-Converting Enzyme 2 Rescue Lipopolysaccharide-Induced Lung Injury

Abstract

Bone marrow-derived mesenchymal stem cells (MSCs), which have beneficial effects in acute lung injury (ALI), can serve as a vehicle for gene therapy. Angiotensin-converting enzyme 2 (ACE2), a counterregulatory enzyme of ACE that degrades angiotensin (Ang) II into Ang 1-7, has a protective role against ALI. Because ACE2 expression is severely reduced in the injured lung, a therapy targeted to improve ACE2 expression in lung might attenuate ALI. We hypothesized that MSCs overexpressing ACE2 would have further benefits in lipopolysaccharide (LPS)-induced ALI mice, when compared with MSCs alone. MSCs were transduced with ACE2 gene (MSC-ACE2) by a lentiviral vector and then infused into wild-type (WT) and ACE2 knockout (ACE2 −/y ) mice following an LPS-induced intratracheal lung injury. The results demonstrated that the lung injury of ALI mice was alleviated at 24 and 72 h after MSC-ACE2 transplantation. MSC-ACE2 improved the lung histopathology and had additional anti-inflammatory effects when compared with MSCs alone in both WT and ACE2 −/y ALI mice. MSC-ACE2 administration also reduced pulmonary vascular permeability, improved endothelial barrier integrity, and normalized lung eNOS expression relative to the MSC group. The beneficial effects of MSC-ACE2 could be attributed to its recruitment into the injured lung and enhanced local expression of ACE2 protein without changing the serum ACE2 levels after MSC-ACE2 transplantation. The biological activity of the increased ACE2 protein decreased the Ang II amount and increased the Ang 1-7 level in the lung when compared with the ALI and MSC-only groups, thereby inhibiting the detrimental effects of accumulating Ang II. Therefore, compared to MSCs alone, the administration of MSCs overexpressing ACE2 resulted in a further improvement in the inflammatory response and pulmonary endothelial function of LPS-induced ALI mice. These additional benefits could be due to the degradation of Ang II that accompanies the targeted overexpression of ACE2 in the lung.

E-Prostanoid 2 Receptor Overexpression Promotes Mesenchymal Stem Cell Attenuated Lung Injury

“…A pathologist, blinded to the identity of the slides, used a light microscope to evaluate lung injury scores according to the following five criteria: edema, alveolar and interstitial inflammation, alveolar and interstitial hemorrhage, atelectasis, and hyaline membrane formation. 21 …”

Mesenchymal Stem Cells Modified with Heme Oxygenase-1 Have Enhanced Paracrine Function and Attenuate Lipopolysaccharide-Induced Inflammatory and Oxidative Damage in Pulmonary Microvascular Endothelial Cells

“…MSCs are capable of homing to and acting as a vehicle for delivery of protective genes to the injury site, which may not only enhance their therapeutic effects but also promote local lung repair [20]. Delivery of a protective gene by MSCs can overcome the limitations of transient gene expression, host immunoinflammatory responses, and nonspecific cell targeting by classic viral or nonviral vectors [46]. Therefore, we chose BM-MSCs as the vehicle to upregulate HO-1 expression in an LPS-induced inflammatory microenvironment.…”

“…The mechanisms of MSC protection against ALI/ARDS include multilineage differentiation potential (e.g., cell replacement and tissue regeneration), paracrine (e.g., secretion of antimicrobial and repair factors), and cell-cell contactdependent (e.g., transfer of nucleic acids and organelles) mechanisms [17]. Currently, it is believed that paracrine activity plays a predominant role in the therapeutic effects of MSCs [46]. MSCs have the ability to release multiple soluble factors, such as growth factors, antiinflammatory cytokines, and antimicrobial peptides, which can improve endothelial and epithelial permeability, modulate innate and adaptive immunity, and protect against oxidative damage-induced apoptosis [50].…”

Genetic Modification of Mesenchymal Stem Cells Overexpressing Angiotensin II Type 2 Receptor Increases Cell Migration to Injured Lung in LPS-Induced Acute Lung Injury Mice

“…In the pathogenesis of ALI, inflammation and the development of lung tissue damage results in large part from the mobilization of inflammatory cells by cytokines. Evidence has demonstrated that the renin‐angiotensin system involved in the pathophysiology of ARDS and ALI results in increased production of angiotensin II (Ang II) . The mediators that promote inflammation might also be the same molecules that attract MSCs to the site of tissue injury.…”