Intrarenal cells, not bone marrow–derived cells, are the major source for regeneration in postischemic kidney
Fangming Lin, … , Ashley Moran, Peter Igarashi
Fangming Lin, … , Ashley Moran, Peter Igarashi
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1756-1764. https://doi.org/10.1172/JCI23015.
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Research Article

Intrarenal cells, not bone marrow–derived cells, are the major source for regeneration in postischemic kidney

Abstract

Ischemic injury to the kidney produces acute tubular necrosis and apoptosis followed by tubular regeneration and recovery of renal function. Although mitotic cells are present in the tubules of postischemic kidneys, the origins of the proliferating cells are not known. Bone marrow cells (BMCs) can differentiate across lineages to repair injured organs, including the kidney. However, the relative contribution of intrarenal cells and extrarenal cells to kidney regeneration is not clear. We produced transgenic mice that expressed enhanced GFP (EGFP) specifically and permanently in mature renal tubular epithelial cells. Following ischemia/reperfusion injury (IRI), EGFP-positive cells showed incorporation of BrdU and expression of vimentin, which provides direct evidence that the cells composing regenerating tubules are derived from renal tubular epithelial cells. In BMC-transplanted mice, 89% of proliferating epithelial cells originated from host cells, and 11% originated from donor BMCs. Twenty-eight days after IRI, the kidneys contained 8% donor-derived cells, of which 8.4% were epithelial cells, 10.6% were glomerular cells, and 81% were interstitial cells. No renal functional improvement was observed in mice that were transplanted with exogenous BMCs. These results show that intrarenal cells are the main source of renal repair, and a single injection of BMCs does not make a significant contribution to renal functional or structural recovery.

Authors

Fangming Lin, Ashley Moran, Peter Igarashi

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Effects of BMCs on tubular regeneration (A–H) and renal function (I). (A...
Effects of BMCs on tubular regeneration (A–H) and renal function (I). (A) Abundant Y chromosome signals located at the periphery of the nuclei in the kidneys of male mice (red, arrows), consistent with the typical nuclear localization of the Y chromosome. The sensitivity of FISH analysis was 64% (n = 5). (B) Kidney of a female mouse without male BMC transplant shows complete absence of Y chromosome signal. (C) A tubular cell that incorporated BrdU (green) shows the presence of Y chromosome (red, arrow). (D–F) Y chromosome FISH (red) was followed by immunostaining of tubular epithelial cell markers (green). (D) The arrow indicates a Y+ cytokeratin+ tubular epithelial cell. (E) The arrow indicates a Y+ LTA+ proximal tubular cell. (F) The arrow indicates a Y+ AQP3+ collecting duct cell. Note the basolateral staining of the AQP3, which defines the intratubular localization of the Y+ cells. (G) Y chromosome–containing tubular cell (arrows) in the kidney of a wild-type female mouse injected with BMCs from a male creksp;Z/EG donor. Arrowheads indicate interstitial cells. (H) The same cell shown in G is negative for EGFP by immunostaining (arrow). The nuclei were counterstained with DAPI (A, B, and D–H), and images were merged. Scale bars: 20 μm. (I) BUN levels in mice with sham operation that did not receive BMC injection (Control; filled triangles), mice with renal IRI that did not receive BMC injection (IRI – BMC; open circles), and mice with renal IRI that received BMC injection (IRI + BMC; filled circles). No statistically significant difference was observed in mice with or without BMC injection. n = 5–13 at each time point; total 84 mice.