Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury.
Mesenchymal stem cells (MSC) were recently shown to migrate to injured tissues when transplanted systemically. The mechanisms underlying the migration and homing of these cells is, however, unclear. In this study, we examine the role of CD44 and its major ligand, hyaluronic acid, in the trafficking of intravenously injected MSC in the glycerol-induced mouse model of acute renal failure (ARF). In vitro, hyaluronic acid promoted a dose-dependent migration of the stem cells that was inhibited by an anti-CD44 blocking monoclonal antibody. In vivo, stem cells injected into mice with ARF migrated to the injured kidney where hyaluronic acid expression was increased. Their presence correlated with morphological and functional recovery. Renal localization of the MSC was blocked by pre-incubation with the CD44 blocking antibody or by soluble hyaluronic acid. Stem cells derived from CD44 knockout mice did not localize to the injured kidney and did not accelerate morphological or functional recovery. Reconstitution by transfection of CD44 knockout stem cells with cDNA encoding wild-type CD44, but not a loss of function CD44 unable to bind hyaluronic acid, restored in vitro migration and in vivo localization of the cells to injured kidneys. We suggest that CD44 and hyaluronic acid interactions recruit exogenous MSC to injured renal tissue and enhance renal regeneration.
Herrera
M B
MB
Department of Internal Medicine, University of Torino, Torino, Italy.
Bussolati
B
B
Bruno
S
S
Morando
L
L
Mauriello-Romanazzi
G
G
Sanavio
F
F
Stamenkovic
I
I
Biancone
L
L
Camussi
G
G
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D000818:Animals; D000911:Antibodies, Monoclonal; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005990:Glycerol; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism* / Q000494:pharmacology; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012038:Regeneration; D014162:Transfection
D000911:Antibodies, Monoclonal; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D005990:Glycerol