Person:

Parekkadan, Biju

Acute kidney injury is a devastating syndrome that afflicts over 2,000,000 people in the US per year, with an associated mortality of greater than 70% in severe cases. Unfortunately, standard-of-care treatments are not sufficient for modifying the course of disease. Many groups have explored the use of bone marrow stromal cells (BMSCs) for the treatment of AKI because BMSCs have been shown to possess unique anti-inflammatory, cytoprotective, and regenerative properties in vitro and in vivo. It is yet unresolved whether the primary mechanisms controlling BMSC therapy in AKI depend on direct cell infusion, or whether BMSC-secreted factors alone are sufficient for mitigating the injury. Here we show that BMSC-secreted factors are capable of providing a survival benefit to rats subjected to cisplatin-induced AKI. We observed that when BMSC-conditioned medium (BMSC-CM) is administered intravenously, it prevents tubular apoptosis and necrosis and ameliorates AKI. In addition, we observed that BMSC-CM causes IL-10 upregulation in treated animals, which is important to animal survival and protection of the kidney. In all, these results demonstrate that BMSC-secreted factors are capable of providing support without cell transplantation, and the IL-10 increase seen in BMSC-CM-treated animals correlates with attenuation of severe AKI.

Background: Immunodeficient mouse models that accept human cell and tissue grafts can contribute greater knowledge to human stem cell research. In this technical report, we used biomaterial implants seeded with genetically engineered stromal cells to create several unique microenvironments in a single mouse. The scope of study was focused on human CD34 hematopoietic stem/progenitor cell (HSPC) engraftment and differentiation within the engineered microenvironment. Results: A mouse model system was created using subdermal implant sites that overexpressed a specific human cytokines (Vascular Endothelial Growth Factor A (hVEGFa), Stromal Derived Factor 1 Alpha (hSDF1a), or Tumor Necrosis Factor Alpha (hTNFa)) by stromal cells in a three-dimensional biomaterial matrix. The systemic exposure of locally overexpressed cytokines was minimized by controlling the growth of stromal cells, which led to autonomous local, concentrated sites in a single mouse for study. This biomaterial implant approach allowed for the local analysis of each cytokine on hematopoietic stem cell recruitment, engraftment and differentiation in four different tissue microenvironments in the same host. The engineered factors were validated to have bioactive effects on human CD34+ hematopoietic progenitor cell differentiation. Conclusions: This model system can serve as a new platform for the study of multiple human proteins and their local effects on hematopoietic cell biology for in vivo validation studies. Electronic supplementary material The online version of this article (doi:10.1186/s40824-016-0066-2) contains supplementary material, which is available to authorized users.