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Blood, 1 February 2002, Vol. 99, No. 3, pp. 1095-1096
CORRESPONDENCE
To the editor:
Bone marrow-derived cells contribute to endothelial
repair after thrombotic microangiopathy
Angiogenesis and mechanisms of vascular repair are currently
gaining a lot of attention as new avenues for cardiovascular and renal
therapy. The present concept is that cells participating in repair can
be either vessel-wall-derived or circulation-derived. In vitro
experiments1-4 showed that human CD34+ cells
were able to differentiate into endothelial cells, suggesting potential involvement of stem cells in processes such as angiogenesis and vascular repair. In agreement, labeled CD34+ cells have
been shown to be incorporated into the vessel wall in
experimental models of neovascularization. Participation of circulating
endothelial cells in human vascular repair was recently shown
by Lagaaij et al5 in kidneys. They identified acceptor endothelial cells in allografted donor kidneys. The number of acceptor
endothelial cells was increased after vascular rejection, suggesting a
role of these cells in vascular repair. The source of these circulating
endothelial cells, however, still remains unclear. Here we present
evidence that human endothelial injury repair involves
bone-marrow-derived re-endothelialization. A 28-year-old woman suffering from malignant hypertension was admitted
to our hospital for a renal biopsy. Six months earlier, she underwent a
bone marrow transplantation because of a relapsing acute myeloid
leukemia M2 (AML-M2). After total body irradiation (2 consecutive 600 cGy doses) and cyclophosphamide conditioning (2 days at 60 mg/kg), she received T-cell-depleted
(< 1 × 105 T cells per kilogram) bone marrow
(5.3 × 109 cells) from her elder brother. After 4 months
her serum creatinin levels and blood pressure started to rise, reaching
448 µM and 180/110 mm Hg, respectively, on the day of admission. Histology of the biopsy showed dilated capillary loops, swollen
foamy endothelial cells, widened subendothelial space, and some double
contours of glomerular basement membranes
(Figure 1). The media of some arterioles
were interrupted, and there were several arteriolar hyalinosis lesions
with occasional fibrin. These histologic findings and the clinical
course are indicative of thrombotic microangiopathy in accordance with
the presence of malignant hypertension and the total body radiation 6 months earlier.
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| Figure 1.
Kidney biopsy.
Histology (A-B) and immunohistochemistry and FISH (C-D).
(A-B) Hematoxylin and eosin silver staining, showing the
characteristics of thrombotic microangiopathy. (A) Reduced vascular
lumen (*) of arteriole next to a glomerulus with reduced capillary
lumina and ischaemic winding of some basement membranes. (B) Renal
arteriole with a reduced vascular lumen (*) and mucoid intima
degeneration. (C-D) The participation of male donor bone marrow cells
in vascular endothelial repair and maintenance in a female kidney.
Endothelial cells are stained with Ulex Europaeus TRITC, and the green
dots in the blue nuclei (DAPI) are FISH-stained Y chromosomes. (C)
Vessel (*) with male endothelial cell (arrow). (D) Vessel (*) with
male endothelial cell (arrow) and a circulating male cell
(arrowhead). Original magnification A, × 630; B-D, × 1000.
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The hallmark of thrombotic microangiopathy is endothelial damage,
generally followed by spontaneous repair. Because the patient underwent
a sex-mismatched bone marrow transplantation, we were able to determine
the origin of the endothelial cells in the kidney by fluorescent in
situ hybridization (FISH) for the Y chromosome. For an
endothelial-cell-specific marker, we used Ulex Europaeus Agluttin I (UEA I) lectin and used DAPI as a nuclear counterstain. The
triple staining revealed nuclear staining for the Y chromosome in
several Ulex-positive cells lining the inside of the vessel, incorporated into the endothelial surface. This shows involvement of
bone marrow (BM)-derived progenitor cells in endothelial repair. This is the first report of participation of BM-derived endothelial
cells in human renal vessels. Our finding suggests that endothelial progenitor cells play a role in renal endothelial repair.
Not only does this provide insights into the mechanism of renal
vascular repair and maintenance, but it also provides a basis for
development of new strategies for treatment of the vascular
lesions of thrombotic microangiopathy.
Maarten B. Rookmaaker, Herman Tolboom, Roel Goldschmeding, Jaap-Jan Zwaginga, Ton J. Rabelink, and Marianne C. Verhaar
Correspondence: M. B. Rookmaaker, University Medical Centre
Utrecht, Room F02.126, Heidelberglaan 100, PO Box 85500, 3508 GA
Utrecht, The Netherlands; e-mail: m.rookmaaker{at}azu.nl
References
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Blood.
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Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors.
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Lagaaij EL, Cramer-Knijnenburg GF, van Kemenade FJ, van Es LA, Bruijn JA, van Krieken JH.
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