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

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

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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Bone marrow MSCs have multilineage potential and are protective in ische...
Bone marrow MSCs have multilineage potential and are protective in ischemic injury without differentiating into tubule cells. (A) Flow cytometry of MSCs for cell surface stem cell markers. Compared with isotype control labeling, which was used to define the marker (data not shown), MSCs lacked expression of c-kit and CD31 but expressed CD34 and Sca-1 (values are expressed as percent positive compared with isotype control antibody labeling). (B) Photomicrograph of MSCs differentiated into capillary-like structures (left). The same structure shows strong immunofluorescent labeling with the endothelial marker CD31 (right). (C) Photomicrograph of MSCs differentiated in vitro into adipocytes and labeled with oil red O for lipid. (D) Fluorescence micrograph showing an EGFP-expressing MSC in the cortex of the postischemic kidney 2 hours after intraparenchymal injection of EGFP-labeled MSCs. (E) Plasma creatinine levels 24 hours after 30-minute bilateral I/R renal injury followed by i.v. injection of control PBS or 0.5 × 106 MSCs cultured on plastic (n = 4 per group). (F) Plasma creatinine levels 24 hours after 30-minute bilateral I/R renal injury followed by i.v. injection of control PBS, 0.5 × 106 MSCs cultured on Matrigel, or embryonic fibroblasts (Fibro) cultured on the same matrix. Note that the level of creatinine was significantly higher in PBS-treated mice (n = 7 per group; **P < 0.01, ANOVA). Scale bars: 50 μm.