![]() ![]() Stem cell research began to thrive when pluripotent stem cells (PSCs) were first isolated and established from mouse embryos in 1981 ( 34, 84). In 1964, Malcolm Steinberg introduced the differential adhesion hypothesis, proposing that cell sorting and rearrangement can be explained by thermodynamics mediated by differential surface adhesion ( 135). A few decades later, several groups performed dissociation-reaggregation experiments to generate different types of organs from dissociated amphibian pronephros ( 46a) and chick embryos ( 158). Alternatively, the 3D structure of the organoids can also be established via “air-liquid-interface.” In this case, cells are cultured on a basal layer of fibroblasts or Matrigel that are initially submerged in medium, which gradually evaporates and exposes the upper cell layers to the air to allow polarization and differentiation ( 61, 147).īack in 1907, Henry Van Peters Wilson described the first attempt of in vitro organism regeneration, where he demonstrated that dissociated sponge cells can self-organize to regenerate a whole organism ( 159). ![]() For scaffold-free techniques, cells are cultured in droplets of a defined culture medium hanging from a plate by gravity and surface tension ( 146). It comprises mainly adhesive proteins such as collagen, entactin, laminin, and heparin sulfate proteoglycans, which resemble the extracellular environment to provide structural support and ECM signals to the cells. The most commonly used one is Matrigel, which is a heterogeneous and gelatinous protein mixture secreted by Engelbreth-Holm-Swarm (EHS) mouse sarcoma cells ( 99). Scaffolds are biological or synthetic hydrogels that resemble the natural ECM. ![]() This can be achieved using scaffold or scaffold-free techniques. The 3D culture system is established by suspension culture to avoid direct physical contact to the plastic dish. Finally, we will evaluate the pros and cons of 3D organoid technology compared with other conventional models.ģD CULTURE MODELS: FROM CELL AGGREGATES TO ORGANOIDS We will explore various applications of organoid technology in biomedicine and discuss its promises and challenges. In this review, we will discuss the history and development of 3D organoid culture and provide the most recent update on organoid research that covers whole range of systems. This is particularly useful for studies of early-stage embryonic development, where primary human material is limited. The pluripotent property of ESCs and iPSCs enables the generation of organoids from all three germ layers. On the other hand, ESC/iPSC-derived organoids involve stepwise differentiation protocols using various growth factors or inhibitors that resemble the developmental cues during gastrulation and organogenesis. Besides normal tissues, ASC-derived organoids can also be established from patient-specific material for disease modeling and precision medicine (see organoid applications below). This is supported by a cocktail of growth factors in the culture media that recapitulate signaling control under normal tissue homeostasis. Self-organization within the organoid occurs through spatially restricted lineage commitment and cell sorting, which requires activation of various signaling pathways mediated by intrinsic cellular components or extrinsic environments such as extracellular matrix (ECM) and media.ĪSC-derived organoids are generated directly from postnatal or adult tissues either from single ASC or ASC-containing tissue units. Organoids can be derived from either embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), or neonatal or adult stem cells (ASCs) ( 52, 70) through a process similar to the way in which the organ acquires its distinctive organization. The modern term organoid refers to cells growing in a defined three-dimensional (3D) environment in vitro to form mini-clusters of cells that self-organize and differentiate into functional cell types, recapitulating the structure and function of an organ in vivo (hence, also called “mini-organs”). ![]()
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