Delivery of EPC embedded in HA-hydrogels for treatment of acute kidney injury

Abstract

Adoptive transfer of stem cells has shown potential as an effective treatment for acute kidney injury (AKI). The current strategy for adoptive transfer of stem cells is by intravenous injection. However, this conventional method of stem cell delivery is riddled with problems causing reduced efficacy of the therapeutic potential of delivered stem cells. This review summarizes the recent advancements in an alternative method of stem cell delivery for treatment of AKI, embedding stem cells in hyaluronic acid (HA-) based hydrogels followed by their implantation. Furthermore, one stem cell type in particular, endothelial progenitor cells (EPC), have shown remarkable therapeutic benefits for treatment of AKI when delivered by HA-hydrogels. The review also summarizes the delivery of EPC by HA-hydrogels in the setting of AKI.

Keywords: Adriamycin-induced kidney injury; acute kidney injury; endothelial progenitor cells; endotoxemia; hyaluronic acid based hydrogels; sepsis; stem cell therapy.

Figure 1. Schematic of the implantation of HA-hydrogels and subsequent release and mobilization of embedded EPC for treatment of AKI in a mouse model. 1) HA-hydrogels with embedded EPC are implanted either superficially into ears or subcapsularly into kidneys. 2) Induction of AKI (cyto-/endotoxins). 3a) Kidney implants are digested by endogenous release of hyaluronidase from the kidneys during AKI and embedded EPC are mobilized into the kidney, or 3b) ear implants are digested by direct injection of hydrogel-digesting enzymes and embedded EPC are mobilized into the circulation. 4) Released EPC generate therapeutic effects (see Tables 1 and 2).

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 (B), or embedded in HA-hydrogels along with MSC (C). Embedding EPC in HA-hydrogels improved EPC viability and resistance to endotoxins, an effect that was considerably enhanced when EPC were co-embedded with MSC. To determine cell viability, cells were subject to a LIVE/DEAD assay in which live cells were stained green with calcein and dead cells were stained red with ethidium homodimer.