Thinking in 3 dimensions: philosophies of the microenvironment in organoids and organs-on-chip.

Organoids and organs-on-a-chip are currently the two major families of 3D advanced organotypic in vitro culture systems, aimed at reconstituting miniaturized models of physiological and pathological states of human organs. Both share the tenets of the so-called "three-dimensional thinking", a Systems Physiology approach focused on recapitulating the dynamic interactions between cells and their microenvironment. We first review the arguments underlying the "paradigm shift" toward three-dimensional thinking in the in vitro culture community. Then, through a historically informed account of the technical affordances and the epistemic commitments of these two approaches, we highlight how they embody two distinct experimental cultures. We finally argue that the current systematic effort for their integration requires not only innovative "synergistic" engineering solutions, but also conceptual integration between different perspectives on biological causality.

Stem Cells and the Microenvironment: Reciprocity with Asymmetry in Regenerative Medicine.

Much of the current research in regenerative medicine concentrates on stem-cell therapy that exploits the regenerative capacities of stem cells when injected into different types of human tissues. Although new therapeutic paths have been opened up by induced pluripotent cells and human mesenchymal cells, the rate of success is still low and mainly due to the difficulties of managing cell proliferation and differentiation, giving rise to non-controlled stem cell differentiation that ultimately leads to cancer. Despite being still far from becoming a reality, these studies highlight the role of physical and biological constraints (e.g., cues and morphogenetic fields) placed by tissue microenvironment on stem cell fate. This asks for a clarification of the coupling of stem cells and microenvironmental factors in regenerative medicine. We argue that extracellular matrix and stem cells have a causal reciprocal and asymmetric relationship in that the 3D organization and composition of the extracellular matrix establish a spatial, temporal, and mechanical control over the fate of stem cells, which enable them to interact and control (as well as be controlled by) the cellular components and soluble factors of microenvironment. Such an account clarifies the notions of stemness and stem cell regeneration consistently with that of microenvironment.

Functional Integration and Individuality in Prokaryotic Collective Organisations.

Both physiological and evolutionary criteria of biological individuality are underpinned by the idea that an individual is a functionally integrated whole. However, a precise account of functional integration has not been provided so far, and current notions are not developed in the details, especially in the case of composite systems. To address this issue, this paper focuses on the organisational dimension of two representative associations of prokaryotes: biofilms and the endosymbiosis between prokaryotes. Some critical voices have been raised against the thesis that biofilms are biological individuals. Nevertheless, it has not been investigated which structural and functional obstacles may prevent them from being fully integrated physiological or evolutionary units. By contrast, the endosymbiotic association of different species of prokaryotes has the potential for achieving a different type of physiological integration based on a common boundary and interlocked functions. This type of association had made it possible, under specific conditions, to evolve endosymbionts into fully integrated organelles. This paper therefore has three aims: first, to analyse the organisational conditions and the physiological mechanisms that enable integration in prokaryotic associations; second, to discuss the organisational differences between biofilms and prokaryotic endosymbiosis and the types of integration they achieve; finally, to provide a more precise account of functional integration based on these case studies.

Motility Control of Symbionts and Organelles by the Eukaryotic Cell: The Handling of the Motile Capacity of Individual Parts Forges a Collective Biological Identity.

Motility occupies a decisive role in an organism's ability to autonomously interact with its environment. However, collective biological organizations exhibit individual parts, which have temporally or definitively lost their motor capacities, but still able to autonomously interact with their host. Indeed, although the flagella of bacterial symbionts of eukaryotic cells are usually inhibited or lost, they autonomously modify the environment provided by their host. Furthermore, the eukaryotic organelles of endosymbiotic origin (i.e., mitochondria and plastids) are no longer able to move autonomously; nonetheless, they make a cytoskeletal-driven motion that allows them to communicate with other eukaryotic cells and to perform a considerable number of physiological functions. The purpose of this article is twofold: first, to investigate how changes in the motile capacities of the parts of a nested biological organization affect their interactive autonomy; second, to examine how the modification of the interactive autonomy of the individual parts influences the constitutive autonomy of the collective association as a whole. The article argues that the emergence and maintenance of collective biological identities involves a strict control of the motile abilities of their constituting members. This entails a restriction, but not necessarily a complete loss, of the agential capacities of the individual parts.