Bone Morphogenic Protein-7 Induces Mesenchymal-to-
Epithelial Transition in Adult Renal Fibroblasts and Facilitates Regeneration of Injured Kidney*
Michael Zeisberg, Amish A. Shah and Raghu Kalluri
From the Center for Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215 and Division of Nephrology, Children’s Hospital and Harvard Medical School, Boston, MA 02215
Running title: MET and adult renal fibroblasts
Address Correspondence to : Dr. Raghu Kalluri, Associate Professor of Medicine, Harvard Medical School, Director, Center for Matrix Biology, Beth Israel Deaconess Medical Center Department of Medicine, Dana 514, 330 Brookline Avenue, Boston, MA 02215 , Tel#: 617-667-0445, Fax#: 617-975-5663, E-Mail: rkalluri@bidmc.harvard.edu
In the kidney, a unique plasticity exists between epithelial and mesenchymal cells. During kidney development the metanephric mesenchyme contributes to emerging epithelium of the nephron via mesenchymal-to-epithelial transition (MET). In the injured adult kidney, renal epithelia contribute to the generation of fibroblasts via epithelial-mesenchymal transition (EMT), facilitating renal fibrosis.
Treatment of renal fibrosis in mice with recombinant human bone morphogenic protein-7 (BMP-7), a morphogen, which is essential for the conversion of epithelia from condensing mesenchyme during kidney development, enhances the repair of tubular structures in the kidney. In this setting, BMP-7 inhibits EMT involving adult renal epithelial tubular cells and decreases secretion of type I collagen by adult renal fibroblasts.
In search of a mechanism behind the ability of BMP-7 to repair damaged renal tubules, we hypothesized that systemic treatment
with BMP-7 might induce MET involving adult renal fibroblasts in the injured kidney, generating functional epithelial cells.
Here we report that BMP-7 induces formation of epithelial cell aggregates in adult renal fibroblasts associated with reacquisition of E-cadherin expression associated with decreased motility, mimicking the effect of BMP-7 on embryonic metanephric mesenchyme to form epithelium. In addition, we provide evidence that BMP-7 mediated repair of renal injury is associated with MET involving adult renal interstitial fibroblasts in mouse models for renal fibrosis.
Collectively, these findings suggest that adult renal fibroblasts might retain parts of their original embryonic epithelial imprint and plasticity, which can be re-engaged by systemic administration of BMP-7 to mediate repair of tubular injury in a fibrotic kidney. |
