Evaluation of the ability of bone marrow derived cells to engraft the kidney and promote renal tubular regeneration in mice following exposure to cisplatin

Abstract

It has been suggested that bone marrow derived stem cells have the ability to engraft the kidney and improve the outcome of severe acute kidney injury (AKI) in mice exposed to high doses of cisplatin, providing hope for cancer patients in whom irreversible renal damage occasionally occurs following the use of this highly effective anti-tumor drug. We tested the therapeutic potential of bone marrow derived cells injected during the acute phase (day 3 after cisplatin administration) of experimentally-induced AKI in C57Bl6/J mice, characterized by massive tubular necrosis, apoptosis, and a low proliferation capacity. We failed to show any benefit of bone marrow derived cells versus a regular homogenate of intact renal cells, or normal saline. Using cell tracers and flow cytometry, we demonstrated that bone marrow derived cells did indeed home to the bone marrow of the recipients but failed to settle in the kidney. Conversely, renal cells homed to injured kidneys. However, neither cell therapy protected the animals against cisplatin-induced death. We therefore question the short-term efficacy of bone marrow derived cells used to repair established injuries of the tubular epithelium.ARTICLE HISTORY

The effect and molecular mechanism of hypoxia on proliferation and apoptosis of CD133+ renal stem cells

“…In mammals, nephrons are limited in number because nephron formation ceases before birth or in the neonatal period. In humans, the ability of regeneration and repair of the kidney is attenuated around 35 weeks of gestation due to the depletion of precursor mesenchymal cells, resulting in no new nephron formation [ 20 , 21 ]. In this study, we collected the samples from children with congenital hydronephrosis at different ages, and our results suggest that CD133 expression is closely associated with the age of patients.…”

Cisplatin-Induced Rodent Model of Kidney Injury: Characteristics and Challenges

“…In contrast, we noticed that clinical signs or mortality of animals in cisplatin nephrotoxicity studies are rarely reported. Moreover, we even found statement that “renal failure per se is not painful” [ 191 ].…”

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

“…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.…”

“…Various approaches have been investigated to help MSCs to cope/resist with the harmful microenvironment into which cells are transplanted [ 19 , 23 ]. Thus, the absence of the effect of MSCs could indicate damaging microenvironment [ 31 ], MSC inactivity due to cryopreservation [ 71 ], and finally cell rejection.…”