Paracrine mechanisms in early differentiation of human pluripotent stem cells: Insights from a mathematical model
With their capability to self-renew and differentiate into derivatives of all three germ layers, human pluripotent stem cells (hPSCs) offer a unique model to study aspects of human development in vitro. Directed differentiation towards mesendodermal lineages is a complex process, involving transitio...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-10-01
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| Series: | Stem Cell Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1873506118302071 |
| _version_ | 1819015364162355200 |
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| author | Erika Gaspari Annika Franke Diana Robles-Diaz Robert Zweigerdt Ingo Roeder Thomas Zerjatke Henning Kempf |
| author_facet | Erika Gaspari Annika Franke Diana Robles-Diaz Robert Zweigerdt Ingo Roeder Thomas Zerjatke Henning Kempf |
| author_sort | Erika Gaspari |
| collection | DOAJ |
| description | With their capability to self-renew and differentiate into derivatives of all three germ layers, human pluripotent stem cells (hPSCs) offer a unique model to study aspects of human development in vitro. Directed differentiation towards mesendodermal lineages is a complex process, involving transition through a primitive streak (PS)-like stage. We have recently shown PS-like patterning from hPSCs into definitive endoderm, cardiac as well as presomitic mesoderm by only modulating the bulk cell density and the concentration of the GSK3 inhibitor CHIR99021, a potent activator of the WNT pathway. The patterning process is modulated by a complex paracrine network, whose identity and mechanistic consequences are poorly understood.To study the underlying dynamics, we here applied mathematical modeling based on ordinary differential equations. We compared time-course data of early hPSC differentiation to increasingly complex model structures with incremental numbers of paracrine factors. Model simulations suggest at least three paracrine factors being required to recapitulate the experimentally observed differentiation kinetics. Feedback mechanisms from both undifferentiated and differentiated cells turned out to be crucial. Evidence from double knock-down experiments and secreted protein enrichment allowed us to hypothesize on the identity of two of the three predicted factors. From a practical perspective, the mathematical model predicts optimal settings for directing lineage-specific differentiation. This opens new avenues for rational stem cell bioprocessing in more advanced culture systems, e.g. in perfusion-fed bioreactors enabling cell therapies. Keywords: Human pluripotent stem cells, Paracrine effects, Differentiation, Primitive streak, Mathematical modeling |
| first_indexed | 2024-12-21T02:30:33Z |
| format | Article |
| id | doaj.art-12a120551cce441da3e8611767bc736c |
| institution | Directory Open Access Journal |
| issn | 1873-5061 |
| language | English |
| last_indexed | 2024-12-21T02:30:33Z |
| publishDate | 2018-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Research |
| spelling | doaj.art-12a120551cce441da3e8611767bc736c2022-12-21T19:18:55ZengElsevierStem Cell Research1873-50612018-10-013217Paracrine mechanisms in early differentiation of human pluripotent stem cells: Insights from a mathematical modelErika Gaspari0Annika Franke1Diana Robles-Diaz2Robert Zweigerdt3Ingo Roeder4Thomas Zerjatke5Henning Kempf6Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden, Germany; Laboratory of Systems and Synthetic Biology, Wageningen University & Research, Wageningen, the NetherlandsLeibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), REBIRTH-Cluster of Excellence, Hannover Medical School, GermanyLeibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), REBIRTH-Cluster of Excellence, Hannover Medical School, GermanyLeibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), REBIRTH-Cluster of Excellence, Hannover Medical School, GermanyInstitute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden, GermanyInstitute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden, Germany; Correspondence to: T. Zerjatke, Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of medicine, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany.Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), REBIRTH-Cluster of Excellence, Hannover Medical School, Germany; Correspondence to: H. Kempf, Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany.With their capability to self-renew and differentiate into derivatives of all three germ layers, human pluripotent stem cells (hPSCs) offer a unique model to study aspects of human development in vitro. Directed differentiation towards mesendodermal lineages is a complex process, involving transition through a primitive streak (PS)-like stage. We have recently shown PS-like patterning from hPSCs into definitive endoderm, cardiac as well as presomitic mesoderm by only modulating the bulk cell density and the concentration of the GSK3 inhibitor CHIR99021, a potent activator of the WNT pathway. The patterning process is modulated by a complex paracrine network, whose identity and mechanistic consequences are poorly understood.To study the underlying dynamics, we here applied mathematical modeling based on ordinary differential equations. We compared time-course data of early hPSC differentiation to increasingly complex model structures with incremental numbers of paracrine factors. Model simulations suggest at least three paracrine factors being required to recapitulate the experimentally observed differentiation kinetics. Feedback mechanisms from both undifferentiated and differentiated cells turned out to be crucial. Evidence from double knock-down experiments and secreted protein enrichment allowed us to hypothesize on the identity of two of the three predicted factors. From a practical perspective, the mathematical model predicts optimal settings for directing lineage-specific differentiation. This opens new avenues for rational stem cell bioprocessing in more advanced culture systems, e.g. in perfusion-fed bioreactors enabling cell therapies. Keywords: Human pluripotent stem cells, Paracrine effects, Differentiation, Primitive streak, Mathematical modelinghttp://www.sciencedirect.com/science/article/pii/S1873506118302071 |
| spellingShingle | Erika Gaspari Annika Franke Diana Robles-Diaz Robert Zweigerdt Ingo Roeder Thomas Zerjatke Henning Kempf Paracrine mechanisms in early differentiation of human pluripotent stem cells: Insights from a mathematical model Stem Cell Research |
| title | Paracrine mechanisms in early differentiation of human pluripotent stem cells: Insights from a mathematical model |
| title_full | Paracrine mechanisms in early differentiation of human pluripotent stem cells: Insights from a mathematical model |
| title_fullStr | Paracrine mechanisms in early differentiation of human pluripotent stem cells: Insights from a mathematical model |
| title_full_unstemmed | Paracrine mechanisms in early differentiation of human pluripotent stem cells: Insights from a mathematical model |
| title_short | Paracrine mechanisms in early differentiation of human pluripotent stem cells: Insights from a mathematical model |
| title_sort | paracrine mechanisms in early differentiation of human pluripotent stem cells insights from a mathematical model |
| url | http://www.sciencedirect.com/science/article/pii/S1873506118302071 |
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