Paracrine effects of mesenchymal stem cells in cisplatin-induced renal injury require heme oxygenase-1.
Multipotent mesenchymal stem cells (MSC) have become a popular and promising therapeutic approach in many clinical conditions. MSC are beneficial in animal models of acute kidney injury (AKI), by mediating differentiation-independent paracrine properties, and have prompted ongoing clinical trials to evaluate the safety and efficacy of MSC. Heme oxygenase-1 (HO-1) is induced in response to stress including AKI and has important anti-apoptotic, anti-inflammatory, and proangiogenic properties in these settings. We therefore examined whether HO-1 plays a role in the beneficial effects of MSC in AKI. We isolated MSC from bone marrow of age-matched HO-1+/+ and HO-1-/- mice. Our studies indicate that while differentiation of MSC into osteo- and adipocytic lineages did not differ between cells isolated from HO-1+/+ and HO-1-/- mice, MSC from HO-1-/- mice had significantly lower angiogenic potential. Moreover, HO-1-/- MSC demonstrated reduced expression and secretion of several important growth and proangiogenic factors (stromal cell-derived factor-1, vascular endothelial growth factor-A, and hepatocyte growth factor) compared with MSC derived from HO-1+/+ mice. In addition, conditioned medium of HO-1+/+ MSC rescued functional and morphological changes associated with cisplatin-induced AKI, while the HO-1-/--conditioned medium was ineffectual. Our studies indicate that HO-1 plays an important role in MSC-mediated protection. The results expand understanding of the renoprotective effects of MSC and may provide novel strategies to better utilize MSC in various disease models.
Department of Medicine, Nephrology Research Training Center, University of Alabama at Birmingham, 1900 Univ. Blvd., Birmingham, Alabama 35294, USA.
Abolfazl
A
Zarjou
Junghyun
J
Kim
Amie M
AM
Traylor
Paul W
PW
Sanders
József
J
Balla
Anupam
A
Agarwal
Lisa M
LM
Curtis
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D000818:Animals; D054377:Chemokine CXCL12; D002945:Cisplatin / Q000633:toxicity*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D039902:Multipotent Stem Cells; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019899:Paracrine Communication / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D054377:Chemokine CXCL12; D017077:Culture Media, Conditioned; C515256:Cxcl12 protein, mouse; C553307:HGF protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D017228:Hepatocyte Growth Factor; D051547:Heme Oxygenase-1; D002945:Cisplatin