The functional specificity of ECs forming the microcirculati

The functional specificity of ECs forming the microcirculation of organs has long been appreciated and recently defined molecularly by Nolan et al. (2013). The characterization of the KDR+ endoderm cell-derived ECs generated in mouse and hESC cultures suggests that those are the specialized sinusoidal ECs of the fetal liver. Likewise, two mesoderm-derived organs, the blood and heart, develop their own ECs from a common KDR+ progenitor for hematopoietic hesperetin or cardiomyocytes, respectively. It is tempting to speculate that functional specificity of microvascular ECs is committed very early during organogenesis and ascribed to a common progenitor for the main cell component of the organ and the specialized ECs. Previous studies in blood and heart development and our work in liver development would suggest that this common progenitor expresses KDR. A deeper understanding of the origin of the liver vascular heterogeneity should advance the fields of liver development and regeneration.
Experimental Procedures
Author Contributions
Acknowledgments We thank Dr. Darrell Kotton for providing the Ef1α− GFP lentivirus-tagged mouse ESC line, Catherine Delmau for helpful advice for the artery femoral injury assay, and the Mouse Genetics and Gene Targeting SRF from Icahn School of Medicine at Mount Sinai for the rederivation of the Foxa2-iCre mice. The authors would like to thank Dr. Todd Evans for critical reading of the manuscript. This work was supported by the Black Family Stem Cell Institute and the National Institute of Diabetes and Digestive and Kidney Diseases for the mouse study (R01DK087867-01 to V.G.-E.).
Introduction Human mesenchymal stem cells (hMSCs) have a therapeutic potential in tissue engineering and regenerative medicine (Caplan, 2007), mostly due to immunologic properties (Jones and McTaggart, 2008) and their ability to differentiate into cardiovascular or neuronal cells (Tae et al., 2006) among others. Human dental pulp stem cells are mesenchymal cells derived from the neural crest, which have been already proved to regenerate tissue in oral inflammatory diseases (Aimetti et al., 2014; Nakashima et al., 2009). These cells can be obtained from permanent and deciduous pulp tissue, which is easily available from teeth after extraction without ethical issues. As previously mentioned, they have a potential role for clinical use either immediately after isolation, or for use in stem cell banking. Therefore, it is highly important to obtain and culture them under the best possible conditions. The in vitro culture of MSCs has been routinely carried out under the ambient oxygen tension (18%–21% O2) (Mohyeldin et al., 2010). However, in vivo these cells are not exposed to such a hyperoxic environment (Harrison et al., 2002; Kofoed et al., 1985; Matsumoto et al., 2005; Pasarica et al., 2009). Depending on the cell type, the local oxygen tension in MSCs niches varies between 1% and 7% O2 in bone marrow (Harrison et al., 2002) and between 10% and 15% O2 in the adipose tissue (Bizzarri et al., 2006). Although values of 3% to 6% O2 (20–40 mmHg) in adult organs and tissues have been reported (Hall and Giaccia, 2005; Kozam, 1967), the actual oxygen concentration in situ depends predominantly on the vascularization of the tissue and its metabolic activity (Ward, 2008). The dental pulp has a relatively high blood flow. It is estimated to be 40–50 ml/min/100 g of pulp tissue in a mature tooth (Meyer, 1993). This flow is relatively high, compared to that of other oral tissues and skeletal muscle (Kim, 1985). Previous studies have shown the negative impact of the ambient oxygen tension (21% O2) on the physiology of stem cells, e.g., neuronal (Rodrigues et al., 2010), bone marrow (Dos Santos et al., 2010; Hung et al., 2012), umbilical cord (Lavrentieva et al., 2010), or adipose tissue (Efimenko et al., 2011; Kim et al., 2012). Although reduced rates of cell proliferation have been observed during culture under 21% O2, an oxygen tension that causes oxidative stress, the underlying molecular mechanisms have not been investigated in a systematic manner.