Details
| Original language | English |
|---|---|
| Pages (from-to) | 305-317 |
| Number of pages | 13 |
| Journal | Stem Cell Reports |
| Volume | 8 |
| Issue number | 2 |
| Publication status | Published - 12 Jan 2017 |
Abstract
Subtype-specific human cardiomyocytes (CMs) are valuable for basic and applied research. Induction of cardiomyogenesis and enrichment of nodal-like CMs was described for mouse pluripotent stem cells (mPSCs) in response to 1-ethyl-2-benzimidazolinone (EBIO), a chemical modulator of small-/intermediate-conductance Ca2+-activated potassium channels (SKs 1–4). Investigating EBIO in human pluripotent stem cells (PSCs), we have applied three independent differentiation protocols of low to high cardiomyogenic efficiency. Equivalent to mPSCs, timed EBIO supplementation during hPSC differentiation resulted in dose-dependent enrichment of up to 80% CMs, including an increase in nodal- and atrial-like phenotypes. However, our study revealed extensive EBIO-triggered cell loss favoring cardiac progenitor preservation and, subsequently, CMs with shortened action potentials. Proliferative cells were generally more sensitive to EBIO, presumably via an SK-independent mechanism. Together, EBIO did not promote cardiogenic differentiation of PSCs, opposing previous findings, but triggered lineage-selective survival at a cardiac progenitor stage, which we propose as a pharmacological strategy to modulate CM subtype composition.
Keywords
- 1-ethyl-2-benzimidazolinone (EBIO), cardiomyocyte enrichment, cardiomyocyte subtype, CyPPA, differentiation, human pluripotent stem cells, NS309, proliferation, SK channel
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Genetics
- Biochemistry, Genetics and Molecular Biology(all)
- Developmental Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Cell Biology
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In: Stem Cell Reports, Vol. 8, No. 2, 12.01.2017, p. 305-317.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - EBIO Does Not Induce Cardiomyogenesis in Human Pluripotent Stem Cells but Modulates Cardiac Subtype Enrichment by Lineage-Selective Survival
AU - Jara-Avaca, Monica
AU - Kempf, Henning
AU - Rückert, Michael
AU - Robles-Diaz, Diana
AU - Franke, Annika
AU - de la Roche, Jeanne
AU - Fischer, Martin
AU - Malan, Daniela
AU - Sasse, Philipp
AU - Solodenko, Wladimir
AU - Dräger, Gerald
AU - Kirschning, Andreas
AU - Martin, Ulrich
AU - Zweigerdt, Robert
N1 - Funding information: We are grateful for the technical assistance of Maria Ensthaler and the support by the “Core facility Cell Sorting.” We also thank the Research Core Unit Transcriptomics of Hannover Medical School for generating and processing the microarray raw data. This work was funded by grants to R.Z. including the German Research Foundation (DFG; including grants: Cluster of Excellence REBIRTH DFG EXC62/3 and ZW64/4-1), the German Ministry for Education and Science (BMBF; including grants: 13N12606 and 13N14086), StemBANCC (support from the Innovative Medicines Initiative joint undertaking under grant 115439-2, whose resources are composed of financial contribution from the European Union [FP7/2007-2013] and EFPIA companies' in-kind contribution), and TECHNOBEAT (European Union H2020 grant 668724). H.K. was supported by Hannover Medical School Internal Program (HiLF) and by Joachim Herz Stiftung.
PY - 2017/1/12
Y1 - 2017/1/12
N2 - Subtype-specific human cardiomyocytes (CMs) are valuable for basic and applied research. Induction of cardiomyogenesis and enrichment of nodal-like CMs was described for mouse pluripotent stem cells (mPSCs) in response to 1-ethyl-2-benzimidazolinone (EBIO), a chemical modulator of small-/intermediate-conductance Ca2+-activated potassium channels (SKs 1–4). Investigating EBIO in human pluripotent stem cells (PSCs), we have applied three independent differentiation protocols of low to high cardiomyogenic efficiency. Equivalent to mPSCs, timed EBIO supplementation during hPSC differentiation resulted in dose-dependent enrichment of up to 80% CMs, including an increase in nodal- and atrial-like phenotypes. However, our study revealed extensive EBIO-triggered cell loss favoring cardiac progenitor preservation and, subsequently, CMs with shortened action potentials. Proliferative cells were generally more sensitive to EBIO, presumably via an SK-independent mechanism. Together, EBIO did not promote cardiogenic differentiation of PSCs, opposing previous findings, but triggered lineage-selective survival at a cardiac progenitor stage, which we propose as a pharmacological strategy to modulate CM subtype composition.
AB - Subtype-specific human cardiomyocytes (CMs) are valuable for basic and applied research. Induction of cardiomyogenesis and enrichment of nodal-like CMs was described for mouse pluripotent stem cells (mPSCs) in response to 1-ethyl-2-benzimidazolinone (EBIO), a chemical modulator of small-/intermediate-conductance Ca2+-activated potassium channels (SKs 1–4). Investigating EBIO in human pluripotent stem cells (PSCs), we have applied three independent differentiation protocols of low to high cardiomyogenic efficiency. Equivalent to mPSCs, timed EBIO supplementation during hPSC differentiation resulted in dose-dependent enrichment of up to 80% CMs, including an increase in nodal- and atrial-like phenotypes. However, our study revealed extensive EBIO-triggered cell loss favoring cardiac progenitor preservation and, subsequently, CMs with shortened action potentials. Proliferative cells were generally more sensitive to EBIO, presumably via an SK-independent mechanism. Together, EBIO did not promote cardiogenic differentiation of PSCs, opposing previous findings, but triggered lineage-selective survival at a cardiac progenitor stage, which we propose as a pharmacological strategy to modulate CM subtype composition.
KW - 1-ethyl-2-benzimidazolinone (EBIO)
KW - cardiomyocyte enrichment
KW - cardiomyocyte subtype
KW - CyPPA
KW - differentiation
KW - human pluripotent stem cells
KW - NS309
KW - proliferation
KW - SK channel
UR - http://www.scopus.com/inward/record.url?scp=85009827961&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2016.12.012
DO - 10.1016/j.stemcr.2016.12.012
M3 - Article
C2 - 28089668
AN - SCOPUS:85009827961
VL - 8
SP - 305
EP - 317
JO - Stem Cell Reports
JF - Stem Cell Reports
SN - 2213-6711
IS - 2
ER -