Comparing therapeutic potency of healthy and disease-derived human mesenchymal stromal cells in expe
Diabetic kidney disease (DKD) is the most common cause of kidney failure in the United States and has no adequate cure. Regenerative medicine, applying cell-based therapy is a promising treatment option for DKD. Mesenchymal stromal/stem cells (MSC) possess paracrine anti-fibrotic, anti-apoptotic, pro-angiogenic, anti-inflammatory, and immunomodulatory regenerative activities that aid in kidney repair in animal models of early DKD. MSC may be harvested from the tissue of patients (autologous) or healthy donors (allogeneic) and administered to treat DKD. However, it is unclear whether autologous MSC, favored for decreased risk of allosensitization and reduced immune cell destruction, is equally effective as allogeneic MSC in rejuvenating the repair process of diabetic kidneys. Furthermore, most studies to date test repair capacity in animals with kidney lesions mimicking early human DKD. However, cell-based therapy is likely to also benefit those with advanced DKD. Thus, studies in animal models of advanced DKD are needed to optimize treatment strategies and enable translation from the bench to the bedside. Finally, there is also a need for non-invasive testing of kidney injury and repair biomarkers, such as relevant profibrotic or inflammatory factors and kidney tissue hypoxia that may contribute to our understanding of processes that promote DKD. Our long-term goal is to develop a novel cell-based therapy for DKD. Interim findings from our Phase I, autologous MSC trial in renovascular disease show safety and evidence of preserved kidney function and reduced kidney hypoxia after 3 months compared to medically-treated controls. Based on these exciting findings, we recently launched a pilot trial applying autologous MSC in individuals with DKD. In preparation for this trial, we tested human DKD-MSC function finding some impairment but preserved paracrine repair activities. Still, it remains unclear how these changes reflect MSC reparative capacity when administered to animals or humans. Thus, there is a critical need to determine the impact of cell source on MSC reparative capacity in the damaged kidney, to tailor and leverage cell based treatments for DKD. Our hypothesis underlying the proposed studies is that MSC harvested from individuals with DKD have comparable kidney repair effects in vivo to age-matched controls. Hence the proposed DiaComp Pilot and Feasibility studies aim to compare kidney repair capacity of DKD-MSC and age-matched Control-MSC with two approaches: 1) Transplantation of human adipose-derived MSC in two obese, Type 2 diabetes mouse models (eNOS-/- db/db and db AngII) and 2) Assessment of mouse kidney repair effects in vivo by measuring changes in albuminuria, kidney function, inflammation, fibrosis, microvascular density and a non-invasive biomarker of kidney hypoxia. Significance: Cell-based therapy to delay DKD progression is extremely promising. Assessing the most optimal cell source (autologous or allogeneic) and/or need for autologous cell preconditioning treatments could lead to successful large-scale clinical trials testing the therapeutic potential of MSC in DKD and other chronic diseases.