Regeneration at the cellular level

Dr. Eduard Willms

How does regeneration unfold at the level of the smallest structural units of life - our cells?

‘Omnis cellula e cellula’ - every cell stems from another cell - Rudolf Virchow

In biology, regeneration refers to the process by which a living organism repairs or

replaces damaged tissues or organs. Certain organisms, such as salamanders, planarian
worms, and some plants, have the unique ability to more extensively regenerate from
fragments or specialized cells. Regeneration allows organisms to restore their functionality
and recover from injuries. What can we learn from these regenerative processes and how
can we integrate their principles into systemic thinking and regenerative design?

When we zoom in on living organisms we observe that they are composed of the basic
units of life - cells. Living organisms are complex biological systems, and the individual
cells are organized into patterns of multicellular networks (e.g. tissues and organs).
It is through these networks of cells and their interactions that physiology, in other words,
biological functions emerge. Like the beating of the heart and the resulting pumping of
blood emerging from interactions between the muscle and nerve cells present in the heart.
Along similar lines, regeneration is a physiological process that emerges from cellular
networks.
Within regenerative cellular networks stem cells play an integral role. These cells have the
unique ability to develop from an undifferentiated state (i.e. a cell that does not have a
speci c function yet) into a differentiated state in which the cell has developed specialized
abilities (e.g. the specialized ability of a muscle cell to contract and relax). In cell biology,
this unique capability of stem cells, together with a number of their other unique
capabilities, is termed stemness.

Communication and interaction between cells within cellular networks and between
different cellular networks in an organism are important for the coordination of physiology.
Multiple mechanisms through which cells communicate have been discovered, ranging
from the direct contact and exchange of information between cells through channels called
gap junctions, to chemical signaling between cells making use of secreted
neurotransmitters and hormones.

Intercellular communication through extracellular vesicles

The gure below provides a representation of another more recently discovered

mechanism of cell-to-cell communication, occurring through the release and exchange of
microscopic parcels between cells. As shown in the gure, a cell can release small
parcels, which are termed extracellular vesicles (EVs). Researchers have discovered
different types of EVs such as exosomes and microvesicles that are able to exchange
biological molecules (e.g. proteins, lipids, and nucleic acids) contained within the EVs
between cells. Through this intercellular exchange, cells are able to in uence each other.
Similar to networks that have been discovered connecting fungi and trees - EVs form a
connective network between cells.
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 Extracellular vesicles visualised
using Transmission Electron
Microscopy. This image shows EVs
of various sizes isolated from cells.
The scale bar on the bottom right
represents 100 nm.

Cell-to-cell communication via extracellular vesicles.

The secreting cell on the left produces EVs (microvesicles and
exosomes) packaged with biomolecules that can in uence the
recipient cell on the right. The secreted vesicles can in uence cellular
processes via interactions occuring at the surface of the recipient cells
(1). Alternatively, EVs can fuse with the membrane of the recipient cell
and in uence the processes inside the recipient cell (intracellular
processes) by releasing their packaged biomolecules (2-4).

EVs cannot be seen with the naked eye, they range in size from as small as 30
nanometers up to 10,000 nanometers in diameter. To put this into perspective, an EV is
approximately 10,000 times smaller than a grain of sand visible to the naked eye.

Heterogeneity - the quality or state of being diverse in character or content

As shown in the gure below, cells release different types of EVs. One type of EV called
microvesicles (MVs in the gure) forms by directly budding from the cell membrane.
Another type of EV called exosomes (EXOs in the gure) is generated through a more
complex pathway taking place within the cell. Apoptotic bodies (APOs in the gure) are a
type of EV released by cells that undergo apoptosis, a form of programmed cell death.

EVs are also studied for their roles in diseases. One of the most researched areas in the
EV eld focuses on the roles of EVs in cancer. For instance, EVs are involved in how
cancer spreads from one organ or location to another in the body (e.g. from the lung to
lymph nodes). My 2018 review article Extracellular Vesicle Heterogeneity: Subpopulations,
Isolation Techniques, and Diverse Functions in Cancer Progression discusses the various
roles of EVs in the progression of cancer and highlights the diversity of EVs released by
cells.
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 Cells release extracellular vesicles with divserse characteristics. This gure shows an individual cell (on
the left) releasing EVs into its extracellular environment. Exosomes (EXOs) are formed and packaged with
biomolecules inside the cell - the intracellular environment. Apoptotic bodies (APOs) are released when a cell
undergoes apoptosis - programmed cell death.

Extracellular Vesicles in Regeneration and Regenerative Medicine

Regenerative medicine is an area of medicine that explores novel therapeutic approaches

to regenerate damaged or diseased tissues and organs in the body. The approaches can,
for instance, be aimed at promoting cellular behaviors required for successful regeneration
and inhibiting physiological responses to injury that hinder regeneration.

In their article ‘An Emerging Frontier in Intercellular Communication: Extracellular Vesicles

in Regeneration’ Priscilla N. Avalos and David J. Fortshoefel review the role of EVs in
coordinating cellular behaviors during regeneration. Communication between cells in the
vicinity of the injury plays a role in how individual cells collectively repair the damage.
Interestingly, stem cells are also able to release EVs. Scienti c studies have demonstrated
that EVs derived from stem cells can protect against damage and promote repair by
in uencing regenerative cellular processes. The precise roles of EVs in these processes
remain to be elucidated. At this point in time EVs derived from stem cells are actively
explored by scientists as novel regenerative therapies. In this way, scientists are designing
therapies that mimic naturally occurring regenerative processes in living systems.

Zooming out - Sustainable design of urban spaces - An example of how our

understanding of living systems can in uence thinking and design

What can we learn from comparing the smallest structural unit of life - the cell - with the
smallest structural unit of a city - a parcel (i.e. a plot of land)? What insights does this
comparison provide for urban planning and what can urban spaces learn from nature?

These questions are at the core of an interdisciplinary research project conducted by the
Austrian Centre for Industrial Biotechnology (acib) and the Graz Of ce for spatial and
urban planning (adasca). As the architects involved in the project point out: “We don’t just
want to ask about the systematics and properties of a cell from a biotechnological point of
view, but think of the cell as a parcel. Like the cells in the human body, there is also an
exchange between the parcel of land and the environment.”
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This project provides an excellent example of how our understanding of living systems on
a cellular/micro-scale can in uence our thinking and design on a macro-scale.

Discussion Points

• Stem cells play an integral role in the process of cellular regeneration. Stemness
highlights the need for components of the systems to stay open and adaptable, open to
(un)learn and change. In light of systemic design of regenerative systems, this points to
the importance of staying open to continuously and exibly adapt, of moving with and as
part of the system.

• A healthy network is a well-connected and exible network with an active exchange of

information. In a systemic view, EVs can be seen as carriers of information from one
part of the network to other parts, connecting nodes and components of the system.
This dynamic transfer contributes to an integrated system that coordinates its behavior
and adapts according to information communicated in the system.

• Processes occurring between the cells in a cellular network are important for emergent
biological functions. When studying and designing systems on a different scale we
should therefore not just focus on the individual nodes, but also on what happens in
between them - how do they communicate and interact?

• In living systems, there is an intrinsic recognition and process based on the fact that
certain components have a natural end-point. Certain cells undergo apoptosis
(programmed cell death) and cease to exist, and, in a circular way, contribute back to
the network. The apoptotic cells release fragments (apoptotic bodies) that signal to the
remaining cells and may be used by the remaining living cells to maintain and
regenerate the network.

• Heterogeneity. Living systems are composed of many types of cells and cells release a
diverse range of EV types. This diversity allows a wide range of biological functions to
emerge. Diversity in a system is an important contributor to the system's adaptability
and resilience.

• Physiological functions of living systems are not dictated by the genome - the genes of
the cells. In other words, there is no code or program dictating these functions. At the
single-cell level, the functions emerge from the interactions of biomolecules within cells
and the interaction of the cell with its environment. At the multi-cellular level, the function
emerges from interactions between cells and biomolecules and EVs released into the
intercellular environment. If there is no xed program (i.e. genetic code) directing this
behaviour it means that living systems (humans) are open to (un)learn and change.

References
• Regeneration: what does it mean and how does it work? - EuroStemCell
• Regeneration - National Institute of General Medical Sciences
• Extracellular vesicles: Exosomes, microvesicles, and friends
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• Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse
Functions in Cancer Progression
• An Emerging Frontier in Intercellular Communication: Extracellular Vesicles in
Regeneration
• Sustainable design of urban spaces - Cell - ParCels - Translated from original in German

Learn more about biological systems and regeneration

• Regeneration is the essence of life’s self-organisation - Daniel Christian Wahl & Fritjof
Capra
• Michael Levin - Biologist studying novel ways to understand and control complex pattern
formation in biological systems. - Lex Fridman Podcast
• Denis Noble on Biological Sytems and reductionism in biology
• Denis Noble - Dance to the tune of life
• Fritjof Capra - Systems view of life

Biography - Eduard Willms

DPhil - efwillms@gmail.com - Linkedin - Google Scholar

Eduard studied Pharmacy at Utrecht University followed by a PhD in Physiology at Oxford

University. After completing his PhD, Eduard worked as a postdoctoral researcher at La Trobe
University in Melbourne, Australia. His research explored the biological role and therapeutic
application of cell-derived particles, called exosomes and extracellular vesicles, in cell-to-cell
communication. After more than a decade of working in laboratories, he became increasingly
aware of, and troubled by, the environmental footprint of scienti c research. This led him on a
journey to address sustainability in science and in 2021 he headed the certi cation of the rst My
Green Lab certi ed lab in Australia. This lab sustainability journey and his interest in biological
systems were the stepping stone for his current research in which he examines how cellular
processes in living systems can inform and in uence our thinking and the design of more
sustainable and regenerative processes.
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