Bone Marrow Origin of Endothelial Progenitor Cells Responsible for Postnatal Vasculogenesis in Physiological and Pathological Neovascularization

Abstract

Circulating endothelial progenitor cells (EPCs) have been isolated in peripheral blood of adult species. To determine the origin and role of EPCs contributing to postnatal vasculogenesis, transgenic mice constitutively expressing beta-galactosidase under the transcriptional regulation of an endothelial cell-specific promoter (Flk-1/LZ or Tie-2/LZ) were used as transplant donors. Localization of EPCs, indicated by flk-1 or tie-2/lacZ fusion transcripts, were identified in corpus luteal and endometrial neovasculature after inductive ovulation. Mouse syngeneic colon cancer cells (MCA38) were implanted subcutaneously into Flk-1/LZ/BMT (bone marrow transplantation) and Tie-2/LZ/BMT mice; tumor samples harvested at 1 week disclosed abundant flk-1/lacZ and tie-2/lacZ fusion transcripts, and sections stained with X-gal demonstrated that the neovasculature of the developing tumor frequently comprised Flk-1- or Tie-2-expressing EPCs. Cutaneous wounds examined at 4 days and 7 days after skin removal by punch biopsy disclosed EPCs incorporated into foci of neovascularization at high frequency. One week after the onset of hindlimb ischemia, lacZ-positive EPCs were identified incorporated into capillaries among skeletal myocytes. After permanent ligation of the left anterior descending coronary artery, histological samples from sites of myocardial infarction demonstrated incorporation of EPCs into foci of neovascularization at the border of the infarct. These findings indicate that postnatal neovascularization does not rely exclusively on sprouting from preexisting blood vessels (angiogenesis); instead, EPCs circulate from bone marrow to incorporate into and thus contribute to postnatal physiological and pathological neovascularization, which is consistent with postnatal vasculogenesis.

The characteristics of bone marrow-derived endothelial progenitor cells and their effect on glioma

“…Nevertheless, it has been documented that EPCs could specially home and incorporate into sites of physiological vessel formation in vivo and incorporate into the vasculature of tumors, ischemic skeletal and cardiac muscle, and ulcers [20-22]. It is well known that the pivotal process of tumor growth and metastasis is angiogenesis.…”

Involvement of circulating endothelial progenitor cells and vasculogenic factors in the pathogenesis of diabetic retinopathy

“…[9][10][11][12] EPCs are characterized by CD34, Flk-1, and CD133 antigen-positive cells, 13,14 and these cells are localized predominantly in the bone marrow. 15 In the peripheral circulation of adults, more mature, differentiated EPCs are found that are characterized by a decreased expression of CD133, are positive for VEGFR-2, and still express CD34.…”

“…12 These EPCs are derived from adult bone marrow, and are known to be stimulated by several modulators such as VEGF, erythropoietin (Epo), substance P (SP), etc. 9,16,17 Sublethal hypoxia induces upregulation and nuclear translocation of hypoxia-inducible factor, whose target gene is Epo. [18][19][20][21] Epo stimulates postnatal neovascularization at least in part by enhancing mobilization of EPCs from the bone marrow.…”

Cells as vehicles for therapeutic genes to treat liver diseases

“…53 Moreover, when EPCs are administered to immunocompromized mice, they incorporate into the vasculature of xenotransplanted tumors. 54,55 Our recent data showed that EPCs can be transduced by lentiviral and adenoviral vectors. Immunohistochemical and immunofluorescence analysis showed that EPCs were incorporated in the tumor tissues in animal model with orthotopic tumor models ( Figure 2).…”