期刊
ACTA BIOMATERIALIA
卷 170, 期 -, 页码 519-531出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2023.08.053
关键词
Human pluripotent stem cells; Cystogenesis; Elastic substrate; Actomyosin contractility; Contact mechanics model
This study reveals that human pluripotent stem cells can self-organize into cysts resembling human epiblast sac on soft elastic substrates without the need for a three-dimensional extracellular matrix overlay. The formation of these cysts is facilitated by the nesting of the soft substrate and requires the activation of the ROCK-Myosin II pathway. These findings highlight the interplay between the mechanical microenvironment and cells in tissue morphogenesis, offering a mechanics-based strategy for generating models of early human embryogenesis using stem cells.
Understanding the principles underlying the self-organization of stem cells into tissues is fundamen-tal for deciphering human embryo development. Here, we report that, without three-dimensional (3D) extracellular matrix (ECM) overlay, human pluripotent stem cells (hPSCs) cultured on two-dimensional soft elastic substrates can self-organize into 3D cysts resembling the human epiblast sac in a stiffness-dependent manner. Our theoretical modeling predicts that this cyst organization is facilitated and guided by the spontaneous nesting of the soft substrate, which results from the adhesion-dependent mechanical interaction between cells and substrate. Such substrate nesting is sufficient for the 3D assembly and po-larization of hPSCs required for cyst organization, even without 3D ECM overlay. Furthermore, we iden-tify that the reversible substrate nesting and cyst morphogenesis also require appropriate activation of ROCK-Myosin II pathway. This indicates a unique set of tissue morphomechanical signaling mechanisms that clearly differ from the canonical cystogenic mechanism previously reported in 3D ECM. Our findings highlight an unanticipated synergy between mechanical microenvironment and mechanotransduction in controlling tissue morphogenesis and suggest a mechanics-based strategy for generation of hPSCs-derived models for early human embryogenesis. Statement of significance Soft substrates can induce the self-organization of human pluripotent stem cells (hPSCs) into cysts with-out three-dimensional (3D) extracellular matrix (ECM) overlay. However, the underlying mechanisms by which soft substrate guides cystogenesis are largely unknown. This study shows that substrate nesting, re-sulting from cell-substrate interaction, plays an important role in cyst organization, including 3D assem-bly and apical-basal polarization. Additionally, actomyosin contractility mediated by the ROCK-Myosin II pathway also contributes to the substrate deformation and cyst morphology. These findings demonstrate the interplay between the mechanical microenvironment and cells in tissue morphogenesis, suggesting a mechanics-based strategy in building hPSC-derived models for early human embryo development. (c) 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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