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Understanding Multicellularity: The Functional Organization of the Intercellular Space

Bich, Leonardo and Pradeu, Thomas and Moreau, Jean-François (2019) Understanding Multicellularity: The Functional Organization of the Intercellular Space. Frontiers in Physiology, 10. ISSN 1664-042X


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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.

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Item Type: Published Article or Volume
Bich, Leonardo
Pradeu, Thomas
Moreau, Jean-François
Depositing User: Thomas Pradeu
Date Deposited: 19 Oct 2020 02:49
Last Modified: 19 Oct 2020 02:49
Item ID: 18270
Journal or Publication Title: Frontiers in Physiology
Official URL:
DOI or Unique Handle:
Date: 2019
Volume: 10
ISSN: 1664-042X

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