Differentiation, Survival, and Function of Embryonic Stem Cell–Derived Endothelial Cells for Ischemic Heart Disease

Li, Zongjin; Wu, Jenny; Sheikh, Ahmad Y.; Kraft, Daniel; Cao, Feng; Xie, Xiaoyan; Patel, Manishkumar; Gambhir, Sanjiv S.; Robbins, Robert C.; Cooke, John P.; Wu, Joseph C.

doi:10.1161/circulationaha.106.680561

Cited by 170 publications

(194 citation statements)

References 36 publications

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“…GFPs were also stably incorporated into hESC-ECs, indicated by positive green fluorescence (data not shown). These observation are consistent with previous studies, in which minimal effects of reporter gene transfection on hESC-ECs survival, proliferation, and differentiation were reported [14,17,24].…”

Section: Characterization Of Hesc-ecssupporting

confidence: 93%

Human embryonic stem cells-derived endothelial cell therapy facilitates kidney regeneration by stimulating renal resident stem cell proliferation in acute kidney injury

Jia

Lű

et al. 2013

Chin. Sci. Bull.

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Endothelial cell therapy has been implicated to enhance tissue regeneration and vascularization in ischemic kidney. However, no published study has yet examined direct effects of endothelial cell treatment in kidney recovery. This study investigated the therapeutic efficacy of endothelial cells in a mouse model with acute kidney injury (AKI). Thus, human embryonic stem cells-derived endothelial cells (hESC-ECs) labeled with a reporter system encoding a double fusion reporter gene for firefly luciferase (Fluc) and green fluorescent protein (GFP) were characterized by Fluc imaging and immunofluoresence staining. Cultured hESC-ECs (1×10 6 ) were injected into ischemic kidney shortly after AKI. Survival of the transplanted hESC-ECs was monitored in vivo from day 1 to 14 after endothelial cell transplantation and potential impact of hESC-EC treatment on renal regeneration was assessed by histological analyses. We report that a substantial level of bioluminescence activity was detected 24 h after hESC-EC injection followed by a gradual decline from 1 to 14 d. Human ESC-ECs markedly accelerated kidney cell proliferation in response to ischaemia-induced damage, indicated by an elevated number of BrdU + cells. Co-expression of Sca-1, a kidney stem cell proliferation marker, and BrdU further suggested that the observed stimulation in renal cell regeneration was, at least in part, due to increased proliferation of renal resident stem cells especially within the medullary cords and arteriole. Differentiation of hESC-ECs to smooth muscle cells was also observed at an early stage of kidney recovery. In summary, our results suggest that endothelial cell therapy facilitates kidney recovery by promoting vascularization, trans-differentiation and endogenous renal stem cell proliferation in AKI.

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Section: Characterization Of Hesc-ecssupporting

confidence: 93%

Human embryonic stem cells-derived endothelial cell therapy facilitates kidney regeneration by stimulating renal resident stem cell proliferation in acute kidney injury

Jia

Lű

et al. 2013

Chin. Sci. Bull.

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“…Living Image 4.0 (Caliper Life Sciences) was used to quantify signal intensity as described previously (15,16).…”

Section: Control Animals Received Pbs Injection Instead (N ϭ 8)mentioning

confidence: 99%

“…Fractional shortening was acquired using standard M-mode image acquisitions of left ventricular short axis images as described previously (15,16).…”

Section: Control Animals Received Pbs Injection Instead (N ϭ 8)mentioning

confidence: 99%

“…Model-Previous studies have demonstrated potential of iPSCand ESC-derived endothelial cells to improve systolic function following myocardial infarction through revascularization (15,16). Hence, we next delivered ciPSC-ECs stably transduced with TF reporter gene into the border zone of infarcted murine hearts.…”

Section: Transplantation Of Cipsc-ecs For Murine Myocardial Injurymentioning

confidence: 99%

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Preclinical Derivation and Imaging of Autologously Transplanted Canine Induced Pluripotent Stem Cells

Lee

Plews

et al. 2011

Journal of Biological Chemistry

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110

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Derivation of patient-specific induced pluripotent stem cells (iPSCs) opens a new avenue for future applications of regenerative medicine. However, before iPSCs can be used in a clinical setting, it is critical to validate their in vivo fate following autologous transplantation. Thus far, preclinical studies have been limited to small animals and have yet to be conducted in large animals that are physiologically more similar to humans. In this study, we report the first autologous transplantation of iPSCs in a large animal model through the generation of canine iPSCs (ciPSCs) from the canine adipose stromal cells and canine fibroblasts of adult mongrel dogs. We confirmed pluripotency of ciPSCs using the following techniques: (i) immunostaining and quantitative PCR for the presence of pluripotent and germ layer-specific markers in differentiated ciPSCs; (ii) microarray analysis that demonstrates similar gene expression profiles between ciPSCs and canine embryonic stem cells; (iii) teratoma formation assays; and (iv) karyotyping for genomic stability. Fate of ciPSCs autologously transplanted to the canine heart was tracked in vivo using clinical positron emission tomography, computed tomography, and magnetic resonance imaging. To demonstrate clinical potential of ciPSCs to treat models of injury, we generated endothelial cells (ciPSC-ECs) and used these cells to treat immunodeficient murine models of myocardial infarction and hindlimb ischemia.

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“…However, their use is afflicted with several difficulties including technical limitations of undifferentiated propagation in vitro and purification of spontaneously differentiated cardiomyocytes from cell culture. Despite these difficulties, recent progresses in stem cell biology have paved the way to exploit embryonic stem cells as a clinically relevant and renewable source to generate cardiomyocytes and endothelial cells for engraftment 20,21 . The cardiomyocytes and endothelial cells thus generated formed stable grafts in animal hearts without tumor formation.…”

Section: An Overview Of Heart Cell Therapymentioning

confidence: 99%

Strategies to promote donor cell survival: Combining preconditioning approach with stem cell transplantation

Haider

Ashraf

2008

Journal of Molecular and Cellular Cardiology

182

150

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Stem cell transplantation has emerged as a potential modality in cardiovascular therapeutics due to their inherent characteristics of self-renewal, unlimited capacity for proliferation and ability to cross lineage restrictions and adopt different phenotypes. Constrained by extensive death in the unfriendly milieu of ischemic myocardium, the results of heart cell therapy in experimental animal models as well as clinical studies have been less than optimal. Several factors which play a role in early cell death after engraftment in the ischemic myocardium include; absence of survival factors in the transplanted heart, disruption of cell-cell interaction coupled with loss of survival signals from matrix attachments, insufficient vascular supply and elaboration of inflammatory cytokines resulting from ischemia and/or cell death. This article reviews various signaling pathways involved in triggering highly complex forms of cell death and provides critical appreciation of different novel anti-death strategies developed from the knowledge gained from using an ischemic preconditioning approach. The use of pharmacological preconditioning for up-regulation of pro-survival proteins and cardiogenic markers in the transplanted stem cells will be discussed. An overview of heart cell therapyDuring the last decade, widespread experimental studies in animal models and clinical studies have shown the safety, feasibility and efficacy of cell based therapies for myocardial regeneration. Starting with the use of unipotent myogenic cells including skeletal muscle derived stem cells and cardiomyocytes, heart cell therapy has progressed to assess the feasibility of multipotent and pluripotent stem cells for cardiac repair 1,2 . Despite recent reports for their successful cardiomyogenic differentiation in vitro 3 , failure of skeletal myoblasts to electromechanically integrate and synchronously contract with the host myocytes post engraftment have restricted their use as the choice donor cells in clinical settings 4 . Similarly, cardiomyocytes are an excellent option for use as donor cells but their limited availability remains an issue of concern in clinical application 5,6 . Engraftment of non-myogenic fibroblasts and smooth muscle cells with contractility characteristics different from cardiomyocytes have also been shown to improve cardiac function 7,8 . Nevertheless, a repertoire of stem and progenitor cells in the bone marrow with differing plasticity and differentiation potentials have emerged as the most extensively studied cells for their myocardial regenerative potential in experimental animals and clinical studies 9,10 . In case of bone marrow derived stem cell engraftment, the mainstay of mechanisms for cardiac repair is #Corresponding Author: Muhammad Ashraf, Ph.D, Department of Pathology and Laboratory Medicine, 231-Albert Sabin Way, University of Cincinnati, OH-45267-0529, USA. Fax:1-513-558-0807, E-mail:E-mail: muhammad.ashraf@uc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has bee...

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Differentiation, Survival, and Function of Embryonic Stem Cell–Derived Endothelial Cells for Ischemic Heart Disease

Abstract: Background-Embryonic

Cited by 170 publications

References 36 publications

Human embryonic stem cells-derived endothelial cell therapy facilitates kidney regeneration by stimulating renal resident stem cell proliferation in acute kidney injury

Human embryonic stem cells-derived endothelial cell therapy facilitates kidney regeneration by stimulating renal resident stem cell proliferation in acute kidney injury

Preclinical Derivation and Imaging of Autologously Transplanted Canine Induced Pluripotent Stem Cells

Strategies to promote donor cell survival: Combining preconditioning approach with stem cell transplantation

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