The Role of Aging in Kidney Repair by Adult Stem Cells

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): We propose to study the role of alterations in adult stem cell function in acute renal failure in elderly patients, and thus submit this application for consideration of funding under Research Objective 13, "Stem cells, tissue repair, and cell replacement in aging". Acute renal failure due to tubular necrosis (ATN) is the most common cause of renal failure in the hospital and carries a mortality rate of 60-80% in patients in the Intensive Care Unit. Recent studies have demonstrated an approximately 10-fold increase in susceptibility to ATN in patients>65 years of age, with greater associated morbidity and mortality in this age group. The present paradigm for recovery from acute renal failure is that surviving epithelial cells from areas bordering the injury migrate into the regions of tubular damage and proliferate to re-establish the normal tubular epithelium. However, therapies aimed at stimulating these events have failed to alter the course of acute renal failure in humans. We have found that mouse adult bone marrow contains stem cells (BMSCs) that enter the systemic circulation after ischemic renal injury, and that these cells rapidly migrate to injured regions of the renal tubule where they appear to differentiate into renal tubular epithelial cells and support recovery from injury. Our hypothesis is that BMSCs from elderly patients fail to sufficiently populate the injured renal tubule, leading to both an increased incidence of acute renal failure, and a worse prognosis for recovery. We plan to test this hypothesis by examining the ability of renal ischemic injury to mobilize stem cells in the old mouse, and the ability of those older cells to home to and repair the kidney (SA 1). We then Will design and test pharmacologic protocols for the rapid mobilization of stem cells that can home to and populate the kidney, and determine whether those protocols enhance recovery in a murine model of ischemic ATN in old mice (SA 2). Finally, the role of stem cells in recovery from other forms of acute renal failure will be determined in old mice (SA 3). These experiments are designed to provide the functional basis for an entirely novel approach to enhancing the rate and degree of organ repair following ischemic injury in the elderly, and will specifically provide the preliminary information necessary for the development of prospective trials aimed at the use of this approach to minimize the morbidity and mortality associated with acute renal failure in older patients.