Abstract
Organoids are a novel three-dimensional stem cells’ culture system that allows the in vitro recapitulation of organs/tissues structure complexity. Pluripotent and adult stem cells are included in a peculiar microenvironment consisting of a supporting structure (an extracellular matrix (ECM)-like component) and a cocktail of soluble bioactive molecules that, together, mimic the stem cell niche organization. It is noteworthy that the balance of all microenvironmental components is the most critical step for obtaining the successful development of an accurate organoid instead of an organoid with heterogeneous morphology, size, and cellular composition. Within this system, mechanical forces exerted on stem cells are collected by cellular proteins and transduced via mechanosensing—mechanotransduction mechanisms in biochemical signaling that dictate the stem cell specification process toward the formation of organoids. This review discusses the role of the environment in organoids formation and focuses on the effect of physical components on the developmental system. The work starts with a biological description of organoids and continues with the relevance of physical forces in the organoid environment formation. In this context, the methods used to generate organoids and some relevant published reports are discussed as examples showing the key role of mechanosensing–mechanotransduction mechanisms in stem cell-derived organoids.
Highlights
There has been significant advancement of three-dimensional (3D)-cell culture systems to address the limitations of two-dimensional (2D) culture systems and to better mimic tissue structure and functionality
While the building of PSCs-derived organoids requires the reprogramming of somatic differentiated cells isolated from patients followed by expansion and differentiation, the use of AdSCs permits the production of healthy and diseased tissues in a shorter time: as a result, the latter allows a more manageable expansion of models from patients, potentially facilitating personalized medicine (Rossi et al 2018; Lancaster and Huch 2019; Schutgens and Clevers 2020)
The step of germ-layer specification for PSCs is obtained through Activin A (Endoderm), Activin A and Bone Morphogenetic Protein 4 (BMP4, Mesoderm) and WNT + PBM4 (Ectoderm), which is followed by a step in which tissue-specific growth factor cocktails and molecules activate particular signaling pathways, such as WNT and Fibroblast Growth Factors (FGF) (Yin et al 2016; Lancaster and Huch 2019; Kim et al 2020)(Figs. 1a, 2)
Summary
PSCs can differentiate toward all three germ layers (Endoderm, Ectoderm, Mesoderm) and are used for building more complex organoids useful for studying the embryonic development and are needed when the organ that has to be modeled is not accessible (e.g., the brain) (Brassard and Lutolf 2019; Liu et al 2021; Yu et al 2021). While the building of PSCs-derived organoids requires the reprogramming of somatic differentiated cells isolated from patients followed by expansion and differentiation, the use of AdSCs permits the production of healthy and diseased tissues in a shorter time: as a result, the latter allows a more manageable expansion of models from patients, potentially facilitating personalized medicine (Rossi et al 2018; Lancaster and Huch 2019; Schutgens and Clevers 2020). All methods used for organoids generation consist in the inclusion of stem cells in an environment characterized by specific biophysical and biochemical components (Fig. 3) These elements mimic the role of the structure as a well as of soluble biomolecules in the in vivo stem cell niche, allowing for better regulation of cellular growth and differentiation and, as a result, more physiological applicable model systems that can be translated into clinical practice (Hofer and Lutolf 2021). Organoids are generated by including stem cells in an environment consisting of a biophysical component, generally natural (Matrigel, Collagen, Alginate, Fibrin, Laminin) or synthetic (e.g., Polyethylene Glycol, PEG) hydrogels, and biochemical component, such as different types of soluble bioactive chemical/
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