Directed Self-Organization of Human and Non-Human Primate Heart Muscle Organoids from Pluripotent Stem Cells
| Autor: | Daniel Ortmann, Toshiyuki Araki, James E. Hudson, Vijayakumar Muppala, Malte Tiburcy, Dirk Ziebolz, Poh Loong Soong, Angelica Roa, Iris Bartels, Gordon Keller, David A. Elliott, Farah Raad, Roger A. Pederson, Wolfram-Hubertus Zimmermann, Rüdiger Behr, Mei-Ling Chang Liao, Ralf Dressel, Benjamin G. Neel |
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| Rok vydání: | 2019 |
| Předmět: |
Inotrope
0303 health sciences Mesoderm Heart development Somatic cell Growth factor medicine.medical_treatment Stimulation Biology Cell biology 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure medicine Organoid Induced pluripotent stem cell 030217 neurology & neurosurgery 030304 developmental biology |
| Zdroj: | SSRN Electronic Journal. |
| ISSN: | 1556-5068 |
| DOI: | 10.2139/ssrn.3318931 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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