Multipotent stem cells and renal progenitors derived from amniotic fluid as potential tools for chronic kidney disease therapies
A great deal of attention has recently been focused in the area of stem cell technology as a possible alternative modality of treatment for a variety of diseases. End stage renal disease (ESRD) has reached epidemic proportions in the United States. An estimated 390,000 US residents are in treatment for ESRD and just last year more than 56,000 individuals were awaiting a kidney transplant. Currently, dialysis or kidney transplantation remain the only viable treatments despite significant limitations of both treatments. This situation along with an increasing shortage of donor organs has heightened interest in developing novel methods of therapy for kidney replacement. In this research we propose to study Alport Syndrome as a model leading to ESRD. Alport Syndrome is a hereditary glomerulonephritis estimated to affect at least 1 in 20,000 people. It is a chronic kidney disease caused by genetic defects in one of the proteins (type IV collagen) that make up the Glomerular Basement Membrane (GBM), an important component of the filter that allows the kidney to clean the blood. It has been shown that mesenchymal stem cells derived from bone marrow may contribute to kidney repair in acute models of kidney disease as well as slowing down the progression of kidney disease in mice that suffer from chronic kidney injury. Herein we focus on the application of stem cells (AFSC) and kidney-specific progenitors (AFKPC) derived from mouse and human amniotic fluid. We have successfully demonstrated that these cells have the potential to differentiate into multiple cell types in vitro and when injected into experimental animals they can restore the functionality of multiple organs such as the kidney, lung, and pancreas. In particular, when injected in an in vivo model of Acute Tubular Necrosis, AFSC survive, integrate, differentiate into tubular-like cells and restore renal function. Major advantages of AFSC are that they can be easily retrieved through amniocentesis with no injury to the embryo and that they do not form tumors (teratomas) in vivo. We have also identified and characterized specific kidney progenitor cells within the total cell suspension present in the amniotic fluid. We hypothesize that AFSC or AFKPC could represent a readily available source of ethically acceptable, biologically unmodified stem cells that may prove useful as a novel alternative to current stem cell therapeutic techniques in regenerative medicine for chronic kidney disease.
The State of California is home to some of the nation's best organ transplant and treatment centers and becomes acuity aware of the growing shortage of organs for our patients and of the need for good alternative therapies in the field of regenerative medicine. In particular we focused our attention on chronic kidney disease that ultimately leads to ESRD. The need for donor organs continues to rise every year and emerging technologies such as those offered by stem cell research may assist our child patients as well as the adult citizens of California with alternative technologies that perhaps can make a significant impact in this field. Although human embryonic stem cells show the capacity for differentiation into multiple cell types, they also have an inherent propensity to form teratomas (tumors) which may limit their clinical usefulness in future therapies. However, a novel population of pluripotent stem cell exists within amniotic fluid, which can be easily obtained, stored, and possibly used for future regenerative medicine or clinical purposes without some of the same concerns over clinical compatibility as embryonic stem cells. In addition to stem cells, within the amniotic fluid there is a very heterogeneous cell population. In particular we have focused our attention on progenitor cells with specific renal characteristics. These could represent a new tool to ameliorate or cure various kidney diseases, because of their commitment toward kidney cell types. We intend to characterize the potential of these cells in kidney regeneration as preliminary studies to their possible use one day in the clinic. CIRM funding will ensure a competitive advantage for California in this innovative direction.