How to achieve cell division in animal cell-like systems

Image credit: SCIXEL, BaSyC

Because of its complexity, cell division remains difficult for scientists to reconstruct. A research team from the Kavli Institute of Delft University of Technology, involved in the BaSyC (Building a Synthetic Cell) research program, analyzed the various works on cell division. Since the process differs depending on the cell type, the team focused on the division of animal cell-like systems. They published a roadmap, a strategic plan in ACS Publications with the main steps and requirements to achieve the division of an artificial cell. Let’s review what the researchers need to do and some of the strategies they employ.

Whether it’s to unravel the mysteries of life or to develop a nature-inspired technology for a specific application, many researchers around the world are trying to build cells from scratch and replicate some of their functionality, such as the ability to produce energy, communicate and divide. But although cells are the building blocks of life, they are incredibly complex and far from being understood.

Consider the mechanism of cell division. Not even the full division, just the pinching of the cell in the middle and forget about the last cut which is controlled by a separate system. Professor Gijsje Koenderink and her team have analyzed numerous research studies on this topic and highlighted the main conditions required to trigger cell division in animal cell-like systems.

The main conditions to trigger cell division in animal cell-like systems

Crosslinked actin filaments in a giant unilamellar vesicle (GUV)
Crosslinked actin filaments in a giant unilamellar vesicle (GUV). Image: Marcos Arribas Perez
  1. A cell must have a machinery, maintained and regulated, that can deform its shape. In animal cells deformation is done by actomyosin networks. These networks are composed mainly of two complex molecules, a protein called myosin, which holds and pulls on actin, a filamentous protein. To avoid running out of actin during deformation, cells maintain and regulate their actin cortex, the layer of actin filaments just underneath the plasma membrane.
    Actin and myosin are intimately connected and need each other to create the deformation of the cell. Synthetic cell researchers make extensive use of this network, but while each protein is well understood, how they must work together to deform the cell remains unclear.
  2. The cell membrane must grow before division. It is a question of geometry. If you have a spherical cell and you want to divide it into two identical cells without losing volume, you need more surface membrane. Researchers have often overlooked this mechanism because it costs living cells little energy and is actually difficult to replicate. Some methods exist, such as membrane fusion, where researchers create pieces of membrane and fuse them into cells, but they are not yet ready for integration.
  3. A cell needs a mechanism that can break its symmetry. If you have a machinery that pulls on cells everywhere equally, it will eventually crush the cell. To concentrate contractile activity, the cells in our body use biochemical components to break their symmetry. However, this mechanism is difficult to reconstruct, so some researchers are developing another approach. They shine a laser on the artificial cell to activate contraction at a specific location.

Two possible scenarios for achieving synthetic cell division using actin filaments

With these requirements in mind, Professor Koenderink’s team identified two routes, two possible scenarios for achieving synthetic cell division using actin filaments. The Naturalistic Route, where researchers mimic the processes that occur in living cells, is complex but promises to build multifunctional, stable cells and help better understand how life works. The Engineering Route is more practical and attempts to find the simplest possible way to divide a cell. Of course, nothing is black and white and researchers actually use a mix of both approaches.

Routes to actin-based synthetic cell division. There are two main routes to achieve actin-driven division of a synthetic cell: by symmetry breaking of a reconstituted actin cortex, triggered by external or biochemical cues, which leads to self-enhanced furrow constriction (the “naturalistic” route, top), or by construction of a contractile actin-based ring at the cell equator (the “engineering” route, bottom). Yellow arrowheads indicate where contractile activity is concentrated. The final fission step is outside the scope of this review. ACS Synth. Biol. 2022, 11, 10, 3120-3133

The paper also highlights the importance of the interplay between the cell membrane and the actin cortex and recommends making the membrane an active player in cell division.

How close are we to successful synthetic cell division?

Dr. Lucia Baldauf, first author of the paper, and Dr. Marcos Arribas Perez of Koenderink’s lab, who shared their knowledge of cell division in preparation for this paper, both shared their optimism, but also the challenges.

Dr. Perez has seen “an acceleration over the past year,” but “it’s critical to be open and communicate the results better with other researchers.”

An argument shared by Lucia, who added that she would like “reporting standards to be more of a focus” so that the work can be shared properly. The community also needs “advances in the tools and methods for building, manipulating, and studying synthetic cells.”

More information

Actomyosin-Driven Division of a Synthetic Cell
Lucia Baldauf, Lennard van Buren, Federico Fanalista, and Gijsje Hendrika Koenderink
ACS Synthetic Biology 2022 11 (10), 3120-3133
DOI: 10.1021/acssynbio.2c00287

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