Mesenchymal Stem/Stromal Cell (MSCs)

Although mesenchymal stem/stromal cells can be derived from a variety of different tissue sources, bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) have been the most extensively studied in the field of acute lung injury (ALI, the pro-clinical correlate of human ARDS) and will be the main focus of this review. Some controversy remains regarding how to name these pluripotent cells

[14] , stem vs. stromal, and minimal criteria to define them have been established

[15] . First, MSC should be adherent to plastic in standard culture conditions. Second, they should express CD105, CD73, and CD90 and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19, and HLA-DR surface molecules. Finally, they should differentiate to osteoblasts, adipocytes, and chondro- blasts in vitro [15]. MSCs possess various favorable biological characteristics underscoring their clinical utility, including their convenient isolation, their rapid expansion in culture, and high clonogenicity while preserving their genetic stability and minimal immunogenicity making them a viable option for allogenic transplantation. The latter has recently come into question as MSCs may be immune evasive rather than immune privileged [16].

MSCs also preferentially home to the wounded or damaged tissue sites [17]. Traffic of MSCs to areas of tissue injury appears to be driven by different interactions between chemokines released from the injured tissue and chemokine receptors expressed on MSCs. For example, stromal cell-derived factor 1/CXCR4 pathway can mediate traffic of MSCs to ischemic or hypoxic tissues [18-20], while CD44 expressed on MSCs may interact with hyaluronic acid where interstitial matrices are exposed following injury [21-23]. Following intravenous administration, MSCs become entrapped in the capillary beds; this occurs primarily in the lung and liver [24]. In the context of ARDS, the relative biological significance of MSC entrapment is unclear since MSCs from bone marrow, adipose, and other tissues stay in the lungs for only about 24-48 h prior to being cleared [25, 26]. The overall opinion is that these cells may exert their beneficial effect through mechanisms that may not require cell-cell contact, and although cell engraftment with differentiation, transdifferentiation, or cell fusion may contribute to reconstitution of normal organ function, these are of uncertain therapeutic significance [27-29]. In contrast to the engraftment hypothesis, several alternative mechanistic explanations have been proposed for how these cells exert their therapeutic effects including:

(i) Their potential for enhancing tissue-endogenous stem/progenitor cell activity
(ii) Regulation of genes that modulate the response to injury and repair
(iii) Transfer of cellular and genomic contents such as mitochondria and microRNAs
(iv) Secretion of paracrine factors that target key aspects of the pathophysiology of injury and repair in ARDS