Closing the Mitochondrial Permeability Transition Pore in hiPSC-Derived Endothelial Cells Induces Glycocalyx Formation and Functional Maturation
| Autor: | Peter Carmeliet, M. Cristina Avramut, Valeria V. Orlova, Ton J. Rabelink, Wendy M.P.J. Sol, Bernard M. van den Berg, Christine L. Mummery, Gangqi Wang, Tobias K. Karakach, Cathelijne W. van den Berg, Gesa L. Tiemeier, Sébastien J. Dumas |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
endothelial cell differentiation Mitochondrial Membrane Transport Proteins Biochemistry Endothelial cell differentiation 0302 clinical medicine HUMAN IPSCS lcsh:QH301-705.5 reactive oxygen species chemistry.chemical_classification lcsh:R5-920 SHEAR-STRESS hiPSC-ECs Cell Differentiation Mitochondria 3. Good health Cell biology DIFFERENTIATION medicine.anatomical_structure PLURIPOTENT STEM-CELL Pericyte lcsh:Medicine (General) Life Sciences & Biomedicine EXPRESSION Cell type Endothelium Induced Pluripotent Stem Cells INHIBITION VE-CADHERIN METABOLISM Biology Glycocalyx Article shear stress Cell Line 03 medical and health sciences Cell & Tissue Engineering mitochondrial dysfunction Genetics medicine Humans MODULATION Reactive oxygen species Science & Technology maturation Mitochondrial Permeability Transition Pore Endothelial Cells Cell Biology 030104 developmental biology Mitochondrial permeability transition pore chemistry lcsh:Biology (General) BARRIER FUNCTION hiPSC-derived endothelial cells cyclosporine A 030217 neurology & neurosurgery Homeostasis Developmental Biology |
| Zdroj: | Stem Cell Reports, Vol 13, Iss 5, Pp 803-816 (2019) Stem Cell Reports Stem Cell Reports, 13(5), 803-816. CELL PRESS |
| ISSN: | 2213-6711 |
| Popis: | Summary Human induced pluripotent stem cells (hiPSCs) are used to study organogenesis and model disease as well as being developed for regenerative medicine. Endothelial cells are among the many cell types differentiated from hiPSCs, but their maturation and stabilization fall short of that in adult endothelium. We examined whether shear stress alone or in combination with pericyte co-culture would induce flow alignment and maturation of hiPSC-derived endothelial cells (hiPSC-ECs) but found no effects comparable with those in primary microvascular ECs. In addition, hiPSC-ECs lacked a luminal glycocalyx, critical for vasculature homeostasis, shear stress sensing, and signaling. We noted, however, that hiPSC-ECs have dysfunctional mitochondrial permeability transition pores, resulting in reduced mitochondrial function and increased reactive oxygen species. Closure of these pores by cyclosporine A improved EC mitochondrial function but also restored the glycocalyx such that alignment to flow took place. These results indicated that mitochondrial maturation is required for proper hiPSC-EC functionality. Graphical Abstract Highlights • hiPSC-ECs lack a functional glycocalyx and fail to align to flow • hiPSC-ECs have reduced mitochondrial function and increased leakage of ROS • Closing the mPTP with cyclosporine A induces mitochondrial maturation • Improved mitochondrial function restores the glycocalyx and alignment to flow Closure of the mitochondrial permeability transition pore by cyclosporine A improved mitochondrial function and maturation of hiPSC-ECs but also restored the glycocalyx such that alignment to flow took place. This functional glycocalyx, necessary for growth factor signaling and anticoagulation, is a prerequisite for future hiPSC-EC applications in tissue engineering, organoid vascularization and therapeutic use of hiPSC-ECs. |
| Databáze: | OpenAIRE |
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