39-41 Introducing renal MSC into HA-hydrogels to support EPC may improve the quality of the bioartificial niche and enhance the regenerative response of the embedded cells. MSC are especially attractive candidates for the supporting cell role because they have been reported to improve stem cell niche selleck chemicals Sorafenib quality and stem cell mobilization and homing through release of SDF-1, SCF and LIF.42 MSC also possess immuno-modulatory properties due to their release of anti-inflammatory molecules, such as IL-10, and are capable of inducing neighbor cells to secrete cytokines which may inhibit inflammation and pathological remodeling.42 The therapeutic effects of MSC were recently further demonstrated in a study by Gao et al.

, in which renal delivery of adipose-derived MSC embedded in a chitosan based hydrogel improved renal function in an IRI model of AKI, an effect that included reduced renal cell apoptosis, improved microvessel density and enhanced tubular cell proliferation.43 The study by Gao et al. supports the use of hydrogels for therapeutic delivery of stem cells and shows the hydrogel scaffold capable supporting delivery of various stem cell lines. To this end, we rationalized that by embedding MSC along with EPC into HA-hydrogels destined for implantation, the therapeutic efficacy of EPC may be enhanced even farther than if EPC were embedded and delivered alone. In in vitro studies, we observed significant improvement in the resistance of EPC to endotoxins (LPS) when MSC were embedded in combination with EPC, as opposed to EPC embedding alone (Fig. 2) (our unpublished observations).

In in vivo studies on sepsis-induced AKI, delivery of EPC in HA-hydrogels in combination with MSC led to greater improvement in renal microcirculation and renal function, compared with EPC delivered alone. While we are currently investigating the mechanism(s) of beneficial effects that MSC have on EPC, it appears these effects are paracrine in nature and are mediated by the release of protective molecules. Figure 2.Schematic representation (left) and corresponding images (right) (40x magnification) of EPC treated with 10 ug/ml LPS for 24 h. During LPS treatment, EPC were plated on culture plates (A) (without HA-hydrogel embedding), embedded in HA-hydrogels … In our experiments using various AKI models, HA-hydrogel delivery of EPC resulted in enhanced renal engraftment of these cells, as compared with IV delivery.

Although improvement in systemic and renal function parallels the difference in engrafting EPC, the relatively low frequency of kidney-lodged cells suggests that this is not the major route responsible for improved renal function Drug_discovery and microcirculation. Upon further evaluation, we observed significant reduction of circulating pro-inflammatory chemokines and cytokines when EPC are delivered by HA-hydrogel, an effect that concomitantly accompanied improvement of systemic and renal function.