Transplantation of Human Hematopoietic Stem Cells into Ischemic and Growing Kidneys Suggests a Role in Vasculogenesis but Not Tubulogenesis

Abstract

Transplantation of murine bone marrow-derived stem cells has been reported recently to promote regeneration of the injured kidney. We investigated the potential of human adult CD34؉ progenitor cells to undergo renal differentiation once xenotransplanted into ischemic and developing kidneys. Immunostaining with human-specific antibodies for tubular cells (broad-spectrum cytokeratin), endothelial cells (CD31, PECAM), stromal cells (vimentin), and hematopoietic cells (pan-leukocyte CD45) demonstrated that although kidney ischemia enhanced engraftment of human cells, they were mostly hematopoietic cells (CD45 ؉ ) residing in the interstitial spaces. Few other engrafted cells demonstrated an endothelial phenotype (human CD31 ؉ in morphologically appearing peritubular capillaries), but no evidence of tubular or stromal cells of human origin was found. Upregulation of SDF1 and HIF1 transcript levels in the ischemic kidneys might explain the diffuse engraftment of CD45؉ cells following injury. Similarly, when embryonic kidneys rudiments were co-transplanted with human CD34؉ cells in mice, we found both human CD45؉ and CD31 ؉ cells in the periphery of the developing renal grafts, whereas parenchymal elements failed to stain. In addition, human CD34؉ cells had no effect on kidney growth and differentiation. This first demonstration of human CD34؉ stem cell transplantation into injured and developing kidneys indicates that these cells do not readily acquire a tubular phenotype and are restricted mainly to hematopoietic and, to a lesser extent, to endothelial lineages. Efforts should be made to identify additional stem cell sources applicable for kidney growth and regeneration.

Organ-injury-induced reactivation of hemangioblastic precursor cells

“…We have recently suggested a role for human CD34 þ hematopoietic stem cells (enriched for the endothelial progenitor marker CD133) in vasculogenesis and not tubulogenesis, after their engraftment in ischemic murine kidneys. 28 Similar findings of peri-tubular vascularization were reported in postischemic kidneys 34 and more progressive renal injury. 42 Furthermore, in a different model system, Rookmaaker et al 27 induced murine experimental glomerulonephritis and showed that whole murine bone marrow-derived cells (not fractioned into stem cell subtypes) participates in endothelial repair in injured glomeruli.…”

“…Histopathology of adult kidneys 24-48 h after ischemia showing lumen obliteration with loss of brush border as well as the disappearance of nuclei and necrosis of tubular cells has been previously demonstrated. 28 We analyzed SCL transcript levels along with the VEGF receptors FLK1 and FLT1, which have been shown to participate in the angiogenesis of ischemic limb and heart 33 at consecutive time points after ischemic injury. Realtime PCR demonstrated an early decline followed by rapid upregulation of SCL mRNA, peaking 48 h after ischemia (Figure 2).…”

“…In addition, blood and marrow-derived cells have been recently suggested to have vasculogenic potential during kidney damage. 27,28 We have therefore hypothesized that the expression of SCL characterizing embryonic kidney will re-appear during regeneration of adult kidney integrating bi-potential information needed for blood and endothelial development. …”

Autografting of Renal Progenitor Cells Ameliorates Kidney Damage in Experimental Model of Pyelonephritis

“…However, recent studies demonstrated that intrarenal cells, not BMSCs, seem to be responsible for cellular the reconstituted regions of the transplanted kidneys. Our follow-up revealed a declining trend in Ki-67 exreconstitution of the nephron following ARF (4,14).…”

Bone Marrow-Derived Cells Mobilized by Granulocyte-Colony Stimulating Factor Facilitate Vascular Regeneration in Mouse Kidney after Ischemia/Reperfusion Injury

“…Recently, however, by deconvolution microscopic analysis, Duffi eld et al (2005) suggested that tubular epithelial regeneration by BMDC was likely artifacts caused by the staining technique or the superimposition of a tubular cell and an infi ltrating BMDC. Xenotransplantation of human hematopoietic stem cells into immunodefi cient mouse kidneys after I/R injury demonstrated that these cells did not readily acquire a renal tubular cell phenotype and were restricted to hematopoietic lineage and, to a limited extent, endothelial lineages (Dekel et al 2006). Thus, it remains to be clarifi ed whether the cell source of tubular repair is the proliferation of endogenous renal cells or/and BMDC (Krause and Cantley 2005).…”