Details
| Original language | English |
|---|---|
| Article number | 213 |
| Journal | Bioengineering |
| Volume | 8 |
| Issue number | 12 |
| Publication status | Published - 14 Dec 2021 |
Abstract
The proper function of cardiomyocytes (CMs) is highly related to the Z-disc, which has a pivotal role in orchestrating the sarcomeric cytoskeletal function. To better understand Z-disc related cardiomyopathies, novel models of Z-disc damage have to be developed. Human pluripotent stem cell (hPSC)-derived CMs can serve as an in vitro model to better understand the sarcomeric cytoskeleton. A femtosecond laser system can be applied for localized and defined damage application within cells as single Z-discs can be removed. We have investigated the changes in force generation via traction force microscopy, and in gene expression after Z-disc manipulation in hPSC-derived CMs. We observed a significant weakening of force generation after removal of a Z-disc. However, no significant changes of the number of contractions after manipulation were detected. The stress related gene NF-kB was significantly upregulated. Additionally, α-actinin (ACTN2) and filamin-C (FLNc) were upregulated, pointing to remodeling of the Z-disc and the sarcomeric cytoskeleton. Ultimately, cardiac troponin I (TNNI3) and cardiac muscle troponin T (TNNT2) were significantly downregulated. Our results allow a better understanding of transcriptional coupling of Z-disc damage and the relation of damage to force generation and can therefore finally pave the way to novel therapies of sarcomeric disorders.
Keywords
- Cardiomyocyte, Femtosecond laser manipulation, Traction forces, Z-disc
ASJC Scopus subject areas
- Chemical Engineering(all)
- Bioengineering
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In: Bioengineering, Vol. 8, No. 12, 213, 14.12.2021.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - How localized z-disc damage affects force generation and gene expression in cardiomyocytes
AU - Müller, Dominik
AU - Donath, Sören
AU - Brückner, Emanuel Georg
AU - Devadas, Santoshi Biswanath
AU - Daniel, Fiene
AU - Gentemann, Lara
AU - Zweigerdt, Robert
AU - Heisterkamp, Alexander
AU - Kalies, Stefan Michael Klaus
N1 - Funding Information: Funding: S.M.K.K. and A.H. received funding by the REBIRTH Research Center for Translational Regenerative Medicine (ZN3440, State of Lower Saxony Ministry of Science and Culture (Nieders. Vorab)). R.Z. received funding from the German Research Foundation (DFG): Cluster of Excellence REBIRTH EXC 62/3, ZW64/4-1, ZW 64/4-2, KFO311/ZW64/7-1; the German Ministry for Education and Science (BMBF): 01EK1602A, 13N14086, 01EK1601A, 13XP5092B, 031L0249; and “Förderung aus Mitteln des Niedersächsischen Vorab” (ZN3340).
PY - 2021/12/14
Y1 - 2021/12/14
N2 - The proper function of cardiomyocytes (CMs) is highly related to the Z-disc, which has a pivotal role in orchestrating the sarcomeric cytoskeletal function. To better understand Z-disc related cardiomyopathies, novel models of Z-disc damage have to be developed. Human pluripotent stem cell (hPSC)-derived CMs can serve as an in vitro model to better understand the sarcomeric cytoskeleton. A femtosecond laser system can be applied for localized and defined damage application within cells as single Z-discs can be removed. We have investigated the changes in force generation via traction force microscopy, and in gene expression after Z-disc manipulation in hPSC-derived CMs. We observed a significant weakening of force generation after removal of a Z-disc. However, no significant changes of the number of contractions after manipulation were detected. The stress related gene NF-kB was significantly upregulated. Additionally, α-actinin (ACTN2) and filamin-C (FLNc) were upregulated, pointing to remodeling of the Z-disc and the sarcomeric cytoskeleton. Ultimately, cardiac troponin I (TNNI3) and cardiac muscle troponin T (TNNT2) were significantly downregulated. Our results allow a better understanding of transcriptional coupling of Z-disc damage and the relation of damage to force generation and can therefore finally pave the way to novel therapies of sarcomeric disorders.
AB - The proper function of cardiomyocytes (CMs) is highly related to the Z-disc, which has a pivotal role in orchestrating the sarcomeric cytoskeletal function. To better understand Z-disc related cardiomyopathies, novel models of Z-disc damage have to be developed. Human pluripotent stem cell (hPSC)-derived CMs can serve as an in vitro model to better understand the sarcomeric cytoskeleton. A femtosecond laser system can be applied for localized and defined damage application within cells as single Z-discs can be removed. We have investigated the changes in force generation via traction force microscopy, and in gene expression after Z-disc manipulation in hPSC-derived CMs. We observed a significant weakening of force generation after removal of a Z-disc. However, no significant changes of the number of contractions after manipulation were detected. The stress related gene NF-kB was significantly upregulated. Additionally, α-actinin (ACTN2) and filamin-C (FLNc) were upregulated, pointing to remodeling of the Z-disc and the sarcomeric cytoskeleton. Ultimately, cardiac troponin I (TNNI3) and cardiac muscle troponin T (TNNT2) were significantly downregulated. Our results allow a better understanding of transcriptional coupling of Z-disc damage and the relation of damage to force generation and can therefore finally pave the way to novel therapies of sarcomeric disorders.
KW - Cardiomyocyte
KW - Femtosecond laser manipulation
KW - Traction forces
KW - Z-disc
UR - http://www.scopus.com/inward/record.url?scp=85121816535&partnerID=8YFLogxK
U2 - 10.3390/bioengineering8120213
DO - 10.3390/bioengineering8120213
M3 - Article
AN - SCOPUS:85121816535
VL - 8
JO - Bioengineering
JF - Bioengineering
IS - 12
M1 - 213
ER -