Stem Cell Therapies Benefit Alport Syndrome : Journal of the American Society of Nephrology (original) (raw)

BASIC RESEARCH

LeBleu, Valerie*,†; Sugimoto, Hikaru*; Mundel, Thomas M.*; Gerami-Naini, Behzad*; Finan, Elizabeth*; Miller, Caroline A.‡; Gattone, Vincent H. II‡; Lu, Lingge*; Shield, Charles F. III§; Folkman, Judah‖; Kalluri, Raghu*,†,¶

*Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts;

†Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts;

‡Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana;

§Department of Surgery, University of Kansas School of Medicine, Wichita, Kansas;

‖Vascular Biology Program, Department of Surgery, Children's Hospital, Boston, Massachusetts; and

¶Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts

Correspondence: Dr. Raghu Kalluri, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Division of Matrix Biology, 330 Brookline Avenue, Boston, MA 02215. Phone: 617-735-4601; Fax: 617-735-4602; E-mail: [email protected]

Received January 30, 2009

Accepted July 8, 2009

Abstract

Patients with Alport syndrome progressively lose renal function as a result of defective type IV collagen in their glomerular basement membrane. In mice lacking the α3 chain of type IV collagen (Col4A3 knockout mice), a model for Alport syndrome, transplantation of wild-type bone marrow repairs the renal disease. It is unknown whether cell-based therapies that do not require transplantation have similar potential. Here, infusion of wild-type bone marrow-derived cells into unconditioned, nonirradiated Col4A3 knockout mice during the late stage of disease significantly improved renal histology and function. Furthermore, transfusion of unfractionated wild-type blood into unconditioned, nonirradiated Col4A3 knockout mice improved the renal phenotype and significantly improved survival. Injection of mouse and human embryonic stem cells into Col4A3 knockout mice produced similar results. Regardless of treatment modality, the improvement in the architecture of the glomerular basement membrane is associated with de novo expression of the α3(IV) chain. These data provide further support for testing cell-based therapies for Alport syndrome.