Stem cell therapies benefit Alport syndrome.

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 alpha3 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 alpha3(IV) chain. These data provide further support for testing cell-based therapies for Alport syndrome.

[1]  I. Rogers,et al.  Cell therapy for Alport syndrome. , 2009, Journal of the American Society of Nephrology : JASN.

[2]  H. Anders,et al.  Ccl2/Mcp‐1 blockade reduces glomerular and interstitial macrophages but does not ameliorate renal pathology in collagen4A3‐deficient mice with autosomal recessive Alport nephropathy , 2009, The Journal of pathology.

[3]  Jie Ding,et al.  Stem cell therapy for Alport syndrome: the hope beyond the hype. , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[4]  I. Naito,et al.  Irradiation prolongs survival of Alport mice. , 2008, Journal of the American Society of Nephrology : JASN.

[5]  V. LeBleu,et al.  Lymphocytes are dispensable for glomerulonephritis but required for renal interstitial fibrosis in matrix defect-induced Alport renal disease , 2008, Laboratory Investigation.

[6]  Raghu Kalluri,et al.  Structure and Function of Basement Membranes , 2007, Experimental biology and medicine.

[7]  R. Kalluri,et al.  Choosing a mouse model to study the molecular pathobiology of Alport glomerulonephritis. , 2007, Kidney international.

[8]  R. Poulsom,et al.  Bone Marrow‐Derived Cells Contribute to Podocyte Regeneration and Amelioration of Renal Disease in a Mouse Model of Alport Syndrome , 2006, Stem cells.

[9]  D. Abrahamson,et al.  Loss of α3/α4(IV) Collagen from the Glomerular Basement Membrane Induces a Strain-Dependent Isoform Switch to α5α6(IV) Collagen Associated with Longer Renal Survival in Col4a3−/− Alport Mice , 2006 .

[10]  H. Anders,et al.  Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice. , 2006, Kidney international.

[11]  R. Kalluri,et al.  Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[12]  P. Tipping,et al.  T cells in crescentic glomerulonephritis. , 2006, Journal of the American Society of Nephrology : JASN.

[13]  D. Abrahamson,et al.  Loss of alpha3/alpha4(IV) collagen from the glomerular basement membrane induces a strain-dependent isoform switch to alpha5alpha6(IV) collagen associated with longer renal survival in Col4a3-/- Alport mice. , 2006, Journal of the American Society of Nephrology : JASN.

[14]  S. Söder,et al.  The NC1 domain of human collagen IV is necessary to initiate triple helix formation. , 2004, Biochemical and biophysical research communications.

[15]  K. Tryggvason,et al.  Alport's syndrome, Goodpasture's syndrome, and type IV collagen. , 2003, The New England journal of medicine.

[16]  R. Kalluri.  Basement membranes: structure, assembly and role in tumour angiogenesis , 2003, Nature reviews. Cancer.

[17]  C. Antignac,et al.  A human-mouse chimera of the alpha3alpha4alpha5(IV) collagen protomer rescues the renal phenotype in Col4a3-/- Alport mice. , 2003, The American journal of pathology.

[18]  B. Rodriguez-Iturbe,et al.  Role of immunocompetent cells in nonimmune renal diseases. , 2001, Kidney international.

[19]  R. Stokes,et al.  Utilization of CD11b knockout mice to characterize the role of complement receptor 3 (CR3, CD11b/CD18) in the growth of Mycobacterium tuberculosis in macrophages. , 2000, Cellular immunology.

[20]  C. Antignac,et al.  Glomerular expression of type IV collagen chains in normal and X-linked Alport syndrome kidneys. , 2000, The American journal of pathology.

[21]  R. Kalluri,et al.  Assembly of Type IV Collagen , 2000, The Journal of Biological Chemistry.

[22]  R. Kalluri,et al.  Assembly of type IV collagen. Insights from alpha3(IV) collagen-deficient mice. , 2000, The Journal of biological chemistry.

[23]  C. Kashtan,et al.  Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes. , 1999, Medicine.

[24]  W. Couser,et al.  Role of intrinsic renal cells versus infiltrating cells in glomerular crescent formation. , 1998, Kidney international.

[25]  P. Tipping,et al.  Crescentic glomerulonephritis in CD4- and CD8-deficient mice. Requirement for CD4 but not CD8 cells. , 1998, The American journal of pathology.

[26]  R. Zeller,et al.  Rearrangements of the cytoskeleton and cell contacts induce process formation during differentiation of conditionally immortalized mouse podocyte cell lines. , 1997, Experimental cell research.

[27]  W. Kriz,et al.  Synaptopodin: An Actin-associated Protein in Telencephalic Dendrites and Renal Podocytes , 1997, The Journal of cell biology.

[28]  P. Tipping,et al.  Mechanisms of T cell‐induced glomerular injury in anti‐glomeruler basement membrane (GBM) glomerulonephritis in rats , 1997, Clinical and experimental immunology.

[29]  D. Meehan,et al.  Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome. , 1996, Genes & development.

[30]  J. Sanes,et al.  Molecular and functional defects in kidneys of mice lacking collagen alpha 3(IV): implications for Alport syndrome , 1996, The Journal of cell biology.

[31]  J. Folkman,et al.  Splenosis is regulated by a circulating factor. , 1994, Journal of pediatric surgery.

[32]  F. Strutz,et al.  The role of lymphocytes in the progression of interstitial disease. , 1994, Kidney international. Supplement.

[33]  K. Tryggvason,et al.  Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis. , 1993, The Journal of biological chemistry.

[34]  E. Neilson.  The nephritogenic T lymphocyte response in interstitial nephritis. , 1993, Seminars in nephrology.

[35]  Susumu Tonegawa,et al.  RAG-1-deficient mice have no mature B and T lymphocytes , 1992, Cell.