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Directing Human Embryonic Stem Cells to Generate Vascular Progenitor Cells

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Directing Human Embryonic Stem Cells to Generate Vascular Progenitor Cells Gene Therapy (2008) 15, 89–95 & 2008 Nature Publishing Group All rights reserved 0969-7128/08 $30.00 www.nature.com/gt REVIEW Directing human embryonic stem cells to generate vascular progenitor cells H Bai and ZZ Wang Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA Pluripotent human embryonic stem cells (hESCs) differenti- it is also possible that endothelial cells and SMCs derived ate into most of the cell types of the adult human body, from hESCs can be used to engineer artificial vessels to including vascular cells. Vascular cells, such as endothelial repair damaged vessels and form vessel networks in cells and vascular smooth muscle cells (SMCs) are engineered tissues. Here we review the current status of significant contributors to tissue repair and regeneration. In directing hESCs to differentiate to vascular cells. addition to their potential applications for treatment of Gene Therapy (2008) 15, 89–95; doi:10.1038/sj.gt.3303005; vascular diseases and stimulation of ischemic tissue growth, published online 16 August 2007 Keywords: human embryonic stem cells; endothelial cells; smooth muscle cells Introduction which give rise to hematopoietic stem cells and vascular endothelial cells.10–12 Even both of them give rise to Some degenerative diseases are caused by the loss of hematopoietic and endothelial cells, it is unclear whether tissue-specific cells in organs, examples include: (i) type I hemangioblasts are the same as hemogenic endothelial diabetes, in which insulin-producing b cells are de- cells. For easy to discuss, we will use the term stroyed by an autoimmune disorder; (ii) Parkinson’s hemangioblast for both of them. disease, in which dopamine-producing neuronal cells are In the embryo proper, primitive vascular networks are destroyed; (iii) heart failure, which is caused by the formed de novo by the aggregation of embryonic massive loss of cardiomyocytes; and (iv) ischemic endothelial cells, a process termed vasculogenesis. In diseases, which is primarily caused by endothelial addition to originating from hemangioblasts, embryonic dysfunction. Cellular therapies to treat these diseases endothelial cells arise from restricted progenitor cells, are hampered by the lack of donor cells. Therefore, the called angioblasts that are derived from the mesoderm successful derivation of human embryonic stem cells and are committed to the endothelial lineage.13,14 The (hESCs)1 could provide an unlimited source of cells to initial vascular network, which consists of endothelial replace damaged or degenerated cells and tissues caused cells that form interconnected vessels, undergoes a by these diseases. succession of morphogenetic events involving sprouting, The endothelium is the first tissue to differentiate proliferation and migration of endothelial cells, and during vertebrate embryogenesis. Based on the close remodeling to generate large branched vessels, a process relationship of the vascular and hematopoietic systems called angiogenesis. Mural cells, including pericytes and during organogenesis, it was hypothesized that hemato- vascular smooth muscle cells (SMCs) are recruited to the poietic and endothelial cells are derived from a common newly formed vessels, causing the vascular networks to precursor, the hemangioblast.2–4 Commitment to the be mature and become stable.7,15 Controlling vascular hematopoietic and endothelial lineages within the yolk cells and angiogenesis, either positively or negatively, sac at mouse embryonic day (E) 7.5 results in the could be critical for the treatment of various diseases, development of blood islands that consist of an outer including cardiovascular diseases and cancers. layer of endothelial cells and an inner cluster of primitive Vasculogenesis and angiogenesis are largely depen- hematopoietic cells. Endothelial and hematopoietic cells dent on the functional changes of proliferation, differ- in blood islands are derived from aggregates of entiation and migration of endothelial cells, and current hemangioblasts.5–7 The structure of the yolk sac blood angiogenesis research relies primarily on mouse models. islands in the human embryo is similar to those in the Based on mouse models, the three families of receptor mouse embryo.8,9 The aorta-gonad-mesonephros region tyrosine kinases and their ligands found are: (i) vascular of the embryo proper also contains hemogenic endothe- endothelial growth factor receptors (VEGFRs) and lial cells (or called angio-hematopoietic progenitors), VEGFs; (ii) Tie receptors and angiopoietins; and (iii) Eph receptors and ephrins, which play major roles Correspondence: Dr ZZ Wang, Center for Molecular Medicine, in regulating vascular development.15 Members of the Maine Medical Center Research Institute, 81 Research Drive, fibroblast growth factor (FGF) family and the bone Scarborough, ME 04074, USA. E-mail: [email protected] morphogenetic protein (BMP) family influence mesoder- Received 27 April 2007; revised 13 June 2007; accepted 1 July 2007; mal lineage specification, therefore possibly facilitating published online 16 August 2007 vasculature formation.16,17 Generation of blood vessels from hESC H Bai et al 90 and proliferate in the presence of leukemia inhibitory factor (LIF), when MEF feeder cells are removed.24 The requirement for MEF feeder cells to support undiffer- entiated hESCs is supplanted by the addition of FGF-2 and other factors, but not LIF, to the culture medium.1,25 Under serum-free conditions, BMP signaling synergizes with LIF for mES cell self-renewal.26 In contrast to mES cells, suppression of BMP signaling by the antagonist noggin combined with FGF-2 sustains undifferentiation of hESCs.27 The differences of human and mouse ES cells clearly demonstrate that hESCs not only have great potential for clinical application, but also provide a novel opportunity to add significant understanding to the field of early human development, which is hampered by the lack of experimental systems and cannot be accomplished by Figure 1 Development of vascular cells from human embryonic mouse models. ES cells can be triggered to undergo stem cells. Hemangioblasts are bipotential precursors to hemato- spontaneous differentiation by forming 3-dimensional poietic cells and endothelial progenitor cells (EPCs). The origins of embryoid bodies (EBs) containing many differentiated smooth muscle cells (SMCs) are dependent on the location in the cell types. Although the EB is far less organized than an embryo. Vascular progenitor cells (VPCs) can further differentiate to embryo, it can partially mimic the spatial organization of mural cells (SMCs and pericytes) and endothelial cells. EPCs may 23 transdifferentiate into SMCs during vessel formation. EPCs from cells in an embryo. Similar to mES cells, hESCs cardiovascular progenitor cells may have hemogenic potential to differentiate into EBs in vitro, and the differentiation give rise to hematopoietic progenitor cells. process is somewhat directed by the culture environment.28,29 An enzymatic dissociation of hESC colonies into single cells leads to a significant decrease of ES cell propagation due to low efficiency of cell Because of ethical obstacles, the study of early attachment, which is not typically associated with mES vascular development in humans is hampered by the cells.30 Therefore, most of the EB induction experiments lack of experimental systems. Human umbilical vein from hESCs are performed as clumps from undiffer- endothelial cells are often used to study human entiated hESC colonies. Several cell types are character- endothelial cells. However, the signals and signaling ized during hESC differentiation, including cardiac pathways, which regulate embryonic endothelial cell fate tissue,31 neuronal tissue,32 b-islet pancreatic cells,33 and control endothelial cell migration and assembly into hematopoietic cells34 and endothelial cells.35,36 The hESC new vessels during embryonic development, remain differentiation process follows a reproducible temporal unknown in the human system. The study of embryonic pattern of development which, to some extent, resembles endothelial cells generated from hESCs may recapitulate early human embryogenesis. events seen in vascular network formation and increases the understanding of the molecular mechanisms of vascular development (Figure 1). Development of hemangioblasts from hESCs Human and mouse embryonic stem cells Zambidis et al.37 studied cellular kinetics of hESC Similar to mouse embryonic stem (mES) cells, hESCs are differentiation in serum-free clonogenic assays. When derived from the inner cell mass (ICM) of blastocysts or EB differentiation of hESCs were induced in 1% morula stage embryos.1,18,19 After removal from the ICM methylcellulose cultures containing fetal bovine serum and maintenance in culture, hESCs acquire an immortal (FBS), semiadherent mesodermal-hematoendothelial characteristic, that is, hESCs can grow indefinitely. They (MHE) cluster colonies emerged at days 6–9.37 The are capable of prolonged self-renewal and differentiation MHE colonies contained adherent and nonadherent into cells of all three germ layers in vivo and in vitro. cells. Nonadherent cells of MHE colonies expressed Mouse ES cells have been established and studied for CD45 and gave rise to hematopoietic colonies. Some more than 20 years.20–23 There is a substantial overlap adherent cells expressed endothelial markers, CD31, and between human and mouse ES cells in the expression of were capable of Dil-Ac-LDL uptake, whereas other key transcription
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