Functional Cloning of IGFBP-3 From Human Microvascular Endothelial Cells Reveals its Novel Role in Promoting Proliferation of Primitive CD34<sup>+</sup>CD38<sup>−</sup> Hematopoietic Cells In Vitro

Liu, Liqin; Sposato, Margaret; Liu, Haiyan; Vaudrain, Tracy; Shi, Mengjiao; Rider, Kristin; Stevens, Zack; Visser, J. W. M.; Deng, Hongkui; Kraus, Morey

doi:10.3727/096504003108748375

Cited by 25 publications

(18 citation statements)

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“…Our work supports that of Liu et al (41), who showed, by using in vitro cell proliferation assays, that the addition of exogenous IGFBP3 to cultures of purified CD34 ϩ CD38-Lin Ϫ cells stimulated the proliferation of these primitive hematopoietic cells, suggesting that IGFBP3 is capable of expanding primitive human blood cells.…”

Section: Igfbp3-expressing Hscs Inhibit Neovascularization By Protectsupporting

confidence: 81%

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

Chang

Chan‐Ling

McFarland

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

128

106

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We asked whether the hypoxia-regulated factor, insulin-like growth factor binding protein-3 (IGFBP3), could modulate stem cell factor receptor (c-kit ؉ ), stem cell antigen-1 (sca-1 ؉ ), hematopoietic stem cell (HSC), or CD34 ؉ endothelial precursor cell (EPC) function. Exposure of CD34 ؉ EPCs to IGFBP3 resulted in rapid differentiation into endothelial cells and dose-dependent increases in cell migration and capillary tube formation. IGFBP3-expressing plasmid was injected into the vitreous of neonatal mice undergoing the oxygeninduced retinopathy (OIR) model. In separate studies, GFP-expressing HSCs were transfected with IGFBP3 plasmid and injected into the vitreous of OIR mice. Administering either IGFBP3 plasmid alone or HSCs transfected with the plasmid resulted in a similar reduction in areas of vasoobliteration, protection of the developing vasculature from hyperoxia-induced regression, and reduction in preretinal neovascularization compared to control plasmid or HSCs transfected with control plasmid. In conclusion, IGFBP3 mediates EPC migration, differentiation, and capillary formation in vitro. Targeted expression of IGFBP3 protects the vasculature from damage and promotes proper vascular repair after hyperoxic insult in the OIR model. IGFBP3 expression may represent a physiological adaptation to ischemia and potentially a therapeutic target for treatment of ischemic conditions. IGFBP3 ͉ angiogenesis ͉ retinopathy of prematurity V ascular damage associated with diabetic retinopathy and retinopathy of prematurity (ROP) results from tissue ischemia, and, subsequently, this ischemia leads to development of pathological neovascularization. Insulin-like growth factor 1 (IGF1) is required for normal retinal vascular development because vascular development is arrested in its absence despite the presence of VEGF (1). Development of ROP is associated with low levels of IGF1 (2) because the lack of IGF1 in the early neonatal period leads to the development of avascular retina, which results in ROP (3). However, unregulated IGF1 expression can lead to pathological neovascularization (4-13), and IGF1 receptor (IGF1R) antagonists are able to suppress retinal neovascularization in vivo by inhibiting VEGF signaling (1).The effects of IGF1 are mediated by IGF1R and modulated by complex interactions with IGF binding proteins (IGFBPs), which are also modulated at multiple levels. Six IGFBPs function as transporter proteins and storage pools for IGF1 in a tissue-and developmental stage-specific manner. Phosphorylation, proteolysis, polymerization (8), and cell or matrix association (9) regulates the functions of IGFBPs. Specific IGFBPs have been shown to either stimulate or inhibit IGF1 action (10).IGFBP3, the best studied and most abundant of these binding proteins, carries Ն75% of serum IGF1 and IGF2 in heterotrimeric complexes. Besides its endocrine effects, IGFBP3 has auto-and paracrine actions affecting cell mobility, adhesion, apoptosis, survival, and the cell cycle (14,15). Like the other IGFBPs, IGFBP3 has IGF1-in...

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Section: Igfbp3-expressing Hscs Inhibit Neovascularization By Protectsupporting

confidence: 81%

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

Chang

Chan‐Ling

McFarland

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

128

106

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“…24 Also factors other than cytokines derived from endothelial cells support growth of primitive progenitors, as shown for the insulin-like growth factor binding protein-3 (IGFBP-3), a protein that may influence progenitor proliferation by binding IGF or by other mechanisms. 16 In addition, local presentation of membrane-bound factors such as kit-ligand (stem cell factor) particularly by HUVEC 25 may further support the growth of immature hematopoietic cells. We have shown that in reverse, maintenance of endothelial cells in such coculture systems can be achieved by the presence of hematopoietic cells that provide endothelial growth factors such as VEGF.…”

Section: Discussionmentioning

confidence: 99%

“…23 However, the fact that coculture systems with endothelial cells have been used in several studies to successfully expand also more primitive progenitors, suggests a specific advantage of this cell type when used as feeder layer in coculture systems. [7][8][9][10]16 In our study, which aimed at the feasability of an 'autologous' coculture system, the cytokine supplementation was not optimized for a potential use of the expanded cells in a transplantation setting. Therefore, we did not include extensive transplantation studies, which might prove advantageous to ex vivo expansion only when optimal culture conditions are chosen.…”

Section: Discussionmentioning

confidence: 99%

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Expansion of cord blood CD34+ hematopoietic progenitor cells in coculture with autologous umbilical vein endothelial cells (HUVEC) is superior to cytokine-supplemented liquid culture

Yıldırım

Boehmler

Kanz

et al. 2005

Bone Marrow Transplant

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Summary:Expansion of hematopoietic progenitor cells (HPC) in the presence of endothelium has been shown to result in grafts capable of restoring hematopoiesis in a myeloablated host. However, the use of xenogeneic endothelium or cell lines may carry risks in a clinical transplantation setting. We explored the feasibility of cord blood progenitor cell expansion in vitro in an autologous coculture system using umbilical vein endothelial cells (HUVEC). CD34 þ HPC and HUVEC were isolated from the same umbilical cord. For 3 days, HPC were maintained in serum-free medium supplemented with a single cytokine (SCF) or a cytokine combination (SCF, Flt3-ligand, IL-6). Meanwhile, adherent HUVEC cultures were established. After addition of VEGF and IL-1 at day 3, the cells were either added to HUVEC cultures or grown without endothelial cells for further 7 days. Total cells, CD34 þ and clonogenic progenitors were significantly increased when coculture was compared to liquid culture. Long-term cultureinitiating cells (LTC-IC) and cobble stone area-forming cells (CAFC, limiting dilution analysis) were detected more frequently after coculture with endothelial cells. Also precursors and mature myeloid cells were observed after expansion. We conclude that coculture with autologous HUVEC represents a feasable approach for ex vivo expansion of cord blood HPC. Bone Marrow Transplantation (2005) 36, 71-79.

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“…High-serum IGFBP3 levels decrease the risk of breast cancer (7), whereas a high tissue level of IGFBP3 is associated with the formation of large, highly proliferative tumors (8)(9)(10)(11). In cell culture, IGFBP3 has also been shown to promote both apoptosis and survival (3,(12)(13)(14)(15). These data imply that IGFBP3 may enhance or suppress cell growth depending on specific conditions.…”

mentioning

confidence: 99%

IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth

Löfqvist

Chen

Connor

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

158

106

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Vessel loss precipitates many diseases. In particular, vessel loss resulting in hypoxia induces retinal neovascularization in diabetic retinopathy and in retinopathy of prematurity (ROP), major causes of blindness. Here we define insulin-like growth factor binding protein-3 (IGFBP3) as a new modulator of vascular survival and regrowth in oxygen-induced retinopathy. In IGFBP3-deficient mice, there was a dose-dependent increase in oxygen-induced retinal vessel loss. Subsequent to oxygen-induced retinal vessel loss, Igfbp3 ؊/؊ mice had a 31% decrease in retinal vessel regrowth versus controls after returning to room air. No difference in serum insulin-like growth factor 1 (IGF1) levels was observed among groups. Wild-type mice treated with exogenous IGFBP3 had a significant increase in vessel regrowth. This correlated with a 30% increase in endothelial progenitor cells in the retina at postnatal day 15, indicating that IGFBP3 could be serving as a progenitor cell chemoattractant. In a prospective clinical study, we measured IGFBP3 (and IGF1) plasma levels weekly and examined retinas in all premature infants born at gestational ages <32 weeks at high risk for ROP. The mean level of IGFBP3 at 30 -35 weeks postmenstrual age (PMA) for infants with proliferative ROP (ROP stages 3>, n ‫؍‬ 13) was 802 g/liter, and for infants with no ROP (ROP stage 0, n ‫؍‬ 38) the mean level was 974 g/liter (P < 0.03). These results suggest that IGFBP3, acting independently of IGF1, helps to prevent oxygen-induced vessel loss and to promote vascular regrowth after vascular destruction in vivo in a dose-dependent manner, resulting in less retinal neovascularization.angiogenesis ͉ insulin-like growth factor 1 ͉ insulin-like growth factor binding protein-3 ͉ stem cells ͉ retinopathy of prematurity

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Functional Cloning of IGFBP-3 From Human Microvascular Endothelial Cells Reveals its Novel Role in Promoting Proliferation of Primitive CD34⁺CD38⁻ Hematopoietic Cells In Vitro

Cited by 25 publications

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IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

Expansion of cord blood CD34+ hematopoietic progenitor cells in coculture with autologous umbilical vein endothelial cells (HUVEC) is superior to cytokine-supplemented liquid culture

IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth

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Functional Cloning of IGFBP-3 From Human Microvascular Endothelial Cells Reveals its Novel Role in Promoting Proliferation of Primitive CD34+CD38− Hematopoietic Cells In Vitro

Cited by 25 publications

References 0 publications

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

Expansion of cord blood CD34+ hematopoietic progenitor cells in coculture with autologous umbilical vein endothelial cells (HUVEC) is superior to cytokine-supplemented liquid culture

IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth

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Functional Cloning of IGFBP-3 From Human Microvascular Endothelial Cells Reveals its Novel Role in Promoting Proliferation of Primitive CD34⁺CD38⁻ Hematopoietic Cells In Vitro