Stromal cells in health and disease

STROMAL cells are a heterogeneous class of cells and fulfill a variety of highly important roles in health and disease. They are important during development, tissue injury, regeneration, immune responses, cancer, and other pathologies by contributing to several biological processes in different tissues. Their phenotype and function are dependent on the specific tissue microenvironment, but stromal cells themselves also shape the organization, integrity, and the dynamic of their own microenvironment. The multidirectional role of stromal cells in tissues and organs is receiving much needed attention and due to the cutting-edge methods and elegant studies ((1–12); and articles in this issue), we are discovering their key role in fundamental biology and their clinical importance. One of the most studied types of stromal cells is mesenchymal stromal cells (MSC) (12,13). The same acronym is also used to define mesenchymal stem cells; however, it is debatable whether the “stem” nomenclature is appropriate, since postnatal MSC are not necessarily biologically functional stem cells (14). Furthermore, in vitro MSC differentiation does not necessarily recapitulate in vivo differentiation. Thus, the International Society for Cellular Therapy (ISCT) supports that the abbreviation “MSC” should stand for mesenchymal stromal cells (15,16). MSC are known to be present in bone marrow (BM) (17) and adipose tissue (AT) (18) and can also be found in dental pulp (19–21), umbilical cord blood, placenta, and other tissues (22). Recently, it was found that MSC are also present in the heart (23) and other nonmesenchymal vascularized sources (24–26). In cell culture, the cells are plastic adherent and spindleor star-shaped morphology and can be maintained under standardized culture conditions (12,13,27) (Fig. 1). Moreover, they are purported to be multipotent, which can be tested by osteogenic, adipogenic, and chondrogenic differentiation in vitro (Fig. 1). According to Horwitz et al., this feature provides evidence that the investigated cells are indeed MSC (16). MSC are therefore good candidates for cell therapies, as they can easily be isolated, expanded, and re-implanted, in the autologous and allogeneic setting. Their great therapeutic potential in tissue engineering is of utmost relevance, since they have the ability to differentiate into any mesenchymal cell type, such as chondrocytes, adipocytes, and osteocytes. On a molecular level, MSC should routinely express a set of surface markers (Fig. 1), “Clusters of Differentiation” (CD) on their cell membrane composed of CD73, CD90, and CD105, which were defined by the ISCT as the standard minimal required markers for MSC (28). In contrast, MSC should not express the hematopoietic antigens CD45, CD34, CD14, and CD19, which distinguish them from hematopoietic stem cells, often found in the same region (Fig. 1). Additionally, they are negative for CD11b, CD79a, and HLA-DR (23). These criteria, however, are not unique to MSC, and continued research is needed to identify surface markers that are more specific to this kind of stromal cell (14,24,29). As surface markers can be lost or even gained during culturing, the results do therefore not necessarily show the situation in vivo (23). Three aspects of MSC detection by cytometry that are critical to the widespread application of multicolor flow cytometry to both basic and clinical investigations are (30): the