Human Kidney-Derived Cells Ameliorate Acute Kidney Injury Without Engrafting into Renal Tissue

Abstract

Previous studies have suggested that CD133+ cells isolated from human kidney biopsies have the potential to ameliorate injury following intravenous (IV) administration in rodent models of kidney disease by integrating into damaged renal tissue and generating specialized renal cells. However, whether renal engraftment of CD133+ cells is a prerequisite for ameliorating injury has not yet been unequivocally resolved. Here, we have established a cisplatin‐induced nephropathy model in immunodeficient rats to assess the efficacy of CD133+ human kidney cells in restoring renal health, and to determine the fate of these cells after systemic administration. Specifically, following IV administration, we evaluated the impact of the CD133+ cells on renal function by undertaking longitudinal measurements of the glomerular filtration rate using a novel transcutaneous device. Using histological assays, we assessed whether the human kidney cells could promote renal regeneration, and if this was related to their ability to integrate into the damaged kidneys. Our results show that both CD133+ and CD133− cells improve renal function and promote renal regeneration to a similar degree. However, this was not associated with engraftment of the cells into the kidneys. Instead, after IV administration, both cell types were exclusively located in the lungs, and had disappeared by 24 hours. Our data therefore indicate that renal repair is not mediated by CD133+ cells homing to the kidneys and generating specialized renal cells. Instead, renal repair is likely to be mediated by paracrine or endocrine factors. Stem Cells Translational Medicine 2017;6:1373–1384

Non-invasive imaging reveals conditions that impact distribution and persistence of cells after in vivo administration

“…The most common way to administer cells systemically in small animals is via the intravenous (IV) route through the tail vein [29], delivering cells directly to the lungs where they are sequestered as a consequence of the pulmonary first-pass effect [30][31][32][33][34][35]. Previous reports have suggested that IV administered cells labelled with lipophilic dyes bypass the lungs, but this is likely due to false positive staining.…”

“…Previous reports have suggested that IV administered cells labelled with lipophilic dyes bypass the lungs, but this is likely due to false positive staining. For example, in renal regenerative studies, PKH26 dye-labelled IV administered cells have been reported to engraft in injured kidneys and replace damaged renal cells [9][10][11]36], but a more recent study using this lipophilic dye in combination with GFP expression shows that while the dye can sometimes be detected in the kidneys, the cells remain trapped in the lungs [32]. These recent findings are corroborated by in vivo cell tracking studies which show that after IV injection, transplanted cells predominantly accumulate in the lungs [19,33,34], fail to integrate or differentiate into tissue-specific cell types and disappear within 7 days [19,20,37].…”

Concise Reviews: Stem Cells and Kidney Regeneration: An Update

“…Standardized protocols for the characterization, identity, culture, and differentiation of the many stem cell types used in renal regeneration research are not yet fully established. For example, Santeramo et al raised the issue of specificity of RPs by showing a similar degree of renal regeneration induced by both CD133 + and CD133 − cells . Similar results were obtained using NCAM + and NCAM − cells, raising questions about whether RP cells, regardless of specific identity, promote tissue repair similarly to differentiated cells .…”

Kidney Cells Regeneration: Dedifferentiation of Tubular Epithelium, Resident Stem Cells and Possible Niches for Renal Progenitors

“…Despite the fact that the high proliferative activity of putative progenitor cells has been widely shown, it should be kept in mind that cells can behave in vitro in a completely different way than in the organism [48]. For example, human CD133+ cells injected after kidney injury have been shown to be implanted into the tubules of embryonic kidneys, but not in adult rat kidneys [103].…”