Native cell domains as stem cell regulatory microterritories for precise tissue engineering

Accurate sizing of the specific microenvironment of stem cells is of both fundamental and significant practical importance for 3D bioprinting of biological tissues and organs. Current solutions are mainly dedicated to the study and reconstruction of synthetic niches regulating individual stem cells; this is not always possible due to the small size of such native microterritories. In this context, multicellular domains, proposed in 1978 along with niches, are less explored but more promising natural regulatory units for 3D design of next generations of biomaterials. This review describes the current state in natural multicellular domains, compares their properties with known artificial structures (stem cell spheroids and pores in biomaterials), and proposes a more precise 3D design of porous scaffolds for large-scale tissue regeneration based on optimization of domain-like classification of cell and tissue regulatory units. The review discusses the topics of natural domain-like units as tissue-specific structures, correspondence of the dimension of mesenchymal stem cell spheroids with native multicellular domains, and similarity of pores in biomaterials with synthetic domains for hard and soft tissue regeneration. The proposed uniform classification of synthetic regulatory units suggests that the domain-like regulatory microterritories of stem cells are necessary tools for 3D prototyping and printing of next-generation scaffolds to mimic precisely the structure and behavior of living multicellular systems.