Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice

• Published in: Kidney international Vol. 70; no. 1; pp. 121 - 129
• Main Authors: Ninichuk, V., Gross, O., Segerer, S., Hoffmann, R., Radomska, E., Buchstaller, A., Huss, R., Akis, N., Schlöndorff, D., Anders, H.-J.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.07.2006; Nature Publishing; Elsevier Limited
• Subjects: Animals; Autoantigens - genetics; Biological and medical sciences; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins - genetics; Bone Morphogenetic Proteins - metabolism; Cell Movement; Cell Proliferation; chronic kidney disease; Collagen Type IV - deficiency; Collagen Type IV - genetics; Disease Progression; Endothelial Cells - cytology; Endothelial Cells - physiology; Female; fibrosis; Fibrosis - therapy; kidney; Kidney - metabolism; Kidney - pathology; Kidney Failure, Chronic - genetics; Kidney Failure, Chronic - pathology; Kidney Failure, Chronic - therapy; Kidneys; Medical sciences; mesenchymal stem cells; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - physiology; Mice; Mice, Mutant Strains; Multipotent Stem Cells - cytology; Multipotent Stem Cells - physiology; Nephrology. Urinary tract diseases; progression; RNA, Messenger - analysis; RNA, Messenger - metabolism; Stem Cell Transplantation; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Urinary system involvement in other diseases. Miscellaneous; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; kidney; progression; chronic kidney disease; fibrosis; mesenchymal stem cells; Kidney disease; Nephrology; Urinary system disease; Prognosis; Stem cell; Rodentia; Chronic kidney disease; Mesenchymal cell; Delay; Urology; Vertebrata; Mammalia; Mouse; Animal; Fibrosis; Evolution; Interstitial; Multipotent stem cell
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/sj.ki.5001521

Multipotent mesenchymal stem or stromal cells (MSC) have shown to improve outcome of acute renal injury models, but whether MSC can delay renal failure in chronic kidney disease is not known. We injected primary MSC or saline into mice that lack the α3-chain of type IV collagen (COL4A3), a model of chronic kidney disease with close similarities to human Alport disease. Weekly injections of MSC from week 6 to 10 of life prevented the loss of peritubular capillaries and reduced markers of renal fibrosis, that is, interstitial volume, numbers of smooth muscle actin-positive interstitial cells, and interstitial collagen deposits as compared to saline-injected COL4A3-deficient mice. However, renal function, that is, blood urea nitrogen, creatinine levels, proteinuria as well as survival of COL4A3-deficient mice were not affected by MSC injections. Although MSC were found to localize to kidneys of COL4A3-deficient mice after injection, differentiation into renal cells was not detected. However, MSC expressed growth factors, that is, vascular endothelial growth factor (VEGF) and bone morphogenetic protein-7 under basal culture conditions. In fact, VEGF mRNA levels were increased in kidneys of MSC-injected COL4A3-deficient mice and MSC supernatants enhance endothelial cell proliferation in vitro. Thus, weekly injections with MSC prevent loss of peritubular capillaries possibly owing to local production of growth factors rather than by differentiation into renal cells. The maintenance of interstitial vasculature is associated with less interstitial fibrosis but, is insufficient to delay renal failure and survival of COL4A3-deficient mice.