We propose to develop a regenerative gene and cell therapy treatment for acute kidney injury and/or chronic kidney disease. These studies are based on recent advances in isolation of adult stem cells from the urine. Urine-derived stem cells have several remarkable properties: they are easy to obtain, propagate for many passages, are multipotent, and home to sites of injury. We propose to genome modify urine-derived stem cells and track their homing in three mouse models of kidney injury (ischemia reperfusion, rhabdomyolysis, and aristolochic acid). Cells will be modified with transposons to express luciferase. This will permit tracking in live animals by optical imaging together with new techniques for advanced tomography. Biomarkers for kidney injury will be measured and compared. Histology and marker analysis will determine if stem cells have an effect on the mouse phenotype for each condition.
Aim 1 seeks to compare outcomes for mice receiving urine-derived stem cells vs no treatment.
In Aim 2, urine-derived stem cells will be reprogrammed into induced nephron progenitor cells and compared to past methods of deriving induced nephron progenitor cells. These cells are unique because they are similar to cells found in the cap mesenchyme and are capable of differentiating into all parts of the nephron.
These aims will determine if allogeneic or autologous stem cell transplant therapies based on urine- derived stem cells may have the ability to reverse or delay kidney damage in mouse models of acute kidney injury or chronic kidney disease.
Acute kidney injury is a major cause of morbidity and mortality in the Veteran population, affecting 22% of Veterans admitted to VA intensive care units. Those who survive acute kidney injury may never regain full renal function, resulting in chronic kidney disease or end-stage renal disease. One in seven people in the United States has chronic kidney disease. Patients with end-stage renal disease require dialysis or kidney transplantation for survival. Kidney regeneration is poor following acute kidney injury and there are no treatments available at this time to directly encourage regeneration. New treatments that target regeneration of the kidney are needed because the mammalian kidney is comprised of a limited set of nephrons that are present at birth and lost over time, never to be regained, so renal injuries are permanent. We seek to explore the use of adult stem cells for kidney regeneration.!
