Human Unrestricted Somatic Stem Cell Administration Fails to Protect Nude Mice from Cisplatin-Induced Acute Kidney Injury

Abstract

Background: Kidney failure is a debilitating disorder with limited treatment options. The kidney-protective effects of stem cells have been vastly investigated and promising results have been achieved with various sources of stem cells. However, in spite of beneficial effects on other disease models, the renoprotective potential of human cord blood-derived unrestricted somatic stem cells (USSC) has not been examined so far. Methods: In the present study, acute kidney failure was induced in female nude mice and the effect of USSC transplantation on kidney function and structure was assessed. Furthermore, the expression of some cytokine genes was examined by real-time PCR. Homing of the transplanted cells into kidneys was assessed by flow cytometry, immunohistochemistry, and real-time PCR. Results: USSC-conditioned medium did not attenuate the in vitro nephrotoxic effects of cisplatin. Transplantation of USSC to nude mice did not protect kidney function and was associated with worsened kidney structural damage. USSC transplantation was also associated with a decline in the renal expression of VEGF-A gene. In spite of these effects, the transplanted cells could not be detected in the kidneys by any of the exploited methods and they were mainly entrapped in the lungs. Conclusion: These data indicate that USSC are not suitable for cell therapy in the setting of acute kidney injury. Also, this study shows that these stem cells are able to affect damaged kidneys even if they are not homed there.

(Mesenchymal) Stem Cell-Based Therapy in Cisplatin-Induced Acute Kidney Injury Animal Model: Risk of Immunogenicity and Tumorigenicity

“…Most of the studies used labeling to check or confirm the presence of injected cells in kidneys and/or other organs (see Tables 1 and 2 ). It was reported that labeled cells (PKH26, GFP, and DIO) were mostly detected in the lungs, much less in the liver and in the kidneys [ 8 , 10 , 14 , 18 , 20 , 22 , 23 , 25 ]. Cheng et al studied biodistribution and found that one hour after iv injection of syngeneic MSCs most of the radiolabeled (or GFP labeled) cells were trapped in the lungs (62%), followed by liver (12.5%), spleen (11.4%), and kidneys (5.4%), but 7 days after injection no signs of MSCs in any organ was found [ 36 ].…”

“…Cheng et al studied biodistribution and found that one hour after iv injection of syngeneic MSCs most of the radiolabeled (or GFP labeled) cells were trapped in the lungs (62%), followed by liver (12.5%), spleen (11.4%), and kidneys (5.4%), but 7 days after injection no signs of MSCs in any organ was found [ 36 ]. Studies using GFP labeling reported disappearance of GFP + cells in the kidney 4 days after injection [ 22 , 31 ], while studies that used PKH26 [ 12 , 33 ] or CM-Dil [ 13 ] labeling reported presence of positive cells in the kidney until the end of their study, that is, 2–4 wks. Nevertheless, the fact that injected MSCs are mostly trapped in the lungs and cleared without any engraftment in kidney raise questions regarding their pathophysiologic mechanisms, as well as possibility of their potential rejection by the host's immune system.…”

“…First, acute rejection of injected cells in cisplatin model was not evaluated nor reported. It was only reported that cells disappeared within 24 h after injection [ 18 , 22 , 31 ], which could suggest acute rejection. However, sensitization reaction (mixed-lymphocyte reaction—MLR test) that could confirm or omit immune reaction was not done in any of AKI studies.…”

Acute Kidney Injury: Preclinical Innovations, Challenges, and Opportunities for Translation

“…In addition to MSCs, beneficial effects have been reported in animals treated with hematopoietic stem cells [44], induced pluripotent stem cells [45], endothelial progenitor cells [46], and mature endothelial cells [47]. In contrast to these studies, Burger et al and others have shown that certain progenitor populations increase injury in experimental AKI, thereby highlighting the critical need for careful selection of cells to ensure safe promotion of recovery [48–50].…”