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, Xiang Yang Zhu, Amir Lerman, Tamara Tchkonia, James L Kirkland, Lilach O. Lerman

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalJournal of Tissue Engineering and Regenerative Medicine
DOIs
StateAccepted/In press - 2022

Keywords

  • cellular senescence
  • kidney injury molecule-1
  • mesenchymal stem cells
  • renal artery stenosis

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biomaterials
  • Biomedical Engineering

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