Acute kidney injury (AKI) is a common cause of morbidity and mortality worldwide and pre-disposes patients to the development of chronic kidney disease (CKD). Mesenchymal stem cells (MSCs) have been shown to improve outcomes of AKI in murine models of kidney disease via paracrine mechanisms, however, the use of MSCs is currently limited by delivery method and cell viability. A biocompatible and safe delivery method that would allow for local delivery of MSCs is needed. Injectable hydrogels have been shown to improve MSC viability. The purpose of this work is to expand upon our prior research using injectable hyaluronic acid (HA) hydrogels for local delivery of MSCs to the kidney in an animal model of AKI-to-CKD transition. The central hypothesis is that local delivery of MSCs via injectable HA hydrogels will improve outcomes of AKI as well as prevent the progression of CKD.
In aim 1, we will investigate the potential method(s) by which hydrogels alone improve renal outcomes, which has been a consistent finding across studies. We will determine whether the hydrogels adsorb pro-inflammatory cytokines and/or impact local gene expression.
In aim 2, we will determine the localization and proliferation of MSCs following delivery either subcutaneously or locally to the kidney via injectable hydrogels, and compare their fate to MSCs injected intravenously via saline suspension.
In aim 3, we will determine the efficacy and mechanisms of action that MSCs via injectable HA hydrogels have along the AKI-to-CKD continuum. The approach is innovative, because it uses novel biocompatible biomaterials to fulfill an unmet clinical need by providing a local delivery system for MSCs that also improves MSC viability. The proposed research is potentially translational for use in humans because injectable hydrogels can be delivered either subcutaneously or under the kidney capsule in a procedure similar to ultrasound-guided percutaneous kidney biopsies. The proposal is significant because acute and chronic kidney diseases are common and other than supportive therapy, there is no current treatment. Complimentary to the proposed research plan, a five year mentored career development training plan has been devised. The training plan incorporates didactic learning in stem cell biology, immunology and statistical analysis, as well as hands-on training in stem cell biology, bioengineering and basic science research. The candidate is co-mentored by internationally recognized experts in the fields of AKI, bioengineering and stem cells. The candidate?s long-term career goal is to become an independent investigator studying the translational utility of biomaterials to deliver therapeutics in an array of kidney diseases.
The proposed research is relevant to public health because the discovery of a treatment intervention for both acute and chronic kidney disease would improve the health outcomes of millions of people worldwide per year. Thus, the proposal is relevant to the part of NIH?s mission that pertains to the prevention and cure of human disease.