Gastruloids enable modeling of the earliest stages of human cardiac and hepatic vascularization

Oscar J Abilez; Huaxiao Yang; Yuan Guan; Mengcheng Shen; Zehra Yildirim; Yan Zhuge; Ravichandra Venkateshappa; Shane R Zhao; Angello H Gomez; Marcel El-Mokahal; Logan Dunkenberger; Yoshikazu Ono; Masafumi Shibata; Peter N Nwokoye; Lei Tian; Kitchener D Wilson; Evan H Lyall; Fangjun Jia; Hung Ta Wo; Gao Zhou; Bryan Aldana; Ioannis Karakikes; Detlef Obal; Gary Peltz; Christopher K Zarins; Joseph C Wu

doi:10.1126/science.adu9375

Gastruloids enable modeling of the earliest stages of human cardiac and hepatic vascularization

Science. 2025 Jun 5;388(6751):eadu9375. doi: 10.1126/science.adu9375. Epub 2025 Jun 5.

Authors

Oscar J Abilez^#^{1

2

3

4

5

6}, Huaxiao Yang^#^{1

7}, Yuan Guan⁸, Mengcheng Shen¹, Zehra Yildirim¹, Yan Zhuge¹, Ravichandra Venkateshappa¹, Shane R Zhao¹, Angello H Gomez⁷, Marcel El-Mokahal⁷, Logan Dunkenberger^{1

4}, Yoshikazu Ono^{4

5}, Masafumi Shibata^{4

5}, Peter N Nwokoye^{4

5}, Lei Tian¹, Kitchener D Wilson^{1

9

10}, Evan H Lyall¹⁰, Fangjun Jia¹, Hung Ta Wo¹, Gao Zhou^{11

12}, Bryan Aldana¹³, Ioannis Karakikes^{1

4}, Detlef Obal^{1

2

3

8}, Gary Peltz⁸, Christopher K Zarins^{1

3

14}, Joseph C Wu^{1

2

3

15

16}

Affiliations

¹ Cardiovascular Institute, Stanford University, Stanford, CA, USA.
² Maternal and Child Health Research Institute, Stanford University, Stanford, CA, USA.
³ Bio-X Program, Stanford University, Stanford, CA, USA.
⁴ Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA.
⁵ Pediatric Cardiac Surgery, Stanford University, Stanford, CA, USA.
⁶ Bullseye Biotechnologies, Menlo Park, CA, USA.
⁷ Department of Biomedical Engineering, University of North Texas, Denton, TX, USA.
⁸ Department of Anesthesia, Pain, and Perioperative Medicine, Stanford University, Stanford, CA, USA.
⁹ Department of Pathology, Stanford University, Stanford, CA, USA.
¹⁰ Rosebud Biosciences, Orinda, CA, USA.
¹¹ Stanford Center for Genomics and Personalized Medicine, Stanford, CA, USA.
¹² Department of Genetics, Stanford University, Stanford, CA, USA.
¹³ Department of Bioengineering, Stanford University, Stanford, CA, USA.
¹⁴ Department of Surgery, Stanford University, Stanford, CA, USA.
¹⁵ Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
¹⁶ Greenstone Biosciences, Palo Alto, CA, USA.

^# Contributed equally.

PMID: 40472086
DOI: 10.1126/science.adu9375

Abstract

Although model organisms have provided insight into the earliest stages of cardiac and hepatic vascularization, we know very little about this process in humans because of ethical restrictions and the technical difficulty of obtaining embryos during very early development. In this study, we demonstrate that micropatterned human pluripotent stem cell-derived gastruloids enable in vitro modeling of the earliest stages of vascularization. We identify a combination of vascular-inducing factors that give rise to cardiac vascularized organoids with a spatially organized and branched vascular network. To show the broader utility of our vascularization strategy, we use the same vascular-inducing factors to produce hepatic vascularized organoids. Our results suggest that a conserved developmental program generates the vasculature within different types of organs.

MeSH terms

Gastrula* / cytology
Heart* / embryology
Humans
Liver* / blood supply
Liver* / embryology
Neovascularization, Physiologic*
Organoids* / blood supply
Organoids* / embryology
Pluripotent Stem Cells / cytology