Acute lung injury (ALI) remains a devastating syndrome affecting more than 200,000 patients annually in the U.S. with a mortality rate approaching 40%. Currently, there are no pharmacologic therapies that reduce mortality. Consequently, further research into translational therapies is needed. Cell-based therapy with mesenchymal stem cells (MSC) is one attractive new approach. MSC have the capacity to secrete multiple paracrine factors that can regulate lung endothelial and epithelial permeability, decrease inflammation, enhance tissue repair, and inhibit bacterial growth. In over 250 clinical trials registered with clinicaltrials.gov using MSC as therapy, over 2000 patients have received the cells without any major safety issues.
For the past several years, I have focused my research on the mechanisms by which mesenchymal stem cells (MSC) may normalize alveolar epithelial permeability and fluid transport following ALI. Based on the experimental ALI models that I have developed, we have published several articles that identify paracrine soluble factors that mediate protection and recovery from ALI, including (1) primary cultures of human alveolar type II cells with an air-liquid interface injured by an inflammatory insult to measure net fluid transport and epithelial protein permeability (J Biol Chem 282:24109-24119, 2007, & J Biol Chem 285:26211-26222, 2010) and (2) a novel ex vivo perfused human lung preparation injured by E. coli endotoxin and bacteria (Proc Natl Acad Sci USA 106:16357-16362, 2009). Based on these studies, the therapeutic effect of MSC is attributed in part to the secretion of paracrine soluble factors including IL-10, keratinocyte growth factor and angiopoietin-1 (J Immunol 179:1855-1863, 2007). More recently, I found that MSC given intravenously home to the site of alveolar inflammation and injury in the ex vivo perfused human lung injured with endotoxin (Am J Respir Crit Care Med 181: A3773, 2010). In addition, we recently found that human MSC secrete an anti-microbial peptide, LL-37, which inhibits the growth of both E. coli and P. aeruginosa (Stem Cells 28:2229-38, 2010).
Despite the impressive safety profile, however, MSC have the capacity for spontaneous malignant transformation following multiple passages in vitro as well as the ability to promote tumor growth in vivo. Recently, some investigators have found that microvesicles (MV) released by human MSC are as biologically active as the stem cells for the treatment of acute kidney injury, in part through the transfer of mRNA from the MV to the injured renal epithelium. In my current research, I am studying the potential therapeutic use of human MSC MV as an alternative to cellular therapy in models of ALI. The overall hypothesis is that human MSC MV are biologically active, and that their therapeutic value is primarily mediated through transfer of mRNA from the MV to injured lung epithelium and lung endothelium.