title: Attenuation of hind-limb ischemia in mice with endothelial-like cells derived from different sources of human stem cells.
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.
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, HKSAR, China.
authors.forename: Wing-Hon
authors.initials: WH
authors.lastname: Lai
authors.forename: Jenny C Y
authors.initials: JC
authors.lastname: Ho
authors.forename: Yau-Chi
authors.initials: YC
authors.lastname: Chan
authors.forename: Joyce H L
authors.initials: JH
authors.lastname: Ng
authors.forename: Ka-Wing
authors.initials: KW
authors.lastname: Au
authors.forename: Lai-Yung
authors.initials: LY
authors.lastname: Wong
authors.forename: Chung-Wah
authors.initials: CW
authors.lastname: Siu
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
mesh_terms: D000368:Aged; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D015687:Cell Hypoxia; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000637:transplantation*; D006614:Hindlimb / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D007511:Ischemia / Q000473:pathology* / Q000628:therapy*; D008297:Male; D051379:Mice; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D010477:Perfusion; D033581:Stem Cell Transplantation; D013997:Time Factors
chemical_list: D042501:Angiogenic Proteins; D017077:Culture Media, Conditioned; D016207:Cytokines