Prevascularization of cardiac patch on the omentum improves its therapeutic outcome

Dvir, Tal; Kedem, Alon; Ruvinov, Emil; Levy, Oren; Freeman, Inbar; Landa, Natalie; Holbová, Radka; Feinberg, Micha S.; Dror, Shani; Etzion, Yoram; Leor, Jonathan; Cohen, Smadar

doi:10.1073/pnas.0812242106

Cited by 321 publications

(261 citation statements)

References 37 publications

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“…Many of the proposed applications for hPSC-derived cardiomyocytes may require three-dimensional engineered tissue to more accurately reflect drug responses and function in the adult heart. Recent studies suggest that appropriate combinations of cardiac cells, endothelial cells and fibroblasts must be incorporated into such tissue constructs for them to function best in vitro or in vivo [23][24][25] . Our ability to generate pure myocyte and nonmyocyte populations will allow for the generation of engineered constructs consisting of varying proportions of different cell types, enabling us to determine the optimal combination of each required to form heart tissue with structural and functional properties most similar to that of the human heart.…”

Section: Discussionmentioning

confidence: 99%

SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells

et al. 2011

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To identify cell-surface markers specific to human cardiomyocytes, we screened cardiovascular cell populations derived from human embryonic stem cells (hESCs) against a panel of 370 known CD antibodies. This screen identified the signal-regulatory protein alpha (SIRPA) as a marker expressed specifically on cardiomyocytes derived from hESCs and human induced pluripotent stem cells (hiPSCs), and PECAM, THY1, PDGFRB and ITGA1 as markers of the nonmyocyte population. Cell sorting with an antibody against SIRPA allowed for the enrichment of cardiac precursors and cardiomyocytes from hESC/hiPSC differentiation cultures, yielding populations of up to 98% cardiac troponin T-positive cells. When plated in culture, SIRPA-positive cells were contracting and could be maintained over extended periods of time. These findings provide a simple method for isolating populations of cardiomyocytes from human pluripotent stem cell cultures, and thereby establish a readily adaptable technology for generating large numbers of enriched cardiomyocytes for therapeutic applications.Generation of cardiovascular cells from human pluripotent stem cells (hPSCs) in culture could provide a powerful model system for investigating cellular interactions and molecular regulators that govern the specification, commitment and maturation of these lineages, as well as a unique and unlimited source of human cardiomyocytes for drug testing and regenerative medicine strategies [1][2][3][4] . Translating this potential into practice, however, will depend on the development of technologies that enable the reproducible generation of highly enriched populations of cardiomyocytes, as contaminating cell types could affect drug Reprints and permissions information is available online at

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Section: Discussionmentioning

confidence: 99%

SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells

et al. 2011

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“…Sekine et al (28) proposed in vitro fabrication of cardiac tissue with perusable blood vessels using a muscle tissue with a connectable artery and vein as a bed perfused in a bioreactor. Dvir et al (29) constructed a vascularized cardiac patch using both survival and angiogenic factors by first implanting the patch on the omentum. Controlled delivery of proangiogenic factors from growth factoreluting scaffolds has been shown to induce host vessel ingrowth into the implant (30), whereas EC seeding has been attempted to promote additional vascularization on implantation (31).…”

Section: Discussionmentioning

confidence: 99%

An engineered muscle flap for reconstruction of large soft tissue defects

Shandalov¹,

Egozi

Koffler

et al. 2014

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

140

135

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Significance Effective restoration of large soft tissue defects requires the use of tissue flaps, with viability that is largely determined by degree of vascularization. In view of the tedious transfer procedures and donor site morbidity associated with autologous flaps, this work set out to design and evaluate an engineered muscle flap featuring a robust vascular port formed from preseeded endothelial cells and host vasculature. The implanted flap was highly vascularized, well-perfused, and anastomosed with host vessels. Engineered flaps of this nature promise to circumvent the need to harvest and transfer massive tissue volumes, while avoiding the consequential complications.

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“…Lesman et al (28) transplanted prevascularized constructs containing hESC-derived cardiomyocytes, HUVECs, and MEFs and showed that they formed viable, perfused grafts in hearts of immunosuppressed rats. Dvir et al (29) created a neonatal rat cardiomyocyte patch and prevascularized it on the omentum, prior to transplanting it onto the heart. They report these patches integrated structurally and electrically with the host heart.…”

Section: Shortening Contractions Stimulated By Electrical Pacing In Wmentioning

confidence: 99%

Physiological function and transplantation of scaffold-free and vascularized human cardiac muscle tissue

Stevens

Kreutziger

Dupras

et al. 2009

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

386

334

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Success of human myocardial tissue engineering for cardiac repair has been limited by adverse effects of scaffold materials, necrosis at the tissue core, and poor survival after transplantation due to ischemic injury. Here, we report the development of scaffold-free prevascularized human heart tissue that survives in vivo transplantation and integrates with the host coronary circulation. Human embryonic stem cells (hESCs) were differentiated to cardiomyocytes by using activin A and BMP-4 and then placed into suspension on a rotating orbital shaker to create human cardiac tissue patches. Optimization of patch culture medium significantly increased cardiomyocyte viability in patch centers. These patches, composed only of enriched cardiomyocytes, did not survive to form significant grafts after implantation in vivo. To test the hypothesis that ischemic injury after transplantation would be attenuated by accelerated angiogenesis, we created ''second-generation,'' prevascularized, and entirely human patches from cardiomyocytes, endothelial cells (both human umbilical vein and hESC-derived endothelial cells), and fibroblasts. Functionally, vascularized patches actively contracted, could be electrically paced, and exhibited passive mechanics more similar to myocardium than patches comprising only cardiomyocytes. Implantation of these patches resulted in 10-fold larger cell grafts compared with patches composed only of cardiomyocytes. Moreover, the preformed human microvessels anastomosed with the rat host coronary circulation and delivered blood to the grafts. Thus, inclusion of vascular and stromal elements enhanced the in vitro performance of engineered human myocardium and markedly improved viability after transplantation. These studies demonstrate the importance of including vascular and stromal elements when designing human tissues for regenerative therapies.angiogenesis ͉ human embryonic stem cells ͉ tissue engineering ͉ myocardial infarction ͉ cardiomyocyte

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Prevascularization of cardiac patch on the omentum improves its therapeutic outcome

Cited by 321 publications

References 37 publications

SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells

SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells

An engineered muscle flap for reconstruction of large soft tissue defects

Physiological function and transplantation of scaffold-free and vascularized human cardiac muscle tissue

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