on July 14, 2005
Published online before print July 14, 2005, doi: 10.1161/01.ATV.0000177808.92494.14
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Submitted on December 29, 2003
Accepted on July 1, 2005
CD34+ Cells Home, Proliferate, and Participate in Capillary Formation, and in Combination With CD34- Cells Enhance Tube Formation in a 3-Dimensional Matrix
Maarten B. Rookmaaker ;
From the Department of Vascular Medicine (M.B.R., M.C.V., P.E.W.), University Medical Center Utrecht, the Netherlands; the Department of Nephrology (C.J.M.L., A.J.v.Z., T.J.R.), Leiden University Medical Center, Leiden, the Netherlands; the Department of Immunology (C.J.M.L., F.J.T.S.), Erasmus Medical Center, Rotterdam, the Netherlands; the Department of Biomedical Research (E.P., P.K.), Gaubius Laboratory TNO-PG, Leiden, the Netherlands; the Department of Cardiology (T.M.), Nagoya University Graduate School of Medicine, Japan; and the Department of Physiology (R.V., V.W.M.H.), VU University Medical Center, Amsterdam, the Netherlands.
* To whom correspondence should be addressed. E-mail: m.c.verhaar{at}azu.nl.
Objective--Emerging evidence suggests that human blood contains bone marrow (BM)-derived endothelial progenitor cells that contribute to postnatal neovascularization. Clinical trials demonstrated that administration of BM-cells can enhance neovascularization. Most studies, however, used crude cell populations. Identifying the role of different cell populations is important for developing improved cellular therapies.
Methods and Results--Effects of the hematopoietic stem cell-containing CD34+ cell population on migration, proliferation, differentiation, stimulation of, and participation in capillary-like tubule formation were assessed in an in vitro 3-dimensional matrix model using human microvascular endothelial cells. During movement over the endothelial monolayer, CD34+ cells remained stuck at sites of capillary tube formation and time- and dose-dependently formed cell clusters. Immunohistochemistry confirmed homing and proliferation of CD34+ cells in and around capillary sprouts. CD34+ cells were transduced with the LNGFR marker gene to allow tracing. LNGFR gene-transduced CD34+ cells integrated in the tubular structures and stained positive for CD31 and UEA-1. CD34+ cells alone stimulated neovascularization by 17%. Coculture with CD34- cells led to 68% enhancement of neovascularization, whereas CD34- cells displayed a variable response by themselves. Cell-cell contact between CD34+ and CD34- cells facilitated endothelial differentiation of CD34+ cells.
Conclusions--Our data suggest that administration of CD34+-enriched cell populations may significantly improve neovascularization and point at an important supportive role for (endogenous or exogenous) CD34- cells.
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