Computational Analysis of the Mutual Constraints between Single‐Cell Growth and Division Control Models

Vuaridel‐Thurre, Gaëlle; Vuaridel, Ambroise R.; Dhar, Neeraj; McKinney, John D.

doi:10.1002/adbi.201900103

Cited by 9 publications

(6 citation statements)

References 56 publications

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“…We sought to identify which model best described C. elegans growth behavior but were unable to consistently distinguish between linear, exponential, and cubic models using statistical information criterion because of the similarity in the shapes of the growth curves (Figure S6 and Table S2). This result is not surprising because computational simulations have shown that increases in experimental noise, above 2% added noise, limit the correct identification of growth models [35].…”

Section: Resultsmentioning

confidence: 99%

Changes in body shape implicate cuticle stretch inC. elegansgrowth control

Nyaanga¹,

Goss

Zhang³

et al. 2021

Preprint

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Growth control is essential to establish organism size, so organisms must have mechanisms to both sense and adjust growth. Studies of single cells have revealed that size homeostasis can be achieved using distinct control methods: Sizer, Timer, and Adder. In multicellular organisms, mechanisms that regulate body size must not only control single cell growth but also integrate it across organs and tissues during development to generate adult size and shape. To investigate body size and growth control in metazoans, we can leverage the roundworm Caenorhabditis elegans as a scalable and tractable model. We collected precise growth measurements of thousands of individuals throughout larval development, measured feeding behavior to pinpoint larval transitions, and quantified highly accurate changes in animal size and shape during development. We find differences in the growth of animal length and width during larval transitions. Using a combination of quantitative measurements and mathematical modeling, we present two physical mechanisms by which C. elegans can control growth. First, constraints on cuticle stretch generate mechanical signals through which animals sense body size and initiate larval-stage transitions. Second, mechanical control of food intake drives growth rate within larval stages, but between stages, regulatory mechanisms influence growth. These results suggest how physical constraints control developmental timing and growth rate in C. elegans.

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Section: Resultsmentioning

confidence: 99%

Changes in body shape implicate cuticle stretch inC. elegansgrowth control

Nyaanga¹,

Goss

Zhang³

et al. 2021

Preprint

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“…However, an important observation very recently established a similar growth kinetics in different species of the acid‐fast bacteria from the genus Mycobacterium (Hannebelle et al, 2020). An elegant theoretical study verified that bilinear growth is able to maintain population‐level size homeostasis (Vuaridel‐Thurre et al, 2020). Whether the cell cycle and its phases can be considered as sizers, adders and/or timers also seems to be elusive and contradictory, and probably different answers might come from different model cells.…”

Section: Discussionmentioning

confidence: 96%

“…During the last couple of years, there have been many, many new results published on both individual cellular growth and population‐level size homeostasis and the connections between these two aspects (Allard et al, 2018; Barber, Amir, & Murray, 2020; Cantwell & Nurse, 2019; Facchetti, Knapp, Chang, & Howard, 2019; Facchetti et al, 2019; Hannebelle et al, 2020; Nordholt, van Heerden, & Bruggeman, 2020; Opalko et al, 2019; Patterson et al, 2019; Pickering et al, 2019; Si et al, 2019; Vuaridel‐Thurre, Vuaridel, Dhar, & McKinney, 2020; Xie & Skotheim, 2020; Zatulovskiy & Skotheim, 2020; Zatulovskiy, Zhang, Berenson, Topacio, & Skotheim, 2020). The model organisms studied vary from unicellular prokaryotes via yeasts to animal cells; moreover, modern techniques have even made possible to examine mammalian cells in tissues in vivo.…”

Section: Discussionmentioning

confidence: 99%

Strongly oversized fission yeast cells lack any size control and tend to grow linearly rather than bilinearly

Nagy

Medgyes-Horváth

Vörös

et al. 2020

Yeast

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During the mitotic cycle, the rod‐shaped fission yeast cells grow only at their tips. The newly born cells grow first unipolarly at their old end, but later in the cycle, the ‘new end take‐off’ event occurs, resulting in bipolar growth. Photographs were taken of several steady‐state and induction synchronous cultures of different cell cycle mutants of fission yeast, generally larger than wild type. Length measurements of many individual cells were performed from birth to division. For all the measured growth patterns, three different functions (linear, bilinear and exponential) were fitted, and the most adequate one was chosen by using specific statistical criteria, considering the altering parameter numbers. Although the growth patterns were heterogeneous in all the cultures studied, we could find some tendencies. In cultures with sufficiently wide size distribution, cells large enough at birth tend to grow linearly, whereas the other cells generally tend to grow bilinearly. We have found that among bilinearly growing cells, the larger they are at birth, the rate change point during their bilinear pattern occurs earlier in the cycle. This shifting near to the beginning of the cycle might finally cause a linear pattern, if the cells are even larger. In all of the steady‐state cultures studied, a size control mechanism operates to maintain homeostasis. By contrast, strongly oversized cells of induction synchronous cultures lack any sizer, and their cycle rather behaves like an adder. We could determine the critical cell size for both the G1 and G2 size controls, where these mechanisms become cryptic. TAKE AWAY Most individual fission yeast cells in steady‐state cultures grow bilinearly. In strongly oversized fission yeast cells, linear growth dominates over bilinear. Above birth length thresholds, both the G1 and G2 size controls become cryptic.

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“…In general, there are three different models that describe how cells can reach size homeostasis. The sizermechanism controls the beginning of mitosis by a size threshold, for the adder-mechanism the cell size increases by a constant amount independent of initial cell size, and with the timer-mechanism cells grow exponentially for a constant duration (Cadart et al 2018; Vuaridel-Thurre et al 2020). To determine if this correlation applies on the area development of CHO K1 cells, we compared the cell area of single cells at their birth and at their mitosis.…”

Section: Resultsmentioning

confidence: 99%

Development and application of a cultivation platform for mammalian suspension cell lines with single-cell resolution (MaSC)

Schmitz

Taeuber

Westerwalbesloh

et al. 2020

Preprint

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In bioproduction processes cellular heterogeneity can cause unpredictable process outcomes or even provoke process failure. Still, cellular heterogeneity is not examined systematically in bioprocess research and development. One reason for this shortcoming are the applied average bulk analyses, which are not able to detect cell-to-cell differences. In this work we present a microfluidic tool for single-cell cultivation of mammalian suspension cells (MaSC). The design of our platform allows long-term cultivation at highly controllable environments. As model system CHO K1 cells were cultivated over 150 h. Growth behavior was analyzed on single-cell level and resulted in growth rates between 0.85 - 1.16 1/d, which are comparable to classical cultivation approaches such as shake flask and lab-scale bioreactor. At the same time, heterogeneous growth and division behavior, e.g., unequal division time, as well as rare cellular events like polynucleation or reversed mitosis were observed, which would have remained undetected in a standard population analysis based on average measurements. Therefore, MaSC will open the door for systematic single-cell analysis of mammalian suspension cells. Possible fields of application represent basic research topics like cell-to-cell heterogeneity studies, clonal stability, pharmaceutical drug screening and stem cell research, as well as bioprocess related topics such as media development and novel scale-down approaches.

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Computational Analysis of the Mutual Constraints between Single‐Cell Growth and Division Control Models

Cited by 9 publications

References 56 publications

Changes in body shape implicate cuticle stretch inC. elegansgrowth control

Changes in body shape implicate cuticle stretch inC. elegansgrowth control

Strongly oversized fission yeast cells lack any size control and tend to grow linearly rather than bilinearly

Development and application of a cultivation platform for mammalian suspension cell lines with single-cell resolution (MaSC)

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