Abstract
Functional endothelial-like cells (EC) have been successfully derived from different cell sources and potentially used for treatment of cardiovascular diseases; however, their relative therapeutic efficacy remains unclear. We differentiated functional EC from human bone marrow mononuclear cells (BM-EC), human embryonic stem cells (hESC-EC) and human induced pluripotent stem cells (hiPSC-EC), and compared their in-vitro tube formation, migration and cytokine expression profiles, and in-vivo capacity to attenuate hind-limb ischemia in mice. Successful differentiation of BM-EC was only achieved in 1/6 patient with severe coronary artery disease. Nevertheless, BM-EC, hESC-EC and hiPSC-EC exhibited typical cobblestone morphology, had the ability of uptaking DiI-labeled acetylated low-density-lipoprotein, and binding of Ulex europaeus lectin. In-vitro functional assay demonstrated that hiPSC-EC and hESC-EC had similar capacity for tube formation and migration as human umbilical cord endothelial cells (HUVEC) and BM-EC (P>0.05). While increased expression of major angiogenic factors including epidermal growth factor, hepatocyte growth factor, vascular endothelial growth factor, placental growth factor and stromal derived factor-1 were observed in all EC cultures during hypoxia compared with normoxia (P<0.05), the magnitudes of cytokine up-regulation upon hypoxic were more dramatic in hiPSC-EC and hESC-EC (P<0.05). Compared with medium, transplanting BM-EC (n = 6), HUVEC (n = 6), hESC-EC (n = 8) or hiPSC-EC (n = 8) significantly attenuated severe hind-limb ischemia in mice via enhancement of neovascularization. In conclusion, functional EC can be generated from hECS and hiPSC with similar therapeutic efficacy for attenuation of severe hind-limb ischemia. Differentiation of functional BM-EC was more difficult to achieve in patients with cardiovascular diseases, and hESC-EC or iPSC-EC are readily available as “off-the-shelf” format for the treatment of tissue ischemia.
Highlights
In experimental studies [1] and clinical trials [2,3,4], human bone marrow (BM) derived stem cells have been used as potential cell therapy to enhance angiogenesis in ischemic tissue, their therapeutic application are limited by the ability to obtain sufficient number of stem cells for transplantation
In order to overcome the scarcity and functional impairment of autologus BM stem cells, endothelial-like cells (EC) derived from pluripotent stem cells, such as human embryonic stem cells (hESC) have been proposed as an alternative and unlimited source of cells for therapy
We confirmed that one hESC line and two human induced pluripotent stem cells (hiPSC) lines could be differentiated into functional EC which express a comparable level of endothelial markers as bone marrow mononuclear cells (BM-EC) and HUVEC
Summary
In experimental studies [1] and clinical trials [2,3,4], human bone marrow (BM) derived stem cells have been used as potential cell therapy to enhance angiogenesis in ischemic tissue, their therapeutic application are limited by the ability to obtain sufficient number of stem cells for transplantation. Prior studies [9] have demonstrated that functional endothelial-like cells (EC) can be derived from pluripotent human embryonic stem cells (hESC) for therapeutic angiogenesis. Recent advances in the generation of human induced pluripotent stem cells (hiPSC) [10,11,12] may represent an alternative source to derive functional EC for treatment of cardiovascular diseases. The therapeutic efficacy of hiPSC derived EC for angiogenesis as compared with hESC-EC or BM stem cells derived EC have not been studied. We compared the in-vitro and in-vivo angiogenic effects of EC derived from hiPSC, hESC and human BM mononuclear cells
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