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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1843.)
© 2005 American Heart Association, Inc.

Vascular Biology

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; Marianne C. Verhaar; Cindy J.M. Loomans; Robert Verloop; Erna Peters; Peter E. Westerweel; Toyoaki Murohara; Frank J.T. Staal; Anton Jan van Zonneveld; Pieter Koolwijk; Ton J. Rabelink; Victor W.M. van Hinsbergh

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.

Correspondence to Marianne C. Verhaar, MD, PhD, Department of Vascular Medicine, F02.126, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. 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.

In an in vitro 3D neovascularization model, homing, proliferation, differentiation, and participation of purified CD34⁺ cells in capillary tube formation as well as a modest stimulatory effect on neovascularization were shown. Coaddition of CD34^[minus] cells markedly enhanced capillary growth. This suggests a potential role for CD34⁺ cells as vectors for gene therapy and indicates an important supportive role for CD34^– cells in neovascularization.

Key Words: angiogenesis • nitric oxide, endothelium, vascular type • gene therapy • peripheral vascular disease

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