Engineering multiscale structural orders for high-fidelity embryoids and organoids

Abstract

Embryoids and organoids hold great promise for human biology and medicine. Herein, we discuss conceptual and technological frameworks useful for developing high-fidelity embryoids and organoids that display tissue- and organ-level phenotypes and functions, which are critically needed for decoding developmental programs and improving translational applications. Through dissecting the layers of inputs controlling mammalian embryogenesis, we review recent progress in reconstructing multiscale structural orders in embryoids and organoids. Bioengineering tools useful for multiscale, multimodal structural engineering of tissue- and organ-level cellular organization and microenvironment are also discussed to present integrative, bioengineering-directed approaches to achieve next-generation, high-fidelity embryoids and organoids.

Keywords: developmental biology; embryoid; mammalian embryogenesis; mechanobiology; organoid; stem cell engineering.

Figure 1.. Multiscale Orders in Mammalian Embryogenesis.

From a structural perspective, a conceptual framework of multiscale orders in mammalian embryogenesis is proposed. It is based on (A) the formation of distinct tissue structural units and (B&C) their organization, communication, and progression through increasing spatial and temporal scales. This conceptual framework also integrates classical developmental biology concepts (as representatively shown herein) into a coherent, multiscale map to comprehensively illustrate the structural orders and complexities of mammalian embryogenesis. This conceptual map also serves to guide rationally designed structural engineering of high-fidelity embryoids and organoids in vitro. (Abbreviations: EPI, epiblast; ICM, inner cell mass; TE, trophectoderm; PrE, primitive endoderm; AE, amniotic ectoderm; MHP, medial hinge point; DLHP, dorsolateral hinge point; IVC, inferior vena cava)

Figure 2.. Engineered Evolution of Stem Cell Models of Early Embryogenesis.

By leveraging diverse bioengineering approaches, high-order, high-fidelity stem cell models of early embryogenic milestones, including peri- and post-implantation development (A), gastrulation and body axis development (B), and neurulation (C) have been developed recently. In contrast to conventional models based on self-organization, recent evolution of embryoids, gastruloids, and neuruloids acquires meso- and macro-scale orders through guided stem cell organization, which is dictated by structurally engineered tissue boundaries. These models provide important platforms for understanding human embryonic programming, recapitulating developmental abnormalities, as well as embryo toxicology screening.

Figure 3.. Engineered Evolution of Stem Cell Models of Organogenesis and Organismal Biology.

Self-organized, stem cell-based rudimentary models have been long used to recapitulate certain aspects of organ development. But they are mostly limited by their biological fidelity, reproducibility, and standardization. Recently, we witnessed an engineered evolution towards high-order, high-fidelity organoids, which is driven by different types of bioengineering technologies. Such evolution takes the advantage of guided organizations of stem cells dictated by spatiotemporally structured developmental boundary conditions. These models have shown meso- and macro-scale orders with greater similarities to the multiscale organizations and functionalities in ectodermal (A), mesodermal (B), and endodermal (C) organs. Meso- and macro-scale orders manifested in tissue-tissue coupling (D) and organismal biology (E) have also been recapitulated. Recent works have also highlighted the critical role of mechano-biological coupling in the development of high-fidelity organoids. These advances provide important foundations to attack basic questions in developmental biology and to facilitate translational applications in disease modeling, drug screening, and regenerative therapeutics.

Figure 4.. Bioengineering Warehouse for Reconstructing Multiscale Orders of Life

Multiscale, multimodal structural engineering (MUSE) of the cells and their niche has recently emerged as a promising strategy for building micro-, meso-, and macro-scale orders in the development of high-fidelity embryoids and organoids. Guided by this strategy, the large and still expanding bioengineering warehouse has been categorized so as to highlight unique applications of different engineering modalities and their combinations for reconstructing micro- (A), meso- (B), and macro-scale orders (C), respectively. This bioengineering warehouse provides a technological framework to guide rational selection and orthogonal integration of engineering modalities to reconstruct multiscale orders of mammalian life, and therefore to advance high-fidelity embryoids and organoids.