Contribution of Circulating Cells to Neovasculature

Halki Diabetes Remedy

Diabetes Natural Treatments Ebook

Get Instant Access

In their initial report of endothelial progenitor cells Asahara and colleagues showed that following systemic injection, endothelial progenitors incorporate into sites of vessel growth and repair in rodent hind limb ischemia models. Other investigators have since repeated this finding. Several experimental designs have been used to document this process, although each design has possible pitfalls. The supply of endothelial progenitors has varied between experiments. Both undifferentiated early progenitor cells and cells that have been differentiated in vitro to a more endothelial-like phenotype have been delivered systemically and directly into areas of vessel growth. Additionally, bone

Table I. Characteristics of Endothelial Progenitor Preparations. Hematopoietic cells of different types and from different sources have been shown to express endothelial characteristics when cultured with pro-angiogenic cytokines. Starting cell populations and sources are shown in addition to culture additives; vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), insulin-like growth factor I (IGF-I), and epidermal growth factor (EGF). The expression of a set of endothelial and myeloid markers is indicated for each study. Endothelial-like cells derived from hematopoietic progenitors and monocytes are grouped separately.

Starting cell population

Culture additives

EPC characteristics


Cells with Progenitor Markers

Total human PB mononuclear cells

CD34+ human periperal blood

CD34+ human bone marrow, fetal liver, cord blood, peripheral blood

VEGF, bFGF, IGF-1, EGF, hydrocortisone, heparin, FBS

Bovine brain extract FBS VEGF, bFGF, IGF-1

CD133+ GCSF mobilized human FBS, VEGF, SCGF, peripheral blood

CD133+ human bone marrow followed by selection with UEA-1 binding CD34+/CD133+/VEGFR-2+ human peripheral blood, fetal liver, and cord blood hydrocortisone FBS, bFGF, heparin

FBS, bFGF, heparin



CD34+, CD31+, VE-Cad+, Flk-1+, Tie2+, UEA-i, vWF+, CDia-, CD14-

VE-Cad, vWF, P1H12, UEA-i, CD1G5, KDR, WP bodies, CD14-, CD45-, CD34-

AcLDL, VE-Cad, CD13, CD31

Asahara et al. (1997). Science 5302, 964-967

Quirici et al. (2001). Br. J. Haematol. 115, 186-194

Peichev et al. (2000). Blood 95, 952-958


Unselected human peripheral blood mononuclear cells

CD14+ human peripheral blood monocytes

Human CD34+mobilized peripheral blood

Human CD34- peripheral blood monocytes

CD14+ human peripheral blood

FBS, insulin, VEGF, bFGF

FBS, bovine brain extract

VEGF, bFGF, EGF, IGF-1, hydrocortisone, heparin, FBS

AcLDL, UEA-1, CD45+, CD14+, CD11b+, CD11c+, CD31, low VE-Cad, low CD34

VWF, VE-Cad, ecNOS, CD68

VE-Cad, ecNOS, vWF

EcNOS, vWF, VE-Cad, Tie-2, MUC18, CD1G5, CD1a, CD45, acLDL

Ac-LDL, vWF, VE-Cad, CD1G5, CD36, Flt-1, Flk-1, CD1a-, CD83-, CD68, HLA-DR

Rehman et al. (2003). Circulation 107, 1164-1169

Schmeisser et al. (2001). Cardiovasc. Res. 49, 671-680

Nakul-Aquaronne et al. (2003).

Cardiovasc Res 57, 816-823

Harraz et al. (2001). Stem Cells 19, 304-312

Fernandez Pujol et al. (2000).

Differentiation 65, 287-300

marrow transplant studies have been performed to document the incorporation of bone marrow-derived cells into a growing endothelium. The methods of marking the endothelial progenitors have also differed and include dye labeling, green fluorescent protein (GFP) expression, use of transgenic donor animals expressing GFP or b-galactosidase, and identification of the Y chromosome in sex-mismatched donor/recipient pairs. Some criticisms of these studies have been the possibility of dye uptake by other native cells and the inherent difficulty in demonstrating that a cell is functionally incorporated into the vasculature as opposed to spatially located in the vasculature. Despite these criticisms, the ability of several groups to derive essentially the same conclusions using varied experimental methodologies make the data compelling.

Although the potential for circulating cells to incorporate into new vasculature appears to be established, there contin ues to be debate on the relative importance of angiogenesis versus vasculogenesis in the adult. An effort has been made to quantitate the relative amount of endothelium derived from circulating cells versus mature local endothelial cells using rodent bone marrow transplant models. Several groups have used this strategy and found wide ranges of donor versus recipient contribution to new vascular endothelium. In different experimental situations, the donor contribution ranges from 0 to 95 percent (see Table II). The comparison of these experiments is complicated by the use of different models of adult vascular formation ranging from tumors to limb ischemia and by other factors such as differences in the extent of bone marrow engraftment and accuracy with which transplanted cells are differentiated from host cells. Several studies in human transplant patients have also been published. Host contributions to endothelium in donor hearts ranging from 0 to -25 percent have been

Table II. Contribution of Bone Marrow-Derived Cells to Neovasculature in Mouse Transplant Models. The contribution of bone marrow-derived cells in various models of neovascular growth in the adult mouse has been determined using murine transplant models. The wide range of bone marrow-derived cells illustrates possible differences in the contributions of angiogenesis versus vasculogenesis with different experimental conditions.

Model of vascular growth

Percentage of bone marrow-derived cells


Regenerative lung growth

Cerebral ischemia

Brain injury

Ischemic cardiac injury

Sarcoma xenograft

B6RV2 lymphoma xenograft

Glioma xenograft rare

Cells present at infarct border 0

Voswinckel et al. (2003). Circ. Res. 93, 372-379 Zhang et al. (2002). Circ. Res. 90, 284-288 Vallieres et al. (2003). J. Neurosci. 23, 5197-5207 Jackson et al. (2001). J. Clin. Invest. 107, 195-402 Bolontrade et al. (2002). Clin. Cancer Res. 8, 3622-3627 Lyden et al. (2001). Nat. Med. 7, 1194-1201 Ferrari et al. (2003). Gene Therapy 10, 647-656

demonstrated, and recipient-derived endothelial cells have been reported in transplanted kidneys and livers. Transplanted bone marrow has also been found to contribute to endothelium in recipients. There are wide variations in the reported relative contribution of circulating cells to new vascular endothelium even among different patients in the same study. This variation in transplant patients as well as rodent bone marrow transplant models suggests that many factors influence the interplay between angiogenesis and vasculo-genesis and also illustrates the complexity and variability of these experiments.

Was this article helpful?

0 0
Delicious Diabetic Recipes

Delicious Diabetic Recipes

This brilliant guide will teach you how to cook all those delicious recipes for people who have diabetes.

Get My Free Ebook

Post a comment