Name: Cardiac Myofibrillogenesis is Spatiotemporally Modulated by the Molecular Chaperone UNC45B
Keywords: Homo sapiens

Dataset Information

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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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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Project description:The first macrophages that seed the developing heart originate from the yolk sac during fetal life. While murine studies reveal important homeostatic and reparative functions in adults, we know little about their roles in the earliest stages of human heart development due to a lack of accessible tissue. Generation of bioengineered human cardiac microtissues from pluripotent stem cells models these first steps in cardiac tissue development, however macrophages have not been included in these studies. To bridge these gaps, we differentiated human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages; akin to yolk sac macrophages) that stably engrafted within cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts to study reciprocal interactions. Engraftment induced a tissue resident macrophage gene program resembling human fetal cardiac macrophages, enriched in efferocytic pathways. Functionally, hESC-macrophages induced production and maturation of cardiomyocyte sarcomeric proteins, and enhanced contractile force, relaxation kinetics, and electrical properties. Mechanistically, the primary effect of hESC-macrophages was during the stressful events surrounding early microtissue formation, where they engaged in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reinforced core resident macrophage identity, reduced microtissue stress and drove hESC-cardiomyocytes to become more similar to human ventricular cardiomyocytes found in early development, both transcriptionally and metabolically. Inhibiting efferocytosis of hESC-cardiomyocytes by hESC-macrophages led to increased cell stress, impaired sarcomeric protein maturation and reduced cardiac microtissue function (contraction and relaxation). Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial, yet previously unappreciated role for human primitive macrophages in enhancing cardiac tissue function.

Dataset Information

Cardiac Myofibrillogenesis is Spatiotemporally Modulated by the Molecular Chaperone UNC45B

Publications

Cardiac myofibrillogenesis is spatiotemporally modulated by the molecular chaperone UNC45B.

Similar Datasets

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