Kidney fibrosis is a critical health problem in the United States because it represents the final common pathway of all chronic kidney diseases yet there is no approved drug to treat it. There is general agreement that myofibroblasts are the cell type responsible for scar formation in fibrotic kidney disease but little consensus about where these cells come from, which is a critical knowledge gap that needs to be brifged in order to discover new therapies to treat chronic kidney disease. We have discovered a new subpopulation of stromal cells, unappreciated in kidney science to date, that represents the major myofibroblast precursor population. These cells expand in fibrosis according to our genetic fate mapping experiments, and ablating these cells ameliorates fibrosis - proving their functional importance. In this proposal we aim to understand the role of these cells in health and chronic disease, to determine whether their ablation improves renal functional parameters in chronic kidney disease models, and to understand their functional capacities. We will use state of the art genetic approaches in vivo and complementary cell isolation, transplantation and in vitro studies to assess their properties ex vivo. Together, the proposed experiments represent a rigorous evaluation of our hypothesis that these cells play a critical role in kidney fibrogenesis and should be targeted therapeutically to halt chronic kidney disease.

Public Health Relevance

Kidney fibrosis is the leading cause of kidney failure worldwide, and it represents an enormous health burden and unmet medical need. We have discovered a novel stromal cell type present in kidney that plays a critical role in the development of kidney fibrosis. We hypothesize that targeting these cells therapeutically will lead to new and effective treatments for humans with chronic kidney disease. The experiments in this application are designed to better define the origin and function of these cells in kidney disease, and to establish a proof of principle that targeting these cells will ameliorate kidney fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK103740-04
Application #
9528286
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Hoshizaki, Deborah K
Project Start
2015-09-01
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Kramann, Rafael; Machado, Flavia; Wu, Haojia et al. (2018) Parabiosis and single-cell RNA sequencing reveal a limited contribution of monocytes to myofibroblasts in kidney fibrosis. JCI Insight 3:
Wu, Haojia; Uchimura, Kohei; Donnelly, Erinn L et al. (2018) Comparative Analysis and Refinement of Human PSC-Derived Kidney Organoid Differentiation with Single-Cell Transcriptomics. Cell Stem Cell 23:869-881.e8
Malone, Andrew F; Wu, Haojia; Humphreys, Benjamin D (2018) Bringing Renal Biopsy Interpretation Into the Molecular Age With Single-Cell RNA Sequencing. Semin Nephrol 38:31-39
Ó hAinmhire, Eoghainín; Humphreys, Benjamin D (2017) Fibrotic Changes Mediating Acute Kidney Injury to Chronic Kidney Disease Transition. Nephron 137:264-267
Wu, Haojia; Humphreys, Benjamin D (2017) The promise of single-cell RNA sequencing for kidney disease investigation. Kidney Int 92:1334-1342
Kramann, Rafael; Wongboonsin, Janewit; Chang-Panesso, Monica et al. (2017) Gli1+ Pericyte Loss Induces Capillary Rarefaction and Proximal Tubular Injury. J Am Soc Nephrol 28:776-784
Miyagi, Ayano; Lu, Aiwu; Humphreys, Benjamin D (2016) Gene Editing: Powerful New Tools for Nephrology Research and Therapy. J Am Soc Nephrol 27:2940-2947
Ó hAinmhire, Eoghainín; Humphreys, Benjamin D (2016) A Plumbing Solution for Stem Cell-Derived Kidneys. Transplantation 100:3-4
Kramann, Rafael; Goettsch, Claudia; Wongboonsin, Janewit et al. (2016) Adventitial MSC-like Cells Are Progenitors of Vascular Smooth Muscle Cells and Drive Vascular Calcification in Chronic Kidney Disease. Cell Stem Cell 19:628-642