Vascularized hiPSC-derived 3D cardiac microtissue on chip

Stem Cell Reports, vol. 18, pp. 1394–1404

Abstract

Functional vasculature is essential for delivering nutrients, oxygen, and cells to the heart and removing waste products. Here, we developed an in vitro vascularized human cardiac microtissue (MT) model based on human induced pluripotent stem cells (hiPSCs) in a microfluidic organ-on-chip by coculturing hiPSC-derived, pre-vascularized, cardiac MTs with vascular cells within a fibrin hydrogel. We showed that vascular networks spontaneously formed in and around these MTs and were lumenized and interconnected through anastomosis. Anastomosis was fluid flow dependent: continuous perfusion increased vessel density and thus enhanced the formation of the hybrid vessels. Vascularization further improved endothelial cell (EC)-cardiomyocyte communication via EC-derived paracrine factors, such as nitric oxide, and resulted in an enhanced inflammatory response. The platform sets the stage for studies on how organ-specific EC barriers respond to drugs or inflammatory stimuli.

Authors 11

1. Ulgu Arslan Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZC Leiden, the Netherlands

2. Marcella Brescia Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZC Leiden, the Netherlands

3. Viviana Meraviglia Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZC Leiden, the Netherlands

4. Dennis M. Nahon Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZC Leiden, the Netherlands

5. Ruben W.J. van Helden Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZC Leiden, the Netherlands

6. Jeroen M. Stein Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZC Leiden, the Netherlands

7. Francijna E. van den Hil Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZC Leiden, the Netherlands

8. Berend J. van Meer Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZC Leiden, the Netherlands

9. Marc Vila Cuenca Aachen Department of Anatomy and Embryology Department of Clinical Genetics

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZC Leiden, the Netherlands; Department of Clinical Genetics, Leiden University Medical Center, 2333ZA Leiden, the Netherlands

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZC Leiden, the Netherlands

   Department of Clinical Genetics, Leiden University Medical Center, 2333ZA Leiden, the Netherlands

10. Christine L. Mummery Aachen Department of Anatomy and Embryology

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZC Leiden, the Netherlands

11. Valeria V. Orlova corresponding Aachen Department of Anatomy and Embryology

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZC Leiden, the Netherlands. Electronic address: v.orlova@lumc.nl

    Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZC Leiden, the Netherlands