Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells.
Recently, we have identified a population of renal progenitor cells in human kidneys showing regenerative potential for injured renal tissue of SCID mice. We demonstrate here that among all known chemokine receptors, human renal progenitor cells exhibit high expression of both stromal-derived factor-1 (SDF-1) receptors, CXCR4 and CXCR7. In SCID mice with acute renal failure (ARF), SDF-1 was strongly up-regulated in resident cells surrounding necrotic areas. In the same mice, intravenously injected renal stem/progenitor cells engrafted into injured renal tissue decreased the severity of ARF and prevented renal fibrosis. These beneficial effects were abolished by blocking either CXCR4 or CXCR7, which dramatically reduced the number of engrafting renal progenitor cells. However, although SDF-1-induced migration of renal progenitor cells was only abolished by an anti-CXCR4 antibody, transendothelial migration required the activity of both CXCR4 and CXCR7, with CXCR7 being essential for renal progenitor cell adhesion to endothelial cells. Moreover, CXCR7 but not CXCR4 was responsible for the SDF-1-induced renal progenitor cell survival. Collectively, these findings suggest that CXCR4 and CXCR7 play an essential, but differential, role in the therapeutic homing of human renal progenitor cells in ARF, with important implications for the development of stem cell-based therapies.
Mazzinghi
Benedetta
B
Excellence Center for Research, Transfer and High Education DENOthe, University of Florence, 50121 Florence, Italy.
Ronconi
Elisa
E
Lazzeri
Elena
E
Sagrinati
Costanza
C
Ballerini
Lara
L
Angelotti
Maria Lucia
ML
Parente
Eliana
E
Mancina
Rosa
R
Netti
Giuseppe Stefano
GS
Becherucci
Francesca
F
Gacci
Mauro
M
Carini
Marco
M
Gesualdo
Loreto
L
Rotondi
Mario
M
Maggi
Enrico
E
Lasagni
Laura
L
Serio
Mario
M
Romagnani
Sergio
S
Romagnani
Paola
P
D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007668:Kidney / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D039902:Multipotent Stem Cells / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D012206:Rhabdomyolysis / Q000150:complications / Q000378:metabolism / Q000473:pathology
C501896:ACKR3 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D012333:RNA, Messenger; D054387:Receptors, CXCR; D019718:Receptors, CXCR4