Selective kidney targeting increases the efficacy of mesenchymal stromal/stem cells for alleviation of murine stenotic‐kidney senescence and damage
Seo Rin Kim, Kai Jiang, Xiaojun Chen, Amrutesh S. Puranik, Xiangyang Zhu, Amir Lerman, Tamar Tchkonia, James L. Kirkland, Lilach O. Lerman
Abstract
Chronic ischemia triggers senescence in renal tubules and at least partly mediates kidney dysfunction and damage through a p16Ink4a-related mechanism. We previously showed that mesenchymal stromal/stem cells (MSCs) delivered systemically do not effectively decrease cellular senescence in stenotic murine kidneys. We hypothesized that selective MSC targeting to injured kidneys using an anti-KIM1 antibody (KIM-MSC) coating would enhance their ability to abrogate cellular senescence in murine renal artery stenosis (RAS). KIM-MSC were injected into transgenic INK-ATTAC mice, which are amenable for selective eradication of p16Ink4a+ cells, 4 weeks after induction of unilateral RAS. To determine whether KIM-MSC abolish p16Ink4a-dependent cellular senescence, selective clearance of p16Ink4a+ cells was induced in a subgroup of RAS mice using AP20187 over 3 weeks prior to KIM-MSC injection. Two weeks after KIM-MSC aortic injection, renal senescence, function, and tissue damage were assessed. KIM-MSC delivery decreased gene expression of senescence and senescence-associated secretory phenotype factors, and improved micro-MRI-derived stenotic-kidney glomerular filtration rate and perfusion. Renal fibrosis and tubular injury also improved after KIM-MSC treatment. Yet, their efficacy was slightly augmented by prior elimination of p16Ink4a+ senescent cells. Therefore, selective targeting of MSC to the injured kidney markedly improves their senolytic potency in murine RAS, despite incomplete eradication of p16+ cells. KIM-MSC may constitute a useful therapeutic strategy in chronic renal ischemic injury.