Hyaluronidase recruits mesenchymal-like cells to the lung and ameliorates fibrosis

The hyaluronidases (HYALs) are a group of enzymes that regulate hyaluronic acid (HA) metabolism and consequently remodel the extracellular matrix (ECM) [1]. These enzymes are produced by: mammals as a component of seminal fluid, plasma and urine [1]; bacteria as a virulence factor [2,3]; and venomous animals as a non-toxic component of venoms [1]. HYALs have been used therapeutically due to their capacity to reduce biological fluid viscosity, increase vascular permeability and render tissues more accessible to certain drugs [4].There is much interest in the HYAL-HA axis in the treatment of inflammatory disorders [1]. While many studies demonstrated the involvement of HA in inflammatory responses, the involvement of HYALs has been less well studied [5,6]. Although prior investigations have measured tissue HA levels or HYAL messenger RNA (mRNA) levels, few have directly assessed the effect of HYALs on cell or organ function per se.Mesenchymal stem cells (MSCs) are pluripotent cells that can differentiate into a variety of cells, including osteoblasts, myocytes, adipocytes and chondrocytes. Recently, it has been demonstrated that MSC can differentiate along a non-stromal lineage to become lung epithelial cells [7]. The bone marrow is the principal source for MSCs [8,9] but these cells have also been isolated from the umbilical cord [10], fetal membranes [11] and other tissues. The use of MSCs to regenerate tissues has been reported as a promising therapy for the treatment of a variety of diseases [12,13]. However, cellular therapy using MSCs has obstacles, including: the difficulty of obtaining adequate numbers of these cells to transplant; adverse effects of the cells or concomitant immunosuppressive therapies; and the possibility of infection by opportunistic microorganisms [13-15].Increasingly, MSC-based therapies have been considered a promising new means of treating chronic lung diseases such as pulmonary fibrosis, a progressive, highly-lethal disorder for which v