Multiple strategies must be pursued in the development of cellular therapies.

Stem cell-based therapies are at the forefront of research into novel ways to treat many disease processes. However, providing clinically useful diseasespecifi c cellular therapies will require further pre-clinical work. Discovery of new cell lines, development of improved pre-transplantation processing protocols, and further research into the mechanisms behind non-regenerative and regenerative healing are among the important factors involved in driving this fi eld to clinical application (1). The articles in this issue of Cytotherapy provide examples of the above strategies, as applied to peripheral vascular disease, myocardial ischemia and cutaneous wound healing, and highlight the vital role of neo-angiogenesis in the regenerative healing process. In their article, Rahnemai-Azar et al . (2) introduce human marrow-isolated adult multilineage-inducible (MIAMI) cells. When grown at low oxygen tension (3% O 2 ), these cells are capable of differentiation into endothelial cells and produce high levels of proangiogenic factors, including monocyte chemoattractant protein 1 (MCP-1), fractalkine, growth-related oncogene (GRO), interleukin-6 (IL-6), IL-8 and vascular endothelial growth factor (VEGF). Transplantation of these cells into the ischemic hindlimbs of mice signifi cantly reduced limb ischemia and necrosis and improved perfusion compared with fi broblast and vehicle controls. Immunohistochemistry demonstrated that surviving MIAMI cells were associated with blood vessels or the perivascular space, and a portion expressed CD31 and/or von Willebrand factor (vWF). While further work needs to be done, and comparisons made with other endothelial progenitor cell populations, MIAMI cells appear to be a promising cell population in promoting tissue reperfusion and angiogenesis. Huang et al . (3) present their research into human umbilical cord lining epithelial cells (CLEC) as a potential source of skin-type epithelial stem cells. CLECs possess many stem cell characteristics, including long telomere lengths, high proliferative potential and expression of the pluripotent markers OCT-4, SOX2 and Nanog, but in small proportions. CLECs also have many cytokeratin markers usually specifi c to basal keratinocytes, such as CK8 and CK14, as well as p63 and CK19, markers for epidermal skin progenitor cells. In organotypic culture, these cells formed a stratifi ed epithelium typical of skin, but they failed to form a cornifi ed strata layer. CLECs have limitations, as discussed in the article; however, there is potential in applications for promoting wound healing and skin regeneration if these limitations can be addressed. For the treatment of ischemic disease processes, stem cells must fi rst home to the area of insult and then overcome the high oxidative stress of the ischemic tissue (4). Activation of the PI3/Akt pathway is believed to provide protection against apoptosis induced by oxidative stress. Zhang et al . (5) report that zinc supplementation (10 μ mol/mL) of the growth media of bone marrow-derived mesenchymal stromal cells (MSC) reduced apoptosis, enhanced VEGF production and was associated with increased levels of Akt phosphorylation in vitro . Transplantation of zinc-treated MSC into murine ischemic hindlimbs resulted in increased cell survival, angiogenesis and reperfusion compared with untreated MSC. Strategies to improve the survival of transplanted cells in hostile environments are essential in the development of cellular-based therapies. The article by Lee et al . (6) highlights the potential paracrine effects following stem cell therapy. Repeated Cytotherapy, 2011; 13: 133–134