Understanding Multicellularity: The Functional Organization of the Intercellular Space

Abstract

The aim of this paper is to provide a theoretical framework to understand how multicellular systems realize functionally integrated physiological entities by organizing their intercellular space. From a perspective centered on physiology and integration, biological systems are often characterized as organized in such a way that they realize metabolic self-production and self-maintenance. The existence and activity of their components rely on the network they realize and on the continuous management of the exchange of matter and energy with their environment. One of the virtues of the organismic approach focused on organization is that it can provide an understanding of how biological systems are functionally integrated into coherent wholes. Organismic frameworks have been primarily developed by focusing on unicellular life. Multicellularity, however, presents additional challenges to our understanding of biological systems, related to how cells are capable to live together in higher-order entities, in such a way that some of their features and behaviors are constrained and controlled by the system they realize. Whereas most accounts of multicellularity focus on cell differentiation and increase in size as the main elements to understand biological systems at this level of organization, we argue that these factors are insufficient to provide an understanding of how cells are physically and functionally integrated in a coherent system. In this paper, we provide a new theoretical framework to understand multicellularity, capable to overcome these issues. Our thesis is that one of the fundamental theoretical principles to understand multicellularity, which is missing or underdeveloped in current accounts, is the functional organization of the intercellular space. In our view, the capability to be organized in space plays a central role in this context, as it enables (and allows to exploit all the implications of) cell differentiation and increase in size, and even specialized functions such as immunity. We argue that the extracellular matrix plays a crucial active role in this respect, as an evolutionary ancient and specific (non-cellular) control subsystem that contributes as a key actor to the functional specification of the multicellular space and to modulate cell fate and behavior. We also analyze how multicellular systems exert control upon internal movement and communication. Finally, we show how the organization of space is involved in some of the failures of multicellular organization, such as aging and cancer.

Keywords: control; development; extracellular matrix; functional integration; immunity; mobility; physiology.

Figure 1

(A) Image of an adult Volvox carteri (Kirk, 2005, p. 300. Reproduced with permission from John Wiley & Sons, Inc.). Gonidia are the bigger spheres; somatic cells are the smaller dots. (B) Position of gonidia (G/E) and somatic cells (small circles with flagella) within the Volvox carteri’s ECM (Kirk et al., 1986, p. 226. Reproduced with permission from Company of Biologists Ltd.).

Figure 2

Accounts of multicellularity centered on cell differentiation achieved through intercellular signaling in the development of metazoa. (A) The intercellular cross-effects of Wn8 and Delta activate Hox1/13b and trigger cells differentiation (Arnellos et al., 2013, p. 869. Reproduced with permission from Springer Nature). (B) The role of intercellular constraints in histone modification and consequent cell differentiation and proliferation, with generation of intercellular gradients [Veloso, 2017, p. 90. Reproduced under the terms of the Creative Commons Attribution License (CC BY)].

Figure 3

The three main requirements for multicellular functional integration. The organization of space is an enabling condition for the increase in size and cell differentiation. Its functional role in multicellular systems is often underestimated due to an implicit cellular bias.

Figure 4

The main functional properties of multicellular systems realized through the organization of the intercellular space, in most cases by ECM structures acting as control mechanisms together with cells. The functional features of the intercellular space include: the control of cell fate and behavior; the enablement of metabolic capabilities by providing access to nutrients (e.g., through vascularization); physical properties such as resilience to physical stress and structural cohesiveness; the constitution of basement membrane for anchoring epithelial or endothelial cells, tendons, bones, etc.; spatial differentiation and modularity with distinct areas characterized by different boundary conditions for cells, and the realization of specialized areas and tissues; the creation of permeable or semipermeable barriers and interfaces by contributing to structure the epithelium, or directly, like in the kidney; and finally, the organization of mobility and communication at medium and long range (beyond cell-to-cell signaling).

Figure 5

Subsystems for the control of mobility and communication in multicellular systems. They differ with respect to the degree of specificity and the variety of control mechanisms they implement, and for their speed. While vascularization is common to almost all multicellularity, the other subsystems are specific of metazoa. We associated to each of them an analogy from city organization to exemplify their distinctive functioning in multicellular systems. Immune cells’ high specificity and low speed of movement is analogous to a postman delivering letters. The transport of water, nutrients and waste through vascularization can be associated to a hydraulic network which, at least in very basic form, can be found in most human settlements over a certain size. Finally, neuronal architectures in the body can be associated with electric networks in terms of high speed of movement and lower specificity of individual signals.