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Directed Self-Organization of Human and Non-Human Primate Heart Muscle Organoids from Pluripotent Stem Cells

51 Pages Posted: 29 Jan 2019 Sneak Peek Status: Review Complete

See all articles by James E. Hudson

James E. Hudson

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology; DZHK - German Centre for Cardiovascular Research; QIMR Berghofer Medical Research Institute

Farah Raad

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology; DZHK - German Centre for Cardiovascular Research

Malte Tiburcy

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology; DZHK - German Centre for Cardiovascular Research

Angelica Roa

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology; DZHK - German Centre for Cardiovascular Research

Mei-Ling Chang Liao

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology; DZHK - German Centre for Cardiovascular Research

Vijayakumar Muppala

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology; DZHK - German Centre for Cardiovascular Research

Poh Loong Soong

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology; DZHK - German Centre for Cardiovascular Research

Toshiyuki Araki

New York University (NYU) - Laura and Isaac Perlmutter Cancer Center

Benjamin Neel

New York University (NYU) - Laura and Isaac Perlmutter Cancer Center

Gordon Keller

McEwen Centre for Regenerative Medicine

Daniel Ortmann

University of Cambridge - The Anne McLaren Laboratory for Regenerative Medicine

Roger A. Pederson

University of Cambridge - The Anne McLaren Laboratory for Regenerative Medicine

David A. Elliott

Royal Childrens Hospital - Murdoch Childrens Research Institute

Iris Bartels

University of Goettingen (Gottingen) - Institute of Human Genetics

Ralf Dressel

DZHK - German Centre for Cardiovascular Research; University of Goettingen (Gottingen) - Institute of Cellular and Molecular Immunology

Dirk Ziebolz

University of Goettingen (Gottingen) - Clinic for Preventive Dentistry, Periodontology and Cariology; University of Leipzig - Department of Cariology, Endodontology and Periodontology

Rüdiger Behr

DZHK - German Centre for Cardiovascular Research; German Primate Center - Department of Stem Cell Biology

Wolfram Hubertus Zimmermann

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology; DZHK - German Centre for Cardiovascular Research

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Abstract

Pluripotent stem cells (PSCs) can differentiate into all somatic cell lineages, but fail to form functional macro-scale heart muscle organoids in monolayer, suspension, or aggregate cultures. Here we show that human and non-human primate (NHP) PSCs have the capacity to self-organize into bioengineered heart muscle (BHM) if exposed to a serum-free cardio-instructive collagen-hydrogel environment with defined temporarily restricted growth factor, small molecule, and mechanical stimulation. BHMs traversed through distinct developmental stages with molecular signatures representative for: (i) mesoderm induction (3 days), (ii) cardiac specification (+10 days), and (iii) cardiac maturation (+9 days). Matured BHM responded to electrical pacing, preloading, inotropic stimuli and pharmacological agents similar to bona fide myocardium. We further demonstrate the applicability of BHM in modelling of Noonan Syndrome associated with Raf1 mutations. Collectively, we provide proof-of-concept for directed assembly of human and NHP PSCs into force-generating macro-scale myocardial organoids for applications in simulations of heart development and disease.

Suggested Citation

Hudson, James E. and Raad, Farah and Tiburcy, Malte and Roa, Angelica and Liao, Mei-Ling Chang and Muppala, Vijayakumar and Soong, Poh Loong and Araki, Toshiyuki and Neel, Benjamin and Keller, Gordon and Ortmann, Daniel and Pederson, Roger A. and Elliott, David A. and Bartels, Iris and Dressel, Ralf and Ziebolz, Dirk and Behr, Rüdiger and Zimmermann, Wolfram Hubertus, Directed Self-Organization of Human and Non-Human Primate Heart Muscle Organoids from Pluripotent Stem Cells (January 19, 2019). Available at SSRN: https://ssrn.com/abstract=3318931 or http://dx.doi.org/10.2139/ssrn.3318931
This is a paper under consideration at Cell Press and has not been peer-reviewed.

James E. Hudson

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology

Göttingen
Germany

DZHK - German Centre for Cardiovascular Research

Oudenarder Straße 16
Building D/04 (1st Floor)
Berlin, 13316
Germany

QIMR Berghofer Medical Research Institute

Brisbane, Queensland
Australia

Farah Raad

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology

Göttingen
Germany

DZHK - German Centre for Cardiovascular Research

Oudenarder Straße 16
Building D/04 (1st Floor)
Berlin, 13316
Germany

Malte Tiburcy

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology

Göttingen
Germany

DZHK - German Centre for Cardiovascular Research

Oudenarder Straße 16
Building D/04 (1st Floor)
Berlin, 13316
Germany

Angelica Roa

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology

Göttingen
Germany

DZHK - German Centre for Cardiovascular Research

Oudenarder Straße 16
Building D/04 (1st Floor)
Berlin, 13316
Germany

Mei-Ling Chang Liao

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology

Göttingen
Germany

DZHK - German Centre for Cardiovascular Research

Oudenarder Straße 16
Building D/04 (1st Floor)
Berlin, 13316
Germany

Vijayakumar Muppala

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology

Göttingen
Germany

DZHK - German Centre for Cardiovascular Research

Oudenarder Straße 16
Building D/04 (1st Floor)
Berlin, 13316
Germany

Poh Loong Soong

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology

Göttingen
Germany

DZHK - German Centre for Cardiovascular Research

Oudenarder Straße 16
Building D/04 (1st Floor)
Berlin, 13316
Germany

Toshiyuki Araki

New York University (NYU) - Laura and Isaac Perlmutter Cancer Center

20 Cooper Square 3rd Floor
New York, NY 10003-711
United States

Benjamin Neel

New York University (NYU) - Laura and Isaac Perlmutter Cancer Center

20 Cooper Square 3rd Floor
New York, NY 10003-711
United States

Gordon Keller

McEwen Centre for Regenerative Medicine

MaRS Centre, Toronto Medical Discovery Tower
101 College St. 8th Floor, room 701
Toronto, ON M5G 1L7
Canada

Daniel Ortmann

University of Cambridge - The Anne McLaren Laboratory for Regenerative Medicine

Cambridge
United Kingdom

Roger A. Pederson

University of Cambridge - The Anne McLaren Laboratory for Regenerative Medicine

Cambridge
United Kingdom

David A. Elliott

Royal Childrens Hospital - Murdoch Childrens Research Institute

Victoria
Australia

Iris Bartels

University of Goettingen (Gottingen) - Institute of Human Genetics

Göttingen
Germany

Ralf Dressel

DZHK - German Centre for Cardiovascular Research

Oudenarder Straße 16
Building D/04 (1st Floor)
Berlin, 13316
Germany

University of Goettingen (Gottingen) - Institute of Cellular and Molecular Immunology

Göttingen
Germany

Dirk Ziebolz

University of Goettingen (Gottingen) - Clinic for Preventive Dentistry, Periodontology and Cariology ( email )

Göttingen
Germany

University of Leipzig - Department of Cariology, Endodontology and Periodontology

Leipzig
Germany

Rüdiger Behr

DZHK - German Centre for Cardiovascular Research

Oudenarder Straße 16
Building D/04 (1st Floor)
Berlin, 13316
Germany

German Primate Center - Department of Stem Cell Biology

Göttingen
Germany

Wolfram Hubertus Zimmermann (Contact Author)

University of Goettingen (Gottingen) - Institute of Pharmacology and Toxicology ( email )

Göttingen
Germany

DZHK - German Centre for Cardiovascular Research ( email )

Oudenarder Straße 16
Building D/04 (1st Floor)
Berlin, 13316
Germany

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