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Cardiac Myofibrillogenesis is Spatiotemporally Modulated by the Molecular Chaperone UNC45B

ABSTRACT: Sarcomeres are fundamental to cardiac muscle contraction. Their impairment can elicit cardiomyopathies, leading causes of death worldwide. However, the molecular mechanism underlying sarcomere assembly remains obscure. We used human embryonic stem cell (hESC)-derived cardiomyocytes (CMs) to reveal step-wise spatiotemporal regulation of core cardiac myofibrillogenesis-associated proteins.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart Development, Cell Culture, Embryonic Stem Cell

DISEASE(S): Cardiomyopathy

SUBMITTER: Su-Yi Tsai

LAB HEAD: Su-Yi Tsai

PROVIDER: PXD042075 | Pride | 2023-10-24

REPOSITORIES: Pride

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	2021-0421_Sample3-2.mzXML	Mzxml
	2021-0421_Sample3-2.raw	Raw
	2021-0421_Sample5-2.mzXML	Mzxml
	2021-0421_Sample5-2.raw	Raw

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Publications

Cardiac myofibrillogenesis is spatiotemporally modulated by the molecular chaperone UNC45B.

Lu Serena Huei-An SH Wu Yi-Hsuan YH Su Liang-Yu LY Hsu Zi-Ting ZT Weng Tzu-Han TH Wang Hsin-Yu HY Yu Chiao C Hsu Paul Wei-Che PW Tsai Su-Yi SY

Stem cell reports 20230608 7

Sarcomeres are fundamental to cardiac muscle contraction. Their impairment can elicit cardiomyopathies, leading causes of death worldwide. However, the molecular mechanism underlying sarcomere assembly remains obscure. We used human embryonic stem cell (hESC)-derived cardiomyocytes (CMs) to reveal stepwise spatiotemporal regulation of core cardiac myofibrillogenesis-associated proteins. We found that the molecular chaperone UNC45B is highly co-expressed with KINDLIN2 (KIND2), a marker of protoco ...[more]

PMID: 37295424

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Cardiac Myofibrillogenesis 1 is Spatiotemporally Modulated by the Molecular Chaperone UNC45B

Project description:Sarcomeres are fundamental to cardiac muscle contraction. Their impairment can elicit cardiomyopathies, leading causes of death worldwide. However, the molecular mechanism underlying sarcomere assembly remains obscure. We used human embryonic stem cell (hESC)-derived cardiomyocytes (CMs) to reveal step-wise spatiotemporal regulation of core cardiac myofibrillogenesis-associated proteins. We found that the molecular chaperone UNC45B is highly co-expressed with KINDLIN2 (KIND2), a marker of protocostameres, and later its distribution overlaps with that of muscle myosin MYH6. UNC45B-knockout CMs display essentially no contractility. Our phenotypic analyses further reveal that: 1) binding of Z-line anchor protein ACTN2 to protocostameres is perturbed due to impaired protocostamere formation, resulting in ACTN2 accumulation; 2) F-ACTIN polymerization is suppressed; and 3) MYH6 becomes degraded, so it cannot replace non-muscle myosin MYH10. Our mechanistic study demonstrates that UNC45B mediates protocostamere formation by regulating KIND2 expression. Thus, we show that UNC45B modulates cardiac myofibrillogenesis by interacting spatiotemporally with various proteins.

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Modeling acute myocardial infarction in vitro using mature and ventricular hESC-derived cardiomyocytes by FGF4 and ascorbic acid treatment

Project description:hPSC-CMs resemble immature embryonic or fetal CMs rather than mature adult CMs, and have limitations in disease modeling and pharmacological studies. Therefore, hPSCs-derived mature and ventricular CMs are required for more accurate in vitro modeling of adult-onset cardiac disease and drug discovery. FGF4+AA-treated hESC-CMs robustly released acute myocardial infarction (AMI) biomarkers (cTnI, CK-MB, and myoglobin) into culture medium in response to hypoxic injury. Hypoxia-responsive genes related to cellular responses to glycolytic processes, oxygen levels, HIF-1 signaling, apoptotic processes, and regulation of cell death including potential cardiac biomarkers proved in clinical studies in the diagnosis and prognosis of coronary artery diseases were induced in FGF4+AA-treated hESC-CMs in response to hypoxia based on transcriptome analyses.

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The global transcriptome analysis in the time course of hESC-derived cardiac differentiation

Project description:We analyzed the global transcriptome signature over the time course of the cardiac differentiation from hESC by RNA-seq. We characterized the genome-wide transcriptome profile of 5 distinct stages; undifferentiated hESC (day 0), mesodermal precursor stage (hMP, day 2), cardiac progenitor stage (hCP, day 5), immature cardiomyocyte (hCM14) and hESC-CMS differentiated for 14 additional days (hCM28). While the stem cell signature decreases over the five stages, the signatures associated with heart and smooth muscle development increase, indicating the efficient cardiac differentiation of our protocol.

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