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Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells
Jeremy S. Duffield, … , Takaharu Ichimura, Joseph V. Bonventre
Jeremy S. Duffield, … , Takaharu Ichimura, Joseph V. Bonventre
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1743-1755. https://doi.org/10.1172/JCI22593.
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Research Article Stem cells

Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells

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Abstract

Ischemia causes kidney tubular cell damage and abnormal renal function. The kidney is capable of morphological restoration of tubules and recovery of function. Recently, it has been suggested that cells repopulating the ischemically injured tubule derive from bone marrow stem cells. We studied kidney repair in chimeric mice expressing GFP or bacterial β-gal or harboring the male Y chromosome exclusively in bone marrow-derived cells. In GFP chimeras, some interstitial cells but not tubular cells expressed GFP after ischemic injury. More than 99% of those GFP interstitial cells were leukocytes. In female mice with male bone marrow, occasional tubular cells (0.06%) appeared to be positive for the Y chromosome, but deconvolution microscopy revealed these to be artifactual. In β-gal chimeras, some tubular cells also appeared to express β-gal as assessed by X-gal staining, but following suppression of endogenous (mammalian) β-gal, no tubular cells could be found that stained with X-gal after ischemic injury. Whereas there was an absence of bone marrow–derived tubular cells, many tubular cells expressed proliferating cell nuclear antigen, which is reflective of a high proliferative rate of endogenous surviving tubular cells. Upon i.v. injection of bone marrow mesenchymal stromal cells, postischemic functional renal impairment was reduced, but there was no evidence of differentiation of these cells into tubular cells of the kidney. Thus, our data indicate that bone marrow–derived cells do not make a significant contribution to the restoration of epithelial integrity after an ischemic insult. It is likely that intrinsic tubular cell proliferation accounts for functionally significant replenishment of the tubular epithelium after ischemia.

Authors

Jeremy S. Duffield, Kwon Moo Park, Li-Li Hsiao, Vicki R. Kelley, David T. Scadden, Takaharu Ichimura, Joseph V. Bonventre

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Figure 1

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Characterization of I/R injury in chimeric mice. (A) Phalloidin staining...
Characterization of I/R injury in chimeric mice. (A) Phalloidin staining of actin cytoskeleton in sham-operated (control) kidneys and at 2, 7, and 21 days following I/R injury. Note the loss of the tubular cell brush border at 2 days and the denuded tubules (arrow) and the progressive restoration with time of both apical actin staining and tubule integrity. (B) PAS-stained sections at 2 and 7 days following I/R injury. Although the necrotic intratubular debris (arrows) is widespread at 2 days, the tubular architecture is significantly restored at 7 days. (C) PCNA staining of tubules in sham-operated (control) and ipsilateral kidney 2 days following I/R injury. (D) Outer medulla intratubular proliferation as assessed by counting mitotic cells in PAS-stained sections and by anti-PCNA immunofluorescence at 0, 2, and 7 days following I/R injury to the kidney. (E) Plasma creatinine levels at 0, 2, and 7 days following bilateral I/R renal injury. Scale bars: 50 μm.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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