nonequilibrium physics in multicellular...
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![Page 1: Nonequilibrium physics in multicellular systemsithems-stamp-wg.riken.jp/.../slides/Noneq2018-Kawaguchi.pdf5 1. Skin homeostasis is maintained by nearest neighbor fate coupling [Science](https://reader033.vdocuments.pub/reader033/viewer/2022042923/5f72eeff222a597ccd3264c1/html5/thumbnails/1.jpg)
Nonequilibrium physicsin multicellular systems
川口喬吾Kyogo Kawaguchi
Riken BDR (from Sep 2018)
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PhysicsBiology
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PhysicsBiology
Fundamental questions
New experiments
Theory
Data analysis methods
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Outline
1. Skin (tissue) homeostasisInteracting particle system
2. Collective motion in cultured neural stem cellsActive nematics
3. Acknowledgements
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1. Skin homeostasis is maintained bynearest neighbor fate coupling
[Science 352, 1471 (2016), Phys Rev E 96 012401 (2017), Cell Stem Cell 23, 677 (2018)]
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Tissue homeostasis:Epidermal stem cellsare confined in a two-dimensional layer
6
Leblond, Walker (1956)
Cross section sketch
Turn over: 2-10 days
Division Differentiation
Basal layer = stem cells(基底細胞層)
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*
**
Day 0 Day 1 Day 2
5
1 2 34
67
8 9 1011
12
1314* 15
16
18 19
20 2122
24 25 26
*
*25
12
3a
3b57
8 910
11
12a
1316a
16b18 19
212224 26*
17
2323
17
12
3a
3b5a
5b
7
8a
8b
910
11a
11b
12a
13a
13b
16a
16b17a
17b
18a
18b 19a21
22* 2624a
Neighbor fate coupling?
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Neighbor fate coupling model= Voter model (DP2)
8Dornic et al. Phys. Rev. Lett. 87, 045701 (2001)Hammal et al. Phys. Rev. Lett 94, 230601 (2005)
- Model for “voters”- and critical coarsening- Universality class (two absorbing states)
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~10 years ago:clonal analysis showed scaling behavior
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Clayton et al., Nature (2007)Doupe et al., Dev. Cell (2010)Klein & Simons, Development (2011)
Single cell labeling in live mice (Cre-induced)
Average number of cellsin surviving clones
Clone size distribution:
Time post-labeling (weeks)
Aver
age
cells
/ cl
one
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Critical birth death model explains scaling
10
0.5
0.5
Athreya and Ney “Branching Processes” (Dover) Review: Klein & Simons, Development (2011)
Prob.Division
Differentiation
Average number of cellsin surviving clones
Clone size distribution:
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Summary of scaling: experiment and theory
11
> 2
Cell autonomousFate
(Critical birth death)(voter model)Experiment
(skin) 2 Coordinated fate
Average clone size:
Clone size cumulative distribution:
Experiment:Intestine [Lopez-Garcia et al. (2010)
Snippert et al. (2010)]
Seminiferous tubule[Klein et al., (2010)Yoshida lab]
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Average clone size:
Clone size cumulative distribution:
Problem of 2D
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> 2
Cell autonomousFate
(Critical birth death)(voter model) 2 Coordinated fate
Aver
age
size
of
surv
ivin
g cl
one
Time post-labeling (weeks)
Aver
age
cells
/ cl
one
Experiment(skin)
Simulation/theory Experiment
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Fate coordination can be quantified using “fluctuation test”
..Blue – Red = 0 ± 1.5
..
Blue – Red = 0 ± 0.5(s.d.) (s.d.)
~𝑁𝑁1/2 ~𝑁𝑁1/4
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Data shows that fates of neighboring cells are coordinated
14
Time scale of coordination: 1-2 days Length scale of coordination:size of a single cell
Varia
nce
of n
et g
row
th p
er c
ell
Days
Vary window size0.5124
(in cellsize units)
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Modeling neighboring fate coupling by local density feedback
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Division
Differentiation
1-p
p
From more data analysis:
Making model: Cell density =
Cell Stem Cell 23, 677 (2018)
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Division
Differentiation
1-p
p
Making model:
Differentiation Division
Modeling neighboring fate coupling by local density feedback
2L
Cell density =
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Deriving the voter model actionfrom particle dynamics
17Yamaguchi and Kawaguchi, in preparation
Many-body Langevin equation:
-> Continuum dynamics of labeled cell density
-> MSRDJ field theory
-> linearize (around uniform density) -> lots of Gaussian integrals
-> renormalization
-> Voter model action (+ irrelevant terms)
-> Dynamics:
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Model has two regimesseparated at the interaction length scale
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・Small scale regime:critical birth death model (cell autonomous)
・Large scale regime:voter model
2L
0.5
0.5
Crossover at L
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Crossover observed in skin data
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Feedback length scale (L) in the skin is the size of a single cell = neighbor fate coupling
Vary window size0.5124
(in cellsize units)
Window size (in cell size unit)
Varia
nce
of n
et g
row
th (p
er c
ell)
Cell autonomousregime
Voter modelregime
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Feedback length scale can be different across tissues
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L~ single cell level (neighboring feedback)
Signaling through adhesion, Notch-Delta, etc
(ex: skin, intestinal crypt)
L~ scale of >10 cells
Tissue stretching/compression induced mechanical feedback
Quorum sensing, growth factor related feedback
(ex: seminiferous tubule 精細管)
2L
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2. Topological defects induce cell flow
[With Ryoichiro Kageyama and Masaki Sano, Nature 545 327 (2017)][Ongoing work with Masahito Uwamichi]
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Neural stem cells
Multipotent and culturable
20 um Phase contrast image
Growth
Local alignment at high density
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Large scale image
1 mm
Phase contrast Angle 0 180 deg
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Topological defects in cell culture
0 180 deg +1/2
-1/2
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bioRxiv (Dec 13th 2018)
Biopolar cell polarity axis(hepatocytes)
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Cell flow was induced bytopological defects
+1/2 defect is the “sink”
- 1/2 defect is the “source”
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Geometry induced flow in active systems
Activity in nematic systems can induce
macroscopic active force =
Blackwell et al., Soft Matter (2016)
Q-tensor(measures the directionand extent of ordering)
> 0 < 0
= 0 in passive systems
Extensile systems Contractile systems
Spatial inhomogeneity in pattern
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Olfactorybulb
Subventricularzone
Rostral migratory stream
Geometry driven active transport
Mouse/rat brain:
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Summary
• Some concepts in nonequilibrium physics are usefulin understanding multicellular phenomena
• Cell fate dynamics of skin stem cellsseem to follow the 2D voter model
• Geometry induced flow in active systemsas a mechanism of cell flow control
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Kailin Mesa Katherine Cockburn David Gonzalez Valentina Greco(Yale School of Medicine)
Experiments:
Allon M. Klein Harvard Medical School
Tissue homeostasis
Hiroki Yamaguchi Takahiro SagawaUniv. Tokyo
Theory:
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Masaki SanoUniv. Tokyo
Ryoichiro KageyamaKyoto Univ.
MasahitoUwamichi
Univ. Tokyo
Active neural stem cells
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Started lab in Kobe
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Technical StaffsYuko SakaideLisa Yamauchi
From FY 2019Kyosuke AdachiYosuke FukaiDaiki Nishiguchi
Visiting studentUwamichi Masahito (U Tokyo) →
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Summary
• Some concepts in nonequilibrium physics are usefulin understanding multicellular phenomena
• Cell fate dynamics of skin stem cellsseem to follow the 2D voter model
• Geometry induced flow in active systemsas a mechanism of cell flow control
Thank you!33